Breast cancer

Introduction

Definition of breast cancer

Cancer that forms in tissues of the breast, usually the ducts (tubes that carry milk to the nipple) and lobules (glands that make milk). It occurs in both men and women, although male breast cancer is rare.

Anatomy of the breast, showing lymph nodes and lymph vessels.
 

PATIENT INFORMATION BASED ON ESMO CLINICAL PRACTICE GUIDELINES
As treatments are becoming more personalized due to the advances in cancer care, we would kindly ask you to contact info@anticancerfund [dot] org for a more appropriate guidance according to the most recent guidelines on this cancer type. This guide for patients is a service to patients and their families, to help them understand the nature of the disease and the existing treatment choices. We recommend that patients ask their doctors about what tests or types of treatments are needed for their type and stage of disease. This Guide for Patients in particular has been produced in collaboration with the European Society for Medical Oncology (ESMO) and is disseminated with its permission. It has been written by a medical doctor and reviewed by two oncologists from ESMO including the lead author of the clinical practice guidelines for professionals. It has also been reviewed by patients’ representatives from ESMO’s Cancer Patient Working Group.

 

Frequency

PATIENT INFORMATION BASED ON ESMO CLINICAL PRACTICE GUIDELINES
As treatments are becoming more personalized due to the advances in cancer care, we would kindly ask you to contact info@anticancerfund [dot] org for a more appropriate guidance according to the most recent guidelines on this cancer type. This guide for patients is a service to patients and their families, to help them understand the nature of the disease and the existing treatment choices.

 

Is breast cancer frequent?

Breast cancer is the most common of all cancers in women and is the leading cause of death from cancer in European women. It is estimated that one in every 9 European women will develop breast cancer at some point in her life but this estimates varies by country. In the European Union, about 332,000 women were diagnosed with breast cancer in 2008.

Breast cancer occurs more frequently in older women but 1 in 4 breast cancers is diagnosed in women under the age of 50. Less than 5% of all breast cancers are diagnosed in women younger than 35.

In most Western countries, fewer and fewer women have died of breast cancer in recent years (especially in younger age groups) because of improved treatment and earlier detection.

Breast cancer can also occur in men, but is rare, accounting for less than 1% of all breast cancers. Every year, one out of 100,000 men is diagnosed with breast cancer.

There are different types of breast cancer, which will be explained in this guide.

 

Causes

PATIENT INFORMATION BASED ON ESMO CLINICAL PRACTICE GUIDELINES
As treatments are becoming more personalized due to the advances in cancer care, we would kindly ask you to contact info@anticancerfund [dot] org for a more appropriate guidance according to the most recent guidelines on this cancer type. This guide for patients is a service to patients and their families, to help them understand the nature of the disease and the existing treatment choices. 

 

What causes breast cancer?

Today, it is not clear why breast cancer occurs. Some risk factors have been identified. A risk factor increases the risk that cancer occurs, but is neither necessary, nor sufficient, to cause cancer by itself.

Some women with these risks factors will never develop breast cancer and some women without any of these risk factors will develop breast cancer.

The majority of breast cancers need estrogens to grow. Without estrogens they stop growing or grow more slowly. This is why, with a few exceptions, risk factors for breast cancer are linked to estrogens.

The main risk factors for breast cancer in women are:

  • Aging: the risk of breast cancer increases as women get older.
  • Genes: mutations of certain genes that are inherited from the mother or the father increase the risk of breast cancer. Current knowledge suggests that these abnormal genes cause less than 10 percent of breast cancers.
  • Family history of breast cancer: having a first-degree relative (mother, sister, daughter, brother and father) who had breast cancer increases the risk of developing breast cancer, especially if this relative was under 45 years of age at the time of the diagnosis. When multiple family members have been affected by breast and/or ovarian cancer at a young age, a genetic predisposition must be suspected. BRCA1 and BRCA2 are the 2 main genes involved in familial forms of breast cancer. The lifetime risk of breast cancer in a BRCA1 mutation carrier is 80–85%, with a 60% chance that the cancer will be bilateral. The risk of both subsequent breast cancer occurrence and mortality is reduced by prophylactic surgery. Careful genetic assessment and psychological counselling are mandatory before undertaking such surgery.
  • Personal history of breast cancer: having had breast cancer increases the risk of having breast cancer in a different part of the breast or in the other breast.
  • Lifetime exposure to estrogen and progesterone:
    • Women whose menstrual periods began before the age of 12 and ended after the age of 55 are at an increased risk of developing breast cancer.
    • Women who have not had children or had their first child after the age of 30 are at an increased risk of developing breast cancer.
  • History of certain benign breast conditions: the risk of breast cancer occurring is particularly high for women with two conditions called atypical lobular hyperplasia and atypical ductal hyperplasia.
  • Geographic and social factors: women living in western countries and women with a higher level of education are at an increased risk of developing breast cancer.
  • Use of medications containing estrogens and progesterone:
    • Use of the oral contraceptive pill, especially before the first pregnancy, increases the risk of breast cancer. If a woman has not taken the oral contraceptive pill for a period of 10 years, the increased risk of breast cancer from such medication is no longer present.
    • Use of hormone replacement therapy after the menopause increases the risk of developing breast cancer. A higher risk of breast cancer has been confirmed for hormone replacement therapy combining estrogen and progesterone, and to a lesser extent for hormone replacement therapy with estrogen alone. The increased risk of breast cancer is present in current or recent users. Among users who stopped hormone replacement therapy at least five years ago, the risk is no greater than that for someone who has never received hormone replacement therapy.
  • Radiotherapy of the breast during childhood or adolescence: having received radiotherapy in childhood or adolescence (usually for the treatment of lymphomas) increases the risk of developing breast cancer in adulthood.
  • Overweight and obesity: being overweight or obese increases the risk of developing breast cancer, especially after menopause. This is probably due to the production of estrogens in fat tissues - the main source of estrogens after menopause.
  • Alcohol consumption and smoking: the risk of breast cancer increases with alcohol consumption and with smoking, but the mechanisms are unclear.

Other factors have been suspected to be associated with an increased risk of breast cancer, but the evidence is inconsistent. Unfortunately, the factors that have the highest influence on the risk of developing breast cancer like age, genes, personal and familial history of breast cancer and history of atypical hyperplasia cannot be changed.

Diagnosis

PATIENT INFORMATION BASED ON ESMO CLINICAL PRACTICE GUIDELINES
As treatments are becoming more personalized due to the advances in cancer care, we would kindly ask you to contact info@anticancerfund [dot] org for a more appropriate guidance according to the most recent guidelines on this cancer type. This guide for patients is a service to patients and their families, to help them understand the nature of the disease and the existing treatment choices. 

 

How is breast cancer diagnosed?

Breast cancer can be suspected under different circumstances. The main circumstances are a positive screening mammography, the discovery by palpation of a mass in the breast, any modification of the skin of the breast noticed by the patient or her doctor, or any fluid leaking from the nipple of one single breast.

The diagnosis of breast cancer is based on the three following examinations:

  1. Clinical examination. The physical examination of the breasts and neighbouring lymph nodes includes inspection and palpation.
     
  2. Radiological examination. This includes conducting an X-ray, (mammography), and an ultrasound examination of the breasts and neighbouring lymph nodes. Magnetic resonance imaging (MRI) of the breast may be needed in some patients, especially young women with dense breast tissue, women with BRCA gene mutations, and women with silicone gel implants. MRI can also be considered when tumor cells have been found in a suspicious lymph node in the armpit but no tumor can be seen in the breast on mammography, or when several tumors are suspected. Additional investigations such as chest X-ray, abdominal ultrasound and bone scintigraphy may be performed to exclude distant spread of the disease, also known as metastasis.
     
  3. Histopathological examination. This is the laboratory examination of the breast and tumor tissue after removing a sample from the tumor. This is called a biopsy. This laboratory examination will confirm the diagnosis of breast cancer and will give more information on the characteristics of the cancer. The biopsy is obtained manually by the doctor with a needle, often with the help of ultrasound to guide the needle into the tumor. Once the needle is introduced into the tumor, a sample is removed. Depending on the needle used, this is called either a fine needle aspiration or a core biopsy. A second histopathological examination will be performed later when examining the tumor and the lymph nodes removed by surgery.

     

Treatment

PATIENT INFORMATION BASED ON ESMO CLINICAL PRACTICE GUIDELINES
As treatments are becoming more personalized due to the advances in cancer care, we would kindly ask you to contact info@anticancerfund [dot] org for a more appropriate guidance according to the most recent guidelines on this cancer type. This guide for patients is a service to patients and their families, to help them understand the nature of the disease and the existing treatment choices. 

 

Common misconceptions about breast cancer treatment

According to Pr Martine Piccart, expert in breast cancer treatment

According to Prof. Martine Piccart, expert in breast cancer treatment:

  • Breast cancer does not develop within days or weeks! There is always time to seek a second opinion about treatment options.
  • The multidisciplinary consultation before starting treatment is very important and should not be underestimated. The treating physician and the general practitioner should be provided with the written report of this consultation.
  • The importance of the pathological examination of the tumor is often underestimated. The entire treatment strategy depends on a carefully conducted, well standardized pathological examination in a well-experienced laboratory. Asking for a second, independent pathological examination is a good idea if the testing has been done in a laboratory with limited experience in breast cancer diagnosis.
  • Access to new agents or strategies in the context of well-designed and carefully conducted clinical trials has more benefits than risks at all stages of the disease. Patients should ask their doctors which clinical trials are relevant for them.
  • Pregnancies after breast cancer are possible, especially if the ovaries are not damaged by the use of certain chemotherapy drugs which are toxic to them. This needs to be discussed upfront with young women who want to preserve their fertility. For women who become pregnant following completion of breast cancer therapy, neither pregnancy nor subsequent breastfeeding increase the likelihood of relapse.

 

What is important to know to get the optimal treatment?

Doctors will need to consider many aspects of both the patient and the cancer in order to decide on the best treatment.

Relevant information about the patient

  • Personal medical history
  • History of cancer in relatives, especially breast cancer and ovarian cancer
  • Status regarding menopause, which in some cases requires taking a blood sample to measure the level of some hormones in the blood (estradiol and FSH)
  • Results from the clinical examination by the doctor
  • General well-being
  • Results from blood tests performed to assess the white blood cells, the red blood cells and the platelets, and tests performed to exclude any problems in the liver, the kidneys and the bones.
     

Relevant information about the cancer

Doctors use staging to assess the risks and prognosis associated with specific characteristics of the patient and the type of cancer involved. The TNM staging system is commonly used. The combination of size of the tumor (T) and invasion of nearby tissue, involvement of lymph nodes (N), and metastasis or spread of the cancer (M) to other organs of the body, will classify the cancer into one of the following stages.

The stage of cancer is fundamental for decisions regarding treatment. The less advanced the stage, the better the prognosis is. Staging is usually performed twice: after clinical and radiological examination as well as after surgery. If surgery is performed, staging may also be influenced by the laboratory examination of the removed tumor and lymph nodes.

Additional radiological examinations such as chest X-ray, abdominal ultrasound or CT and bone scintigraphy can be performed to be sure that there is no metastasis in the lung, the liver and the bones. CT and/or MRI of the brain should only be performed if there are symptoms pointing in that direction. All of these examinations are usually only recommended for stages II or higher (see below). They are also considered for patients for whom a pre-surgery therapy is planned. Conversely, for patients with small tumors and no suspicious lymph nodes (stage I), there is no reason to do all these exams.

The table below presents the different stages for breast cancer. The definitions are very technical so it is recommended to ask doctors for more detailed explanations.

 

Stage

Definition

Stage 0

The abnormal cells are still contained in the duct where they initially appeared.

Stage I

The tumor is less than 2 cm in diameter and small clusters of cancer cells may be found in the lymph nodes.

Stage I breast cancer is divided into stages IA and IB.

Stage II

The tumor is either smaller than 2 cm in diameter and has spread to the lymph nodes in the armpit or the tumor is between 2cm and 5cm in diameter, but has not spread to the lymph nodes in the armpit.

Stage II breast cancer is divided into stages IIA and IIB.

Stage III

The tumor maybe of any size, but:

  • has spread either to the chest wall and/or the skin of the breast
  • has spread to at least 10 lymph nodes in the armpit or the lymph nodes in the armpit are attached to each other or to other structures
  • has spread to lymph nodes near the sternum (breastbone).
  • has spread to lymph nodes below or above the clavicle (collar bone).

Stage III breast cancer is divided into stages IIIA, IIIB, and IIIC

Stage IV

Cancer has spread to other organs of the body, most often the bones, lungs, liver, or brain. Such distant tumor deposits are called metastases.

Tumor obtained by biopsy will be examined in the laboratory. The method and the result of such an examination are called histopathology. A second histopathological examination is performed on the tissues obtained by surgical removal of the tumor and the lymph nodes. This is very important to confirm the results of the biopsy and to provide further information on the cancer. Results of the examination of the biopsy should include:

Assignment of histological type is based on the type of cells that compose the tumor. Breast cancers form in tissues of the breast, usually the ducts or the lobules. The main histological types of breast cancer are ductal carcinomas and lobular carcinomas. The histopathological examination will also classify the cancer as invasive or non-invasive. Non-invasive cancers are also called cancer in situ

Assignment of grade is based on the heterogeneity of tumor cells, the architectural structure of the tissue they form and the frequency of mitosis (cell division) of tumor cells. A well differentiated tumor (grade 1) has low heterogeneity of cells, preserved architectural structure and few mitoses. An undifferentiated tumor (grade 3) has high heterogeneity, loss of architecture and many mitoses. A moderately differentiated tumor (grade 2) is in between grade 1 and grade 3. The lower the grade, the better the prognosis.

When systemic treatment is planned before surgery, the biopsy results should include hormone receptor status and HER2 status. When no systemic treatment is planned before surgery, these can be determined in the tumor (and/or the lymph nodes) after their removal by surgery.

Tumor cells can present receptors to estrogen and receptors to progesterone on their surface or inside the cell. Cells of some tumors present a high level of receptors. This means that their growth and multiplication are stimulated by hormones. Tumors with a high level of estrogen receptors (ER+) and/or progesterone receptors (PR+) have a better prognosis than tumors lacking estrogen receptors (ER-) and/or lacking progesterone receptors (PR-).

  • HER2 status

HER2 is a cell surface protein present in about 20% of breast cancer cases. HER2 is involved in the growth and migration of cells.. HER2 status of tumor tissue can be analysed by various tests in the laboratory: by Immunohistochemistry (IHC), by Fluorescence In Situ Hybridization (FISH) or by Chromogenic In Situ Hybridization (CISH). A cancer is HER2 positive when the result of the IHC test is 3+ or the result of a FISH or CISH test is positive as stated in the pathology report. Otherwise, the HER2 status is negative. Before anti-HER2 directed therapy was available, HER2 positive cancers had more aggressive behaviour than other cancers.

  • Multigene expression profiles

The quantification of the expression of distinct sets of genes expressed by the tumor can also be performed on the biopsy. Such multigene signature analyses are not routinely performed, but can help to predict the risk of recurrence and the likelihood of benefit from chemotherapy.

  • Ki-67 labelling index

Ki-67 is a protein found in the nucleus of cells when they are dividing but not when they rest. Ki-67 labelling index indicates the percentage of cells in which Ki-67 can be found. Analysing the proportion of dividing cells is a method to determine the level of proliferation of the tumor. Highly proliferating tumors grow faster and have a worse prognosis than slowly proliferating tumors, but at the same time highly proliferating tumors are more sensitive to chemotherapy.

It is important to know that tests used to define hormone receptor status and HER2 status may give an incorrect result. No test used to assess HER2 status today is 100% reliable. Moreover, it is also possible that the piece of tissue examined classifies the tumor as HER2 negative but examination of another piece of the tumor would have classified it as HER2 positive. That is why, whenever possible, these analyses should be performed on both the biopsy material and on the tumor tissue removed by surgery.

Another very important part of the histopathological examination after tumor removal by surgery is to check whether the tumor has been completely removed. This is done by analyzing if the microscopic edges of the tumor are surrounded completely by normal tissue. It is reported either as negative margins of resection, (meaning that it is very likely that the whole tumor has been removed) or as positive margins of resection (meaning that it is very likely that the tumor has not been removed completely).

  • Hormone responsiveness

Based on the analysis of the biopsy and/or of the tumor removed by surgery, tumors are classified into three groups according to their hormonal receptor status:

  • Hormone responsive (ER+ and/or PR+) when estrogen or progesterone receptors have been detected on cancer cells.
  • Hormone non-responsive (ER- and PR-) when no estrogen and no progesterone receptors have been detected on cancer cells.
  • A third in-between group with uncertain hormone responsiveness.

Based on this analysis the decision is made whether to add hormone treatment. A hormonal treatment will usually stop or slow the growth of hormone responsive tumors because these tumors need hormones to grow, but will have no effect on the growth of hormone non-responsive tumors.

  • Intrinsic subtypes of breast cancer

The combination of the results regarding hormone receptor status, HER2 status and Ki-67 labelling index is used to classify breast cancer in 5 subtypes. This is also important in order to know which therapies are most likely to be effective. The 5 subtypes are presented in the table below. This classification is rather technical and it is recommended to ask a doctor for a more detailed explanation.

 

Subtype of breast cancer

Hormone receptor status

HER2 status

Ki-67 status

Luminal A

ER+ and/or PR+

HER2 negative

Low (<14%)

Luminal B HER2 negative

ER+ and/or PR+

HER2 negative

High

Luminal B HER2 positive

ER+ and/or PR+

HER2 positive

Any

HER2 positive non-luminal

ER- and PR-

HER2 positive

Any

Triple negative

ER- and PR-

HER2 negative

Any

 

What are the treatment options?

Planning of the treatment involves an inter-disciplinary team of medical professionals. This usually implies a meeting of different specialists, called multidisciplinary opinion or tumor board. In this meeting, the planning of treatment will be discussed based on the relevant information summarized above.

The treatment will usually combine intervention methods that:

  • act on the cancer locally, such as surgery or radiotherapy
  • act on cancer cells all over the body with systemic therapy such as chemotherapy, hormone therapy and/or HER2-directed therapy.

The extent of the treatment will depend on the characteristics of the tumor cells and on the stage of the cancer, as well as on the age, the menopausal status and the co-morbidity of the patient.

Treatments listed below have their benefits, their risks and their contraindications. It is recommended to ask an oncologist about the expected benefits and risks of every treatment in order to be informed of the consequences of the treatment. For some treatments, several options are available. The choice should be discussed according to the balance between benefits and risks.

 

Treatment plan for non-invasive cancer (Stage O)

A non-invasive cancer has not spread outside the duct (ductal carcinoma in situ). Treatment options include the following two possibilities of local therapies.

  • Either the tumor or a part of the breast is removed, but not the whole breast. This is called breast-conserving surgery. This is usually followed by whole breast irradiation except in patients with very low risk of recurrence where radiation may be omitted. Additional irradiation (called a boost) of the area from which the tumor has been removed can be considered for patients who have a high risk of local recurrence, for instance in very young patients.
  • Or the whole breast is removed by mastectomy, without muscles and skin surrounding the breast. When mastectomy is performed, additional radiation treatment is not necessary for non-invasive cancer.

In addition, treatment with tamoxifen, a drug which counteracts the action of estrogens on the breast, can be considered if the tumor is estrogen receptor positive, since it lowers the risk of recurrence, i.e. that the cancer comes back in the breast. Tamoxifen also lowers the risk of developing contralateral breast cancer, i.e. cancer in the opposite breast.

Lobular neoplasia, which was formerly called lobular carcinoma in situ, is now regarded as a risk factor for future development of breast cancer in both breasts. It therefore requires a discussion with the doctor whether to pursue a surveillance strategy by close follow-up and/or a treatment strategy.

 

Treatment plan for invasive cancer (Stage I to III)

An invasive cancer has spread outside the duct (invasive ductal carcinoma) or outside the lobule (invasive lobular carcinoma). The treatment will target the cancer locally as well as cancer cells potentially spread in the body.

In most cases, the treatment will consist of surgery, radiotherapy and systemic therapy. Treating cancer cells that have spread to other parts of the body can be done with the help of hormone therapy, chemotherapy or HER2-directed therapy.

For tumors of more than 2 cm in diameter, systemic therapy is sometimes preferred as the first treatment since shrinkage of the tumor with drugs can facilitate local therapy and might permit breast conservation. Surgery is preceded by chemotherapy for most cases of stage IIIA and IIIB cancers. This is called neo-adjuvant chemotherapy. It is also indicated to reduce tumor size so as to permit breast-conserving surgery. Trastuzumab is added in cases with HER2-positive tumors.

 

Surgery

The surgery will be performed under general anaesthesia. The surgeon will remove the tumor and some lymph nodes during the same operation by one of two methods.

  • Removal of the tumor or a part of the breast including the tumor, but not the whole breast. This is called breast-conserving surgery.
  • Removal of the whole breast but not muscles and skin surrounding the breast. This is called total mastectomy.

The choice between breast-conserving surgery and total mastectomy depends on the characteristics of the tumor, on the size of the breast and on the patient’s preference. Some patients require a mastectomy because of tumor size, multiple locations of the tumor(s) in the breast or other reasons. This has to be discussed with doctors. Currently in Western Europe, breast-conserving surgery can be performed in 2 out of 3 women with breast cancer.

For some patients, a treatment is given before surgery (neo-adjuvant) with the intent of reducing the size of the tumor and allowing for breast-conserving surgery. Once the neo-adjuvant treatment has produced its effect, the doctor will ask for an MRI to check whether it will indeed be possible to conserve the breast without decreasing the chances of cure. In some cases, the complete removal of the breast will still be necessary.

For women requiring mastectomy, a breast reconstruction may be recommended. This reconstruction can be immediate or delayed (for medical reasons or for personal preference). It is not necessary that patients should wait 2 years after mastectomy before being offered reconstruction. It is also not true that reconstruction of the affected sites makes detection of recurrence of cancer more difficult.

One or several lymph nodes in the armpit will also be removed

This removal is very important to know whether the cancer has spread to lymph nodes, but it has a limited effect in treating the cancer. Two types of surgery of the lymph nodes can be performed:

  • The surgeon performs a sentinel lymph node biopsy. After injection of a marker near the tumor, the marker will naturally be led to lymphatic vessels and then to lymph nodes. With the help of a probe, the surgeon will be able to identify in which lymph node(s) the marker is located. He/she will remove the lymph node(s) to check if cancer cells are present. A rapid examination of the lymph nodes will be made while the patient is still in surgery. If cancer cells are found in the lymph node(s), the surgeon will usually perform an axillary dissection (see below). For patients with tumors of less than 5 cm in diameter, axillary dissection might not be necessary if the examination shows that only 1 or 2 sentinel lymph nodes contain cancer cells.
  •  The surgeon performs an axillary dissection. The surgeon makes an incision under the arm and removes the axillary soft tissue where lymph nodes are located. These lymph nodes will be checked for the presence of cancer cells.

Sentinel lymph node biopsy causes less arm swelling (lymphedema) and shoulder stiffness than axillary dissection. Sentinel lymph node biopsy is recommended in stage I and stage II breast cancer, unless involved lymph nodes can be detected preoperatively on physical examination or by ultrasound. In higher stages, an axillary dissection will be performed.

Laboratory examination of the tumor and lymph nodes removed by surgery

Once the tumor and lymph nodes have been removed, they will be examined in the laboratory to:

  • Confirm the results of the biopsy regarding histological type, grade, hormone receptor status, HER2 status and possibly multigene expression profile.
  • Measure the size of the tumor and see if it has spread to surrounding tissues.
  • Check whether cancer cells have entered lymphatic vessels or blood vessels, which would make it more likely that they have spread outside of the breast.
  • Check whether the whole tumor has been removed and margins are free of tumor tissue.
  • Check whether cancer cells have spread to the lymph nodes and count the number of lymph nodes affected.

Second surgery

Some patients may be operated on a second time. The two main reasons are:

  • The margins of resection were positive; the tumor is not completely surrounded by normal tissue. The new operation should remove the rest of the tumor.
  • After a more thorough examination of the lymph node(s) from the sentinel lymph node biopsy, it turns out that they contain cancer cells. An axillary dissection will usually be performed. For patients with tumors of less than 5 cm in diameter, axillary dissection might not be necessary if the examination shows that only 1 or 2 sentinel lymph nodes contain cancer cells.

Adjuvant therapy

An adjuvant therapy is a therapy given in addition to surgery. For patients with stage I to III breast cancer, possible adjuvant therapies are radiotherapy, chemotherapy, hormone therapy and targeted therapy. In this setting, radiotherapy is a local treatment whereas chemotherapy, hormone therapy and targeted therapy can reach cancer cells that may have spread to other parts of the body. These latter treatments are called systemic therapies.

Radiotherapy

Radiotherapy is the use of radiation to kill cancer cells. Generally, cancer cells are less capable of recovery from radiation damage than normal cells.

Radiotherapy is recommended for almost all invasive breast cancers. A limited number of patients may not benefit from radiotherapy, which could therefore be omitted. This concerns patients of more than 70 years of age who have a tumor of less than 2 cm in diameter that is hormone-responsive. In addition, one should be sure that the whole tumor has been removed by surgery with negative margins.

Radiotherapy in breast cancer aims to destroy cancer cells locally using high-energy radiation produced by a radiotherapy device.

  • After breast-conserving surgery radiotherapy is strongly recommended for all patients: radiotherapy of the whole breast, followed by additional irradiation (called a boost) of the area from which the tumor has been removed.
  • After mastectomy radiotherapy is recommended or should be considered for patients with large tumors and/or for whom cancer cells have been found in axillary lymph nodes. The radiotherapy will target the chest wall and sometimes the regional lymph node areas as well. When there is a clear and extensive spread of cancer cells to the lymph nodes over the collar bone or behind the breastbone (sternum), the field of irradiation can be extended to include these areas.

 

The dose of radiation to be delivered is between 45 and 50 Grays (Gy). A Gray is the unit used to measure the quantity of radiation delivered in radiotherapy. This total dose is divided into fractions. Each fraction is given during one session of radiotherapy. Typically for breast cancer, 25 to 28 fractions are planned, but a shorter treatment using 16 fractions has shown the same efficacy without increased side effects. When a boost is planned, an additional 10 to 16 Gy is administered in fractions of 2 Gy. The goal of giving the treatment in fractions is to lower the risk of significant damages to normal tissues and to increase the probability of long-term tumor control.

In order to shorten the time of treatment duration and to avoid the patient having to come between 16 and 35 times to the radiotherapy unit, attempts have been made to deliver radiotherapy during surgery. This has been called accelerated partial breast irradiation. Research is ongoing but preliminary results suggest that this could be considered for patients of at least 50 years of age, with a single tumor of less than 3 cm in diameter and resection margins of more than 2 mm, and no spread to the lymph nodes. In addition, the tumor should have specific histological characteristics (non-lobular histology without any intraductal component and no lymphovascular invasion). This type of radiotherapy requires specific devices that are not available in many centres because research is still on-going.

Systemic therapy

The goal of systemic therapy is to act on cancer cells that might have reached other parts of the body.

The characteristics of the tumor tissue identified by laboratory examination of the biopsy and of surgically removed tumor are essential to decide which therapy or combination of therapies is most appropriate. These tumor characteristics include tumor size, histological type, grade, margins of resection, number of lymph nodes involved, hormone receptor status, HER2 status and, if available, multigene expression profile. Age, menopausal status and medical conditions of the patient are the patient factors important for making an informed decision regarding adjuvant systemic treatment.

For each individual, the choice must take into account the potential benefits, the possible side effects and the patient’s preference.

Three types of treatment can be used for systemic therapy: hormonal therapy, chemotherapy and HER2-directed therapy.

Tumors are classified into three groups according to hormonal receptor status: hormone responsive (ER+ and/or PR+), hormone non-responsive (ER- and PR-) and a third in-between group with uncertain hormone responsiveness. A hormonal treatment will usually stop or slow the growth of hormone responsive tumors because these tumors need hormones to grow, but will have no effect on the growth of hormone non-responsive tumors.

  • Patients with hormone responsive tumors may receive either hormone therapy alone or a combination of hormone therapy and chemotherapy.
  • Patients with tumors of uncertain hormone responsiveness may receive a combination of hormone therapy and chemotherapy.
  • Patients with hormone non-responsive tumors should receive chemotherapy, but no hormone therapy.

Hormone therapy

This therapy consists of one or possibly a combination of two of the following treatments:

  • A drug called tamoxifen which counteracts the action of estrogens on the breast andis active in both premenopausal and in postmenopausal patients
  • A drug from the aromatase inhibitor family like anastrozole, exemestane or letrozole which inhibit the production of estrogens in post-menopausal women
  • A drug from the gonadotropin-releasing hormone analogues family that lower the level of estrogens in pre-menopausal women
  • Ovariectomy - the removal of the ovaries in premenopausal women

The choice of hormone therapy is based on the menopausal status of the patient.

For patients in whom menopause has not yet begun (pre-menopausal patients), tamoxifen alone for 5 years, or the combination of a bilateral ovariectomy or a drug from the gonadotropin-releasing hormone analogue family plus tamoxifen for 5 years, are the usual treatments. Tamoxifen should not be used simultaneously with chemotherapy.

For patients after their menopause (post-menopausal patients), aromatase inhibitors for 5 years is preferred for women at higher risk, but for patients treated with tamoxifen, a switch after 2-3 years to aromatase inhibitor for 2-3 years could be considered. Patients treated with aromatase inhibitors are at higher risk of developing osteoporosis. This should be counteracted by sufficient intake of calcium and vitamin D. Other examinations such as measurement of bone mineral density and treatments such as bisphosphonates are available to deal with osteoporosis.

Tamoxifen slightly increases the risk of blood clots and should be stopped if a surgical intervention is planned. It also doubles the risk of developing endometrial cancer (a cancer of the uterus).

Chemotherapy

Chemotherapy for early-stage breast cancer consists of combining two or three anti-cancer drugs, which are given according to a precise protocol. For breast cancer, the treatment is generally given for 4 to 8 cycles, a cycle being a time period of 2 to 4 weeks with a precise dosage, duration and sequence of drugs including a resting period before a new cycle is started.

It is not clear which combination of drugs is best, but it is recommended that it contains doxorubicin or epirubicin, which are anti-cancer drugs from the anthracycline family. Assessment of heart function is important before therapy with anthracyclines. However, regimens without any anthracycline have been shown to be as effective, for instance the combination of docetaxel and cyclophosphamide. Treatments are often named with acronyms using the initial letter of each drug name (e.g. FEC, stands for the combination of Fluorouracil, Epirubicin and Cyclophosphamide). For frail or elderly patients the CMF (Cyclophosphamide, Methotrexate and Fluorouracil) regimen may still be appropriate.

Another option, especially for women in whom tumor cells have spread to the lymph nodes, is to combine an anthracycline (doxorubicin or epirubicin) with a taxane drug (paclitaxel), preferably given in sequence rather than in combined fashion.

HER2-directed therapy

HER2-directed systemic treatments are used for HER2 positive cancers, i.e. when the result of the laboratory examination reports that the IHC test is “3+” or the FISH or CISH test is “positive”. Trastuzumab is a drug effective in patients with HER2 positive tumors, regardless of the size of the tumor and of its hormonal status. In the studies performed to evaluate its efficacy as an adjuvant therapy, trastuzumab was always given in combination with chemotherapy. It is not clear, whether the adjuvant use of trastuzumab without chemotherapy has a positive effect.

The standard recommended duration of adjuvant treatment with trastuzumab is 1 year. Results from studies comparing this standard duration to shorter or to longer durations are pending.

Trastuzumab can be given together with paclitaxel or carboplatin but should not be given together with doxorubicin or epirubicin. The latter two drugs and trastuzumab are both toxic to the heart. Trastuzumab cannot be given to patients whose heart function is abnormal. If there is doubt about the  heart function, it should be assessed before trastuzumab treatment.

 

Treatment plan for metastatic cancer (Stage IV)

A metastatic breast cancer is one that has spread to other parts of the body. The most frequent locations of metastases in breast cancer are bone, the liver, the lungs and the brain. Since tumor cells have spread to other parts of the body, systemic therapy is the mainstay of treatment. About 5% of women with breast cancer have metastases at the time of diagnosis.

For the treatment of patients with metastatic breast cancer:

  • The main treatment goal is to maintain or improve quality of life. Patients should be offered appropriate psychological, social and supportive care.
  • The realistic treatment goals should be discussed with the patient and her family and the patient should be encouraged to actively participate in all decisions. The patient’s preferences should always be taken into account, including preferences relating to the practicalities of the treatment (for instance, oral or intravenous).

In many hospitals, specialist breast nurses can provide crucial support to patients and should be available to all patients.

Surgery and radiotherapy

Some patients exhibiting metastasesmay benefit from having the primary breast tumor removed by surgery or treated by radiotherapy. In some rare cases, surgery can also be used to treat patients with a single or very few metastases e.g. in the liver, in the lung or in the brain. Radiotherapy is also used in the management of bone and brain metastases.

Systemic therapy

The goal of systemic therapy is to simultaneously act on cancer cells in various organs involved in metastases. Systemic therapy options are the same as for invasive cancer without metastasis (hormone therapy, chemotherapy and HER2-directed therapy) with a few additional targeted biological agents such as bevacizumab or everolimus. If chemotherapy is used, its composition and duration should be tailored to the individual patient.

The choice of the systemic therapy depends on the hormone receptor status, on the HER2 status, on the urgency of obtaining a response and on prior therapies and their effectiveness.

Hormone therapy

Hormone therapy is the treatment of choice for patients with hormone responsive (ER+ and/or PR+) metastatic breast cancer. The choice of the hormone therapy depends on the menopausal status and on previous hormone therapy applied.

  • For patients before their menopause
    • If there has been no prior treatment with tamoxifen or if the use of tamoxifen has been discontinued for more than 12 months, tamoxifen with either gonadotropin-releasing hormone analogues or an ovariectomy is the preferred option.
    • Otherwise, aromatase inhibitors like anastrozole, exemestane or letrozole in combination with either gonadotropin-releasing hormone analogues or an ovariectomy. Calcium and vitamin D supplements are recommended in addition to this treatment.
  • For patients after their menopause
    • If there has been no prior treatment with aromatase inhibitors like anastrozole, exemestane or letrozole or treatment with them has been discontinued for more than 12 months, they are the preferred option. Calcium and vitamin D supplements are recommended in addition to this treatment.
    • Otherwise, tamoxifen, fulvestrant, megestrol or androgens can be used.
    • When there are signs that the cancer progresses or comes back despite treatment with anastrozole or letrozole, an option is to use a combination of exemestane and everolimus. Combining tamoxifen and everolimus may also be an option, but cannot yet be proposed in Europe.

Cancers change over time and it is possible that an ER+ cancer becomes ER- or that an ER+ cancer becomes otherwise resistant to hormone therapy.

 Patients with clear evidence of resistance to hormone therapy should be offered chemotherapy or participation in clinical trials.

HER2-directed therapy

HER2-directed therapy, such as trastuzumab or lapatinib should be offered early to all patients with HER2 positive metastatic disease, in addition to chemotherapy,  to hormone therapy, or alone. This should be the case in patients who didn’t receive such therapy in the adjuvant treatment and who do not have contraindications for it (e.g. heart insufficiency). If the cancer continues to expand and to progress under a trastuzumab treatment, trastuzumab may be continued with a different chemotherapy. Lapatinib, an oral drug that also targets the HER2 receptor, can be given in combination with the oral chemotherapy drug capecitabine. The choice of treatment should be discussed with an oncologist. Two new drugs, namely pertuzumab and ado-trastuzumab emtansine, may soon be available in Europe for patients with HER2-positive tumors.

Chemotherapy

Chemotherapy should be offered to:

  • Patients with fast-growing tumors involving vital organs (e.g. extensive liver involvement), where an immediate response to systemic treatment is necessary.
  • Patients with cancers that are both hormone non-responsive and HER2 negative. Such cancers are called “triple negative” (ER-, PR- and HER2-) and for these chemotherapy is the main treatment option.
  • Patients with hormone-responsive cancers that do not respond to hormone therapy, or that have ceased to respond to hormone therapy.

If patients have previously received chemotherapy with anthracyclines (epirubicin or doxorubicin), they should be offered chemotherapy including a taxane (paclitaxel or docetaxel).

Single drug chemotherapy is mostly preferred over a combination of drugs because it is associated with a better quality of life without a decrement in survival duration. Duration of chemotherapy should be tailored to the individual patient. In general, in patients with triple-negative tumors, metastases may be more frequent and disease progression more rapid. Therefore, the combination with chemotherapy may be offered.

Continuing chemotherapy after the patient has received 3 different types of regimens is possible for patients who are in good general condition and whose tumor has “responded” (shown shrinkage) to previous chemotherapy.

Other biologic therapies

Bevacizumab is a drug that is thought to limit the development of new vessels around the tumor. In Europe, it is now available only for patients with metastatic breast cancer in combination with first-line chemotherapy (paclitaxel or capecitabine). This combination could be considered in selected patients with limited treatment options, but only upon evaluation of possible side effects and expected benefits. Bevacizumab is not anymore authorized for patients with breast cancer in the USA.

Other therapies

Radiotherapy can be used as a palliative therapy for the management of bone metastases, brain metastases or other local tumor masses such as fungating soft tissue lesions.

Bisphosphonates should be used for the treatment of hypercalcemia and when bone metastases are present. The goal is to relieve pain and to prevent consequences of bone metastases, such as fractures. Bisphosphonates exist in oral or intravenous forms. They are generally well tolerated, but in rare instances they can induce a complication called osteonecrosis of the jaw. These are lesions of the upper or lower jaw bones with bone denudation that take a long time to heal. This complication occurs more often in patients with poor dental conditions. It is therefore recommended to have a dental check-up prior to a bisphosphonate treatment.

Denosumab is a new therapy used for bone metastases. It seems to be slightly more efficacious than bisphosphonates in preventing bone complications, and has also less kidney toxicity. Like bisphosphonates, denosumab can also cause osteonecrosis of the jaw.

Clinical trials

Clinical trials of new drugs are often proposed to patients with metastatic cancer. Participation in clinical trials should be encouraged since they are the only way to make progress in a context where cure remains extremely rare.

Response evaluation

The response to treatment has to be evaluated in order to weigh the benefit of the treatment against the adverse events experienced. This response evaluation is recommended after 2-3 months of hormone therapy and after 2- 3 cycles of chemotherapy. The evaluation relies on clinical and symptom evaluation, assessment of quality of life, blood tests and repeating the initially abnormal radiological examinations with comparative measurements.

If the balance between benefits and side-effects is not favourable, new treatment options should be discussed between the patient, family and doctors.

For some patients, measuring the blood levels of substances called tumor markers such as CA15.3 or CEA may be done to help in the evaluation of treatment response. A tumor marker decrease would indicate that the treatment is efficacious and an increase would indicate the opposite. However, these tests are not very reliable and their use is usually restricted to patients for whom no radiological tumor assessments are available.

 

What are the possible side effects of the treatment?

 

Main side effects of the therapies used to treat breast cancer

Risk and side effects of surgery

Some risks are common for every surgical intervention performed under general anaesthesia. These complications are rare and include deep vein thrombosis, heart or breathing problems, bleeding, infection, or reaction to the anaesthesia. Pain right after the operation is frequent, so painkillers will be proposed to prevent and treat it. Shoulder stiffness can also occur, but it does not usually last.

When lymph nodes in the armpit are removed, it can damage or block the lymph system resulting in lymphedema, a condition where lymph fluid accumulates in the arm and makes it swell. It can occur right after the intervention but also later. The risk is lower when only a sentinel lymph node biopsy is performed. The risk is high when axillary dissection is followed by radiotherapy, in which case up to 40% of the patients can develop lymphedema.

Side effects can be relieved through the proper consultation and advice provided by the specialists in oncology.

 

Side effects of radiotherapy

Most people will have few side effects, and for many people they will be mild. As radiotherapy affects people in different ways, it is difficult to predict exactly how the patient will react to the treatment.

Some strategies are available to prevent or relieve a certain range of these side effects. There are important improvements in radiotherapy machines and severe side effects are now very rare. Most side effects of radiotherapy disappear gradually once the course of treatment is over. For some people however, they may continue for a few weeks.

The main side effect of radiotherapy of breast cancer is redness, soreness or/and itchiness of the skin of the chest after three to four weeks of having external radiotherapy. This usually settles down two to four weeks after the treatment has finished. The area, however, may stay slightly more pigmented than the surrounding skin.

There are some long-term side effects that can take months and sometimes years to develop.

  • The skin can feel different or may be more pigmented than before. Red ‘spidery’ marks (telangiectasia) may appear on the skin because small blood vessels are damaged.
  • Swelling in the arm (lymphedema) can occur because lymph nodes are damaged.
  • Radiotherapy itself can cause cancer and a small number of people will develop a second cancer because of the treatment they have had. However, the chance of a second cancer developing is small and the risks of having radiotherapy are out-weighed by the benefits. The risk is not dependent of the dose received and increases with time.

Side effects of chemotherapy

Side effects of chemotherapy are very frequent. They will depend on the drug(s) administered, on the doses and on individual factors. If you have suffered from other problems (such as heart problems) in the past, some precautions should be taken and/or adaptation of the treatment should be made. Combinations of different drugs usually lead to more side effects than the use of a single drug.

The most frequent side effects of the drugs used for chemotherapy in breast cancer are hair loss and decreased blood cell count. Decreased blood cell count can result in anaemia, bleeding and infections. Once the chemotherapy is completed, the hair grows back and the blood cell count returns to normal.

Other frequent side effects include:

  • allergic reactions, such as flushing and rash
  • nerve problems affecting the hands and/or feet (peripheral neuropathy), which can cause tingling feelings in the skin, numbness and/or pain
  • temporary loss of or changes in your eyesight
  • ringing in the ears or changes in your hearing
  • low blood pressure
  • nausea, vomiting and diarrhea
  • inflammation of areas such as the lining of the mouth
  • loss of sense of taste
  • lack of appetite
  • slow heart beat
  • dehydration
  • mild changes in nails and skin which soon disappear
  • painful swelling and inflammation where the injection is given
  • muscle or joint pain
  • seizures
  • tiredness

Other less frequent but more serious side effects can occur. These especially include, stroke, myocardial infarction and damage to the function of the kidneys and liver. Any of these symptoms should be reported to a doctor.

For younger women who have not gone through menopause, some drugs used in chemotherapy can lead to early menopause by stopping the production of hormones by the ovaries. Symptoms of menopause can therefore occur and include no more periods, hot flushes, sweats, mood swings and vaginal dryness. Fertility can be also affected.

Most side effects of chemotherapy can be treated. Therefore it is important to tell the doctor or nurse about any discomfort that you feel.

Apart from these, each drug can also have different unwanted effects. The most common ones are listed below, although not everyone will have side effects, or experience them to the same extent.

  • Doxorubicin and epirubicin (in less extent) can cause damage to the heart muscle, therefore the assessment of heart function is important before therapy with these two drugs. Trastuzumab can also cause heart damage and should not be given together with doxorubicin or epirubicin. Doxorubicin and epirubicin can make the skin more sensitive to sunlight and cause reddening in areas where the patient has had radiotherapy in the past. The urine may turn red or pink for a few days after treatment. This is not blood and is only due to the color of the medication.
  • Capecitabine can cause soreness of the palms of the hands and soles of the feet. This condition is called palmar - plantar syndrome and may cause tingling, numbness, pain, dryness and possibly peeling of the palms and soles.
  • Docetaxel sometimes causes fluid retention, temporary nail discoloration and an itchy skin rash. Some people also develop the palmar-plantar syndrome mentioned with capecitabine, or simple numbness and tingling in hands and feet. About one in four patients will suffer from an allergic reaction during the first or second infusion with docetaxel.
  • Paclitaxel can cause a peripheral neuropathy which is dependent upon the dose administered, the duration of the infusion, and the schedule of administration. With lower doses of paclitaxel or with weekly regimens, neuropathy is less common. Symptoms include numbness, paresthesias and burning pain in a glove-and-stocking distribution. Symptoms are often symmetrical, and usually have their origins distally in the lower extremities. Patients commonly report the simultaneous onset of symptoms in toes and fingers, but asymmetric presentations have been described too. Facial involvement is less common. Although mild symptoms have been reported to improve or resolve completely within several months after discontinuation of therapy, the symptoms and deficits have been reported to persist longer in patients who develop severe neuropathy.

Side effects of hormone therapy

Side effects of hormone therapy are very frequent. They will depend on the drug(s) administered but all hormone therapies share the same main side-effects. Tamoxifen tends to have more side-effects than aromatase inhibitors.

For pre-menopausal women, the first goal of a hormone therapy is to suppress the function of the ovaries, either by removing them or by the action of a drug (gonadotropin-releasing hormone analogues). This will lead to symptoms of the menopause such as hot flushes, sweats, mood swings and vaginal dryness. And of course, periods will stop.

The main side effects shared by hormone therapies are listed below and are related to changes in the level or effect of hormones due to the therapy. On the whole, for almost all women, the benefits of hormone therapy outweigh the risks.

  • Hot flushes and sweats (very frequent and especially with tamoxifen)
  • Vaginal dryness or discharge
  • Muscle and joint pain (especially with aromatase inhibitors)
  • Mood swings
  • Fatigue
  • Nausea
  • Less interest in sex (which can occur for many different reasons related to breast cancer, but changes in hormones due to the therapy can explain this at least partly).

Some other rare, but more serious side effects are possible. Most of the drugs have an effect on the bones and can lead to osteoporosis. Sufficient intake of calcium and vitamin D is therefore very important, as can be an assessment of the bone density by radiological examination.

Tamoxifen can increase the risk of developing cancers of the body of the uterus for women taking the drug after their menopause. Any vaginal bleeding after the menopause should be reported to a doctor, even if most vaginal bleedings are not due to uterine cancer.

Tamoxifen can also increase the risk of blood clots, usually in the legs (deep vein thrombosis). Rarely, a piece of the blood clot can become detached (embolize) in the blood flow and may end up in an artery of the lungs (pulmonary embolism) causing chest pain and shortness of breath. Any of these symptoms should be reported to a doctor.

Side effects of targeted biologic therapies

Trastuzumab

Side effects of trastuzumab are more limited than side effects of chemotherapy. Trastuzumab can cause allergic reactions ranging from chills, fever and possibly an itchy rash, feeling sick, breathlessness, wheezing and headaches, to flushes and faintness. Chills, fever, rash, nausea and vomiting are usually due to the infusion itself and tend to happen during the first few infusions before becoming less common.

Trastuzumab can cause harm to the heart, including heart failure. Care should be taken if it is given to patients who already have heart problems or high blood pressure, and all patients need to be monitored during treatment to check their heart.

Trastuzumab should not be used in people who may be hypersensitive to trastuzumab, mouse proteins or to any of the other ingredients. It must not be used in patients who have serious breathing problems when they are at rest because of their cancer, or who need oxygen therapy.

One or more of the above side effects may be seen in a patient, but not necessarily all of them in the same patient.

Lapatinib

Most frequent side effects occurring in more than 30% of patients taking lapatinib in combination with capecitabine are diarrhea and hand-foot syndrome (skin rash, swelling, redness, pain and/or peeling of the skin on the palms of hands and soles of feet). It is usually mild, starts early (usually 2 weeks) after start of the treatment, and may require reductions in drug doses.  Anemia may happen, as well as nausea and vomiting, and an increase in the blood level of liver enzymes.

Bevacizumab

There are rare but serious complications of bevacizumab therapy which include

  • gastrointestinal perforation, fistula formation, wound healing complications;
  • severe bleeding;
  • hypertensive crisis (severe high blood pressure);
  • nephrotic syndrome - a condition marked by very high levels of protein in the urine (proteinuria), low levels of protein in the blood, swelling, especially around the eyes, feet and hands; this syndrome is caused by damage to the tiny blood vessels in the kidney that filter waste and excess water from the blood and send them to the bladder as urine;
  • congestive heart failure in patients who have received bevacizumab prior treatment with anthracyclinebased chemotherapy, or radiation therapy to the chest wall.

The most common side effects of bevacizumab are hypertension, generalized weakness, pain, abdominal pain, nausea and vomiting, poor appetite, constipation, upper respiratory infection, low white blood cell count (which can increase risk for infection), proteinuria, nose bleed, diarrhea, hair loss, mouth sores and headache.

Everolimus

Although not all of these side effects may occur, if they do occur they may need medical attention. Contact your doctor immediately if any of the following side effects occur:

  • swelling of the face, arms, hands, legs, or feet;
  • bloody nose;
  • Tightness of pain in the chest;
  • cough or hoarseness;
  • cracked lips;
  • decreased weight;
  • diarrhea;
  • shortness of breath or difficult breathing;
  • difficulty with swallowing;
  • fever or chills;
  • general feeling of discomfort or illness;
  • lower back or side pain;
  • painful or difficult urination;
  • rapid weight gain;
  • sores, ulcers, or white spots on the lips, tongue, or inside the mouth;
  • swelling or inflammation of the mouth;
  • thickening of bronchial secretions;
  • and tingling of the hands or feet.

 

What happens after the treatment?

It is not unusual to experience treatment-related symptoms once the adjuvant treatment is completed.

  • It is not rare that anxiety, sleeping problems, depression or extreme fatigue are experienced in the post-treatment phase; patients with these symptoms may need psychological support.
  • Memory deficiencies, difficulties in concentrating are not uncommon side effects of chemotherapy and are generally reversible within a few months.
  • Young women may have premature menopause because of the chemotherapy with mood swings, weight gain, hot flushes, joint pain and sleeping problems. The way that these symptoms can be treated should be discussed with their doctor.

Follow-up with doctors

After the treatment has been completed, doctors will propose a follow-up program aiming to:

  • detect possible recurrence as soon as possible
  • detect possible cancer occurring in the other breast
  • evaluate and treat adverse effects of the previous treatment
  • provide psychological support and information to enhance returning to normal life

Follow-up visits with the oncologist should include:

  • History-taking (reviewing the patient’s medical history), eliciting of symptoms and physical examination
  • A mammography of the breast, if no mastectomy was performed, and of the other breast for all women, is recommended every year. This could be replaced by an MRI examination in particular situations such as in patients with familial breast cancer or women younger than 35. For women who have had breast reconstruction, no mammography will be done and an MRI examination will be performed.
  • No further radiological or blood examination if the patient does not exhibit any symptoms.

It is important to be aware that weight gain affects prognosis adversely and should be discouraged; if necessary, nutritional counselling is recommended. Regular long-term moderate to strenuous physical activity is associated with a favourable prognosis; aerobic training and weightlifting does not negatively affect the development of lymphedema.

Return to normal life

It can be hard to live with the idea that the cancer can come back. Based on what is known today, avoiding weight gain and engaging in regular physical activity could decrease the risk of recurrence after completion of the treatment. Regular exercise provides various benefits. It helps one to feel physically and psychologically better and it might also reduce the risk of recurrence. Weight gain after completion of treatment should be avoided since it is likely to have a negative effect on the prognosis. Nutrition counseling could be proposed to avoid weight gain and should be recommended for obese patients. For smokers, it is also strongly recommended to quit and this could be done with the help of specialists in smoking cessation.

As a consequence of the cancer itself and of the treatment, return to normal life may not be easy for some people. Questions related to body image, sexuality, fatigue, work, emotions or lifestyle may come up. Discussing these questions with relatives, friends or doctors may be helpful. Some people may also want to find support from ex-patients’ groups or telephone information services and helplines.

What if the cancer comes back?

If the cancer comes back, it is called a recurrence and the treatment depends on the extent of the recurrence. In general, it happens in up to 30% of patients without tumor cells present initially in their lymph nodes and in up to 70% of those whose tumor has been spread to the lymph nodes at diagnosis.

If it comes back as a recurrence in the same area of the breast and lymph nodes involved the first time, it should be treated like a new cancer. It is always recommended to check for the absence of metastasis in the lung, liver or bone using radiological examinations.

Surgery to remove the recurrent tumor completely is recommended, if feasible. After surgery, radiotherapy can also be given and depends on the previous treatment:

  • Patients not previously exposed to radiotherapy after the operation should receive radiotherapy to the chest wall and regional lymph node areas.
  • Patients previously exposed to radiotherapy should not receive radiotherapy again because it could seriously damage the lungs and the heart. Careful irradiation to limited areas of the chest may be applied.

Is it not clear to what extent the use of chemotherapy, hormone therapy or HER2-directed therapy after the local treatment prolongs the life when cancer comes back in the same area of the breast and lymph nodes involved the first time. The main treatment goal in these patients is palliation, with the aim of maintaining/improving quality of life, and possibly improving survival.

For patients considered to be inoperable at the time of disease recurrence, the first choice is systemic therapy in order to reduce the size of the tumor and render it operable if possible. The second choice is radiotherapy to the chest wall and regional lymph node areas.

Regarding chemotherapy, many factors including aggressiveness of the tumor, previous treatments received and patients’ general well-being and preference have to be considered and discussed before making a treatment decision.

If the cancer recurs as a metastatic cancer, it should be treated as explained in the paragraph “Treatment plan for metastatic cancer (Stage IV)” in the section “What are the treatment options?”. In this case and whenever possible, a biopsy of the metastasis should be made and should undergo a laboratory examination to:

  • Confirm that it is a metastasis of the breast cancer and not a metastasis of another cancer or not a metastasis at all.
  • See if the characteristics of the cancer, like hormone receptor status and HER2 status are still the same because cancer characteristics may change over time.

A biopsy of the metastasis may be avoided if the procedure is too risky, if the time that has elapsed between the first diagnosis and the occurrence of the metastasis is short (no more than 2 years), suggesting that the characteristics of the cancer should not have changed, or if the results of the new biopsy will not change the treatment plan.

 

Standard of care

ESMO-guidelines are available for:

- Primary breast cancer.

- Advanced breast cancer.

- BRCA in breast cancer.

Synonyms

Breast cancer

Breast tumour

Breast tumor

Cancer of the breast

Tumour of the breast

Tumor of the breast

Mammary cancer

Mammary tumour

Mammary tumor

Therapies by type

The following list of treatments is based on what we have found in scientific studies about cancer. More information about the listed therapies can be found under the tab THERAPIES. For registered drugs, radiotherapy and surgical interventions, approval by the authorities is given.

Surgical interventions

Procedures involving instrumental means to investigate or treat a cancer, or to improve the body’s functions or appearance. Generally, a surgical intervention involves an incision. More

Radiotherapy

Medical use of high-energy radiation to kill cancer cells and reduce tumor size. More

Cell-based therapies

Administration to patients of their own or someone else’s manipulated human cells. More

Synthetic products (excluding registered drugs)

Synthetically produced substances or modified natural products that are not registered as anti-cancer drugs.

Natural products (excluding registered drugs)

Diets

Controlled consumption of carefully selected foods and beverages with the intent to influence disease outcome.

Mind-body interventions

Techniques designed to enhance the mind's capacity to affect the biological functioning of the body. More

Energy based therapies

Use of electromagnetic energy including electricity, magnetic fields, radio waves, microwaves, infrared rays and light to diagnose or treat disease.

Body-based & Manipulative therapies

Clinical trials

A clinical trial is a research study conducted with patients to evaluate whether a new treatment is safe (safety) and whether it works (efficacy). Clinical trials are performed to test the efficacy of drugs but also non-drug treatments such as radiotherapy or surgery and combinations of different treatments. Clinical trials take place in all kinds of hospitals and clinics, but mostly in academic hospitals. They are organized by researchers and doctors.
The Anticancer Fund provides a tool to search for phase III clinical trials by type of cancer and by country. For Belgium, the Netherlands, Switzerland, Luxembourg, France and the UK, the Anticancer Fund provides contacts to get more information about the phase III clinical trials currently ongoing. Discuss the possibilities of participating in one of these clinical trials with your doctor.

The list of the phase III clinical trials for breast cancer is available here.
 

For patients

Body Weight and Prognosis in Cancer Survivors

 

Download guide
 

Does being obese, overweight or underweight have an impact on my prognosis after completing my cancer treatment?

 

Overall, individuals with excess weight have a greater chance of dying from cancer than those with normal weight. Normal weight is defined as having a body mass index, or BMI, between 18.5 and 24.9 kg/m2.  Above the level of 25, each 5 kg/m2 increase in BMI accounts for a 10% increase in deaths due to cancer (1;2). The morbidly obese (BMI >40) have a more than 50% greater chance of dying because of cancer than individuals with normal weight (3).

Specifically for breast cancer (BCa), excess weight increases the risk of developing it (the incidence, which is not further discussed in this article) in post-menopausal but not in premenopausal women. After the patient has been diagnosed and completed her anticancer treatment, excess weight worsens the prognosis in both pre- and postmenopausal women. A worse prognosis in these BCa survivors may refer to several different outcomes, such as for example, the breast cancer coming back (recurrence, relapse), or getting another cancer (second primary cancer), or getting another disease (co-morbidity), or dying from BCa (BCa specific mortality), or dying from any cause (overall mortality).

Regarding mortality, a meta-analysis of 43 studies on BCa survivors concludes that being obese (BMI > 30) when diagnosed increases the risk of dying from any cause, or from BCa specifically, by 33% (4). The higher BCa-specific mortality is partly due to more distant recurrences (metastases) appearing after 5 years or later (5;6).

A recent meta-analysis of 21 studies concludes that being obese at diagnosis will worsen overall and BCa-specific mortality to the same extent in pre- and post-menopausal BCa survivors. Likewise, having estrogen/progestin receptors (receptor positive) or not (receptor negative) will not change the unfavorable impact of obesity (7). In the USA, the increase in mortality that is directly linked to obesity was the same in all races (8). However, African Americans have higher obesity rates and more aggressive BCa tumors; as a consequence their overall BCa burden is significantly heavier (9).

There are some studies suggesting that the unfavorable impact of obesity may be stronger (but more evidence is needed) in:

  • Node-positive obese patients (who are more at risk of metastases) (5;10), but was not evident in studies on node-negative patients (11;12);
  • Aromatase inhibitor treatment, but not with tamoxifen (13;14).
  • Hormone replacement therapy use by postmenopausal women (15)

Being overweight (BMI 25.0 - 29.9) does not have a clear impact on mortality from BCa since the evidence from the different studies is not consistent. One study found a 26% increased risk (5), but others did not (10;15;16). We still do not have sufficient data to establish a clear-cut BMI threshold value above which BCa prognosis worsens significantly (4;17).

Being underweight (BMI < 18.5) strongly increases overall mortality by 59% but this poorer survival was due to non-BCa causes (16).

It is important to note that overweight/obese cancer survivors have a four-fold greater risk of suffering and dying from other (co-morbid) diseases such as cardiovascular disease, diabetes mellitus type 2, asthma, osteoporosis and back pain (18).  Nowadays, survivors are equally likely to die from cardiovascular disease as from BCa (19). A meta-analysis of 23 studies shows that patients with diabetes before the diagnosis of BCa have a 61% higher overall mortality (20).

In summary, the relationship between BMI and BCa prognosis shows a U-shape with worse overall survival at both the extremes of BMI, specifically those who are severely obese and those who are underweight (6). The 2014 Continuous Update Project (CUP) Report on “Diet, nutrition, physical activity and breast cancer survivors”, summarizing the evidence from 85 studies (on 164 416 women), concludes that in general there is consistent but still limited evidence that women with greater body fatness (higher BMI), in particular if postmenopausal, have higher overall and BCa specific mortality. More and better-designed studies are still needed to consolidate these findings and to gain more insight into the differences between pre- and postmenopausal women, having excess weight before or after diagnosis, tumor type, disease evolution and amount of treatment received. This information will improve the strength of the evidence from limited to convincing (21).

 

 

Does gaining weight after being diagnosed with breast cancer have an impact on my prognosis?

 

Breast cancer patients often gain weight (on average 2 to 4 kg) during and in the years after chemotherapy (22;23). Weight gain occurs more often in premenopausal and in normal weight women (24;25). The gain is caused by an increase in fat mass generally and especially abdominal fat mass, but muscle mass is lost. These two changes constitute the so-called sarcopenic obesity (a fat belly with thin legs and arms). Several factors may be involved in these changes. Surprisingly, these patients do not eat more calories (intake) but they burn up less (expenditure). Not compensating for the drop in expenditure (by lowering their caloric intake) results in a positive energy balance; the excess of calories is transformed into body fat. Energy expenditure decreases because basal metabolism lowers during the chemotherapy, and patients do less physical exercise and sleep more (26;27). Part of the weight gain could also be explained by the premature menopause caused by anticancer treatment (23).

Gaining weight after diagnosis worsens the prognosis. For example, in the Nurses’ Health Study that followed 121 700 women for 9 years, an increase in BMI of >2 kg/m2 in the first year after diagnosis was associated with a 64% increase in BCa death and recurrence (28). In the Healthy Eating Activity Lifestyle study (HEAL), BCa survivors who had sarcopenia within one year of diagnosis had a 2.86-fold higher overall mortality (29).

 

Why does being obese or gaining weight worsen breast cancer prognosis?

 

This worse prognosis may be caused by a combination of several factors (30). Firstly, anticancer treatment and the response to it are often sub-optimal in obese women. A survey conducted in the USA showed that obese women underwent screening mammography less often than normal weight women (31). This may result in delayed detection, and consequently, in a worse response to treatment. In addition, the dosage of chemotherapy administered is often not sufficient for their real body weight because of fears of toxicity at higher doses (32;33).

Secondly, excess body fat causes alterations that can result in the cancer being more aggressive and progressing faster even after treatment. Some well-identified alterations are the increases in hormones such as insulin and leptin, circulating estrogens, growth factors such as IGF-I, and inflammation (30;33;34).

Lastly and just as important, excess body fat increases co-morbid diseases (see above) which are nowadays an equally important cause of death as the cancer itself.

 

Does losing weight unintentionally after being diagnosed with breast cancer have an impact on my prognosis?

 

It is important to distinguish between weight loss that is intentional (by following a weight-losing diet after diagnosis) or unintentional (unplanned and caused by illness in general). Losing weight unintentionally worsens the prognosis. For instance, in the Life After Cancer Epidemiology (LACE) study, obese women who had lost ≥ 10% of weight unintentionally in the period before the start of the study had a higher risk of recurrence and of death due to any cause (35). In the Shanghai cohort, unintentional decreases in weight of > 1 kg also worsened prognosis (36). In patients who are normal or underweight at diagnosis, further weight losses to BMI levels < 18.5, together with the loss of muscle mass, can eventually lead to cachexia that worsens prognosis and survival considerably.

 

Can fasting during my chemotherapy improve the effectiveness of the anticancer treatment?

 

Novel research in laboratory cell cultures and animals indicates that fasting conditions by lowering the glucose that is available to cells will improve antitoxic defenses in normal, but not in cancer cells. Through this process, the cell-killing effect of chemotherapy will be more effectively targeted to the cancer cells, and with less toxic side effects in non-cancerous tissues (37-39). Studies in human cancer patients investigating if the efficacy of chemotherapy improves during fasting are currently being conducted, but the results have not been published yet (40).

 

Can I benefit from following a diet to lose weight after being diagnosed with breast cancer?

 

If I am obese/ overweight

Numerous studies in both healthy and cancer patients have shown that restricting caloric intake to achieve even modest losses of weight and body fat can reverse the excessive production of insulin, fat-tissue hormones such as leptin, growth factors such as IGF-I, and inflammation. All these factors contribute to the worse prognosis in obese BCa survivors (41-44).

As recommended for all individuals with excess weight, it has been suggested that an intentional weight loss of 5-10% would benefit BCa survivors by decreasing the risk of both BCa recurrences and co-morbidities (45). In practice, safe weight loss can be achieved by a typical hypo caloric diet (decrease daily caloric intake by 500 kcal) (46), or by following the recommendations of the Diabetes Prevention Program (DPP) (47). Even small decreases in caloric intake (by little more than 150 kcal/day), which is achieved by adapting the dietary pattern so that less energy-dense foods are consumed, could have significant beneficial benefits, as shown below, when discussing the various types of diets.

All guidelines emphasize the need to combine diet, physical exercise to maintain energy expenditure as well as bone and muscle mass (prevent sarcopenia), and behavioral therapy (48). A reasonable goal is to reach a normal weight within 2 years.

However, we still need more evidence from randomized controlled trials (RCT) that compare the effect of decreasing caloric intake (intervention) or not (control) on the progression or recurrence of BCa in survivors. These studies need to be conducted in sufficiently large and comparable groups of BCa survivors, and for sufficiently long periods of time.

Of importance, the degree of benefit achieved by such a dietary intervention will not be the same for all individuals. As suggested by the studies that follow survivors for years, those more liable to benefit from losing weight are:

  • Patients with obesity (BMI > 30) at diagnosis (4)
  • Patients rapidly gaining weight and abdominal fat (48), especially if they are premenopausal and with normal weight at diagnosis (24;28)
  • Patients with alterations of the metabolic syndrome such as abdominal obesity, high insulin levels and insulin resistance, high circulating inflammatory markers (6;49-51)

If I have a normal weight

Current guidelines do not encourage weight loss if the BCa survivor has an ideal normal weight, but insist on avoiding weight gain (to levels of BMI > 25) or weight loss (to levels of BMI < 18.5), as well as preserving muscle and bone mass (45).

If I am underweight

In view of the significantly higher mortality of underweight BCa survivors (BMI < 18.5), current guidelines advise an individual symptom-focused approach aimed at meeting nutritional needs, maintaining lean body mass (eventually with tailored physical exercise), and addressing the conditions causing unintentional weight loss such as vomiting and fatigue (45).

 

Which is the best way to achieve the most favorable weight to survive longer and with a better quality of life after being diagnosed with breast cancer?

 

Several RCT have investigated how changing the diet can affect body weight, and if this approach can lower the chance of having a BCa recurrence and improve overall prognosis. Various types of diet, all with the potential to lower body weight, have been investigated so far.

Diet with less fat

The Women’s Intervention Nutrition Study (WINS) showed that by decreasing fat intake from 30% to 20% of their total caloric intake (amounting to a decrease of 167 kcal per day) for 5 years, BCa survivors achieved an average loss of 2.7 kg of body weight. The risk of their BCa returning was decreased by 24%, and even more (by 42%) in the women who did not have estrogen receptors in their tumor (53).

Diet with less carbohydrates

Several trials are currently investigating the effect of changing the proportion of carbohydrates in weight-losing diets. Usually, a decrease in carbohydrate implies a higher proportion of fats often accompanied by a moderate increase in protein intake. Such diets have proved effective to lose weight and normalize high insulin levels, and could therefore improve prognosis in cancer survivors (54). The CHOICE trial, conducted on overweight and obese BCa survivors, aims to reduce caloric intake and to increase physical exercise (to achieve a 700 kcal/day lowering of energy balance). It has so far shown that the loss of weight after 6 months was the same (6 kg) regardless of whether the diet contained 64% or 32% carbohydrate. The impact on BCa prognosis is still being studied (46;55).

Diet with intermittent restriction

Recent trials have shown that hypo caloric diets with intermittent caloric and carbohydrate restriction (for example, by decreasing energy intake by 70% and limiting carbohydrate to 40 g two days per week), are more effective than daily caloric restriction, in improving prognostic factors such as insulin function and body fat, as well as enjoying better adherence by the patients (56). Longer-term trials are needed to investigate if these dietary regimens are effective in improving BCa prognosis.

Which dietary pattern is most appropriate to optimize my prognosis?

The Women’s Healthy Eating and Living study (WHEL) reported that increasing the intake of fruits and vegetables from 6 to 9 servings per day for 7 years did not lower the risk of their BCa returning. (52;57).

Despite the disappointing results of the relatively short WHEL intervention, it should be noted that in this same group of BCa survivors, those who consumed more than 5 servings of vegetables and fruits daily all their life (demonstrated by their higher levels of carotenoids in blood) had a 31% lower risk of BCa recurrence. This observation reinforces the evidence that a lifelong consumption of a good quality diet improves overall survival (45).

The Healthy Eating Activity Lifestyle (HEAL) study on the habitual diet of BCa survivors also shows that those with higher intakes of fiber (more than 9 gram per day) had a 47% lower risk of dying from BCa (58). Likewise, those with the highest Healthy Eating Index-2005 score had an 88% reduced risk of death from BCa after 6 years of follow-up (60). 

Finally, we are awaiting the results of the DIANA-5 trial investigating if consuming a Mediterranean diet will decrease BCa recurrences and improve survival (61).

The effect of alternative diets such as those named after Budwig, Buchinger, Gerson, Gonzalez and Breuss have not been investigated in randomized trials involving BCa cancer survivors. Although the macrobiotic, CRON (caloric restriction optimal nutrition) and the Ornish diets involve dietary changes (more fiber, less fat, less meat etc) similar to the dietary patterns that are associated with a lower cancer incidence, there is currently no evidence of any impact on BCa survival.

 

What should I take into account and be careful about when aiming to lose weight?

 

Excessive weight loss (to BMI values < 20 kg/m2) can lead to loss of muscle and bone with an increased risk of fractures, especially with aromatase inhibitor treatment (62). Promoting physical activity to slow down loss of muscle and bone mass during weight loss regimens is thus indispensable to improve prognosis. These measures are currently incorporated in all the lifestyle guidelines for cancer patients (48;63).

The 2014 CUP Report concludes that there is still insufficient evidence needed to make specific dietary recommendations for breast cancer survivors and gives the following general healthy lifestyle recommendations (21):

  • maintain a healthy body weight
  • be physically active
  • eat foods containing fiber
  • eat foods containing soy
  • lower the intake of total fat and, in particular, saturated fat


Weight and prognosis in prostate and colorectal cancer survivors

 

Compared to BCa, the investigations on the effect of weight and weight-losing diets are scarcer for prostate (PCa) and colorectal (CRC) cancer. Unfortunately, not all the conclusions from the investigations on BCa survivors can be extrapolated to these other types of cancers (30). Some relevant differences are summarized here.

Obese men have a higher risk of advanced, more aggressive PCa when diagnosed (64-66), a higher risk of recurrence after treatment (67) and higher overall mortality (68). This fact has been recently confirmed by the 2014 Continuous Update Project Report on “Diet, nutrition, physical activity and prostate cancer” that updates the evidence on the risk of developing prostate cancer with data from 104 trials on 9 855 000 men (69). For example, gaining around 2 kg in the period 5 years before and 1 year after surgery increases the risk of recurrence by 94% (70).

In agreement with the BCa trials, decreasing fat intake to lose body weight seems to protect against PCa recurrence, but only at very low fat intakes. For example, after one year following an Ornish diet (10% fat intake), body weight decreased by 4.5 kg and recurrence decreased (71;72). More moderate decreases in fat intake (from 36 to 28% energy), however, did not influence tumor growth after 3 weeks (73).

For CRC, it is well known that being obese before diagnosis increases the incidence and mortality in men more than in women, and in colon more than in rectum (66). However, there is still not enough convincing evidence to conclude that excess body weight at and after diagnosis can influence prognosis except in some sub-groups with a very specific molecular subtype of tumor (74;75). More evidence from RCT investigating the impact of weight loss or control on the disease outcome of these cancer survivors is still warranted.

 

Conclusions

 

Breast cancer survivors who are obese or underweight at diagnosis, those rapidly gaining weight, and those with metabolic syndrome, high circulating estrogens and inflammation have a worse prognosis and are more likely to benefit from dietary measures to normalize their body weight. For this purpose, safe weight loss by restricting energy dense foods such as saturated fat and highly refined carbohydrates, and promoting nutrient-rich foods such as fruits and vegetables combined with physical exercise, is currently recommended for BCa survivors with a BMI >25 kg/m2.

However, there is still no consensus on the “ideal” type of diet to achieve the best protection against a recurrence of BCa and against dying from it or other diseases. Although more trials are needed, there is some evidence that prognosis is improved by the post-diagnosis diets that achieve reductions of at least 2 kg body weight in survivors with excess weight. Furthermore, the quality of the diet in terms of fruit and vegetable intake is important when consumed in high amounts for a lifetime, but has less impact when the improvement is limited to short periods as seen in some trials conducted after diagnosis. Changing the proportion of fat or carbohydrate does not seem to influence the degree of weight loss when caloric intake decreases equally, but we still do not have enough data to conclude if the influence on BCa-specific prognosis is different. Finally, any strategy to optimize weight status in BCa survivors must combine dietary improvement with physical exercise (about 150 minutes moderate to intense activity per week), in order to improve hormone and metabolic function and prevent loss of bone and muscle mass.

 

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Body Weight and Prognosis in Cancer Survivors

 

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Highlights

 

What are the goals of “Body Weight and Prognosis in Cancer Survivors”?

  • Cover scientific evidence about the impact of weight management on overall survival, cancer-free survival and risk of recurrence in cancer survivors
  • Give some evidence-based answers to this frequently asked question
  • Does losing weight by restricting caloric intake and changing dietary pattern help a cancer patient to survive longer and better?

Please note that the influence of weight on cancer incidence and primary prevention are not discussed here.

Which cancer types are covered?

  • Since most of the information on this subject derives from studies on breast cancer (BCa) patients with excess weight, the data presented here will mainly refer to these patients.
  • Some specific aspects in prostate (PCa) and colorectal (CRC) cancer survivors will also be shortly discussed.

 

Summary

 

Excess body weight is associated with a higher rate of death from many cancers. In breast cancer (BCa) the higher mortality is not only due to a higher incidence (in postmenopausal women), but also to a poorer survival after diagnosis. Being obese (body mass index BMI >30 kg/m2) at diagnosis increases all-cause and BCa mortality by 33%. Being overweight or obese (ov/ob, BMI ≥ 25 kg/m2) at diagnosis increases the risk of distant BCa recurrence (metastases, appearing later than 5 years after diagnosis) but not of locorregional recurrences. Being underweight (BMI < 18.5 kg/m2) at diagnosis also increases all-cause mortality by 59% in BCa patients.  

Weight gain (2 to 4 kg) after diagnosis of BCa is frequent and associated with a higher mortality. It is caused by a decrease in energy expenditure and results in sarcopenic obesity (increase in abdominal fat mass and decrease in the lean muscle mass). Weight gain tends to be more pronounced in younger (premenopausal) and in normal weight patients.

Unintentional weight loss of more than 10% (in a period of about 7 years after diagnosis) was also associated with higher BCa recurrence and mortality in the LACE (Life After Cancer Epidemiology) study. Unintentional weight loss is caused by the disease itself and can eventually lead to cachexia, especially in normal and underweight survivors, and can worsen prognosis and survival significantly.
The poorer survival associated with obesity and weight gain can in part be explained by an insufficient dosage of adjuvant therapy, in addition to alterations directly due to high adiposity such as insulin resistance, hyperinsulinism, higher bioavailability of IGF-I and estrogens, as well as inflammation.

Fasting or caloric restriction modulates the cellular detoxification and antioxidant response to improve the resistance to the toxic effects of chemotherapy in normal, but not in cancerous cells. In addition, by lowering blood glucose, insulin and IGF-I levels, cancerous growth signals will be down regulated.

Controlled dietary intervention trials investigating the impact of controlling weight on BCa prognosis give inconclusive results. In the WINS (Women’s Intervention Nutrition Study), a moderate lowering of caloric intake by restricting dietary fat resulted in a 24% lower BCa relapse after 5 years of follow-up. The effect was more pronounced in estrogen receptor negative women. In the WHEL (Women’s Healthy Eating and Living) trial, in contrast, a similar lowering of caloric intake achieved by increasing fruits and vegetable intakes did not lead to any difference in survival or BCa events after 7 years. However, in conditions associated with high circulating estrogens (postmenopausal hot flushes-negative women), the WHEL intervention decreased BCa recurrences by 47%.

The impact of body weight and of weight-losing diets is less well studied in prostate (PCa) and colorectal (CRC) cancer. Obesity at diagnosis is associated with a higher risk of advanced, more aggressive forms and a higher risk of recurrence after treatment. Weight gain at the time and after diagnosis also increases the risk of PCa recurrence. Intentional weight loss in obese patients may protect against PCa recurrence by following a diet very low in fat but more evidence is needed.

Current guidelines for cancer survivors uphold the same lifestyle advice given to all individuals with excess weight. Decreasing caloric intake in order to reach or maintain a BMI between 18.5 and 25 kg/m2 and physical activity to prevent bone and muscle loss are strongly indicated in survivors with obesity at diagnosis, those rapidly gaining weight, and those with metabolic syndrome, high circulating estrogens (for BCa) and inflammation.

 

Why is weight management important for cancer survivors?

 

Population studies have shown that morbid obesity (BMI > 40 kg/m2) is associated with a 52% and 62% higher rate of death from all cancers for men and women respectively (1) and that each 5 kg/m2 increase of BMI above 25 kg/m2 accounts for a 10% increase in the mortality due to cancer (2;3). These data, however, do not specify whether the impact of excess body weight and body fat is solely on the risk of developing cancer (incidence) or also on the prognosis after diagnosis. The information emerging from the cohorts of cancer survivors who are being followed up since the moment of diagnosis can give more insight into this question. A cancer survivor is defined by the Center for Disease Control (CDC) as “anyone diagnosed with cancer from the time of diagnosis through the rest of their life”. The National Cancer Survivorship Initiative (NCSI) includes those undergoing primary treatment, in remission following treatment, cured (disease-free), disease-stable and those with active or advanced disease (4;5).

These follow-up studies will also enable us to differentiate between deaths caused by the cancer specifically or by co-morbidities. Cancer patients are more prone to suffer from co-morbid diseases such as type 2 diabetes mellitus, asthma, back pain, osteoporosis and cardiovascular disease, and conditions more specifically linked to the cancer and its treatment such as lymphedema, fatigue, arthralgias and cardiotoxicity (6).


EVIDENCE FROM PROSPECTIVE OBSERVATIONAL STUDIES IN BREAST CANCER SURVIVORS

• Impact of Body Weight & Composition at the time of diagnosis

A meta-analysis of 43 studies (with a median of 1192 subjects per study) showed that women who were obese (BMI > 30 kg/m2) when diagnosed with BCa after a median follow-up of 14 years had a 33% higher death rate due to any cause or due specifically to BCa compared to the non-obese (BMI < 25 kg/m2). This worse survival was still significant after adjustment for age, menopausal status, hormone receptor status, and cancer stage (7). A more recent systematic review encompassing 33 BCa studies highlights the methodological issues that make it difficult to integrate all these results into clear-cut conclusions and recommendations for all cancer survivors (8).
Overall versus Breast Cancer-specific outcomes: In contrast to the clear independent impact of obesity on overall mortality, there is less consistent evidence (from more highly powered recent studies) of an independent effect of obesity on outcomes specifically related to BCa such as disease-free survival, BCa mortality or BCa recurrence. In the most recent systematic review, out of 32 studies reporting BCa recurrence or specific mortality, 22 consistently reported that obesity before or at the time of diagnosis has an unfavorable effect on BCa prognosis (8). As illustrated in the following studies, the impact of excess weight differs depending on which type of outcome is monitored and which cut-offs are used to define excess and normal weight.
The Danish Breast Cancer Cooperative Group (DBCG) followed 18 967 patients with early-stage BCa for more than 10 years. After adjusting for known negative prognostic factors such as tumor size, grade and nodes, DBCG found that the risk of dying from BCa increased by 26% in overweight patients (BMI: 25.0 - 29.9 kg/m2) and by 38% in the obese when compared to normal weight (BMI < 25 kg/m2). Whereas there was no impact on locoregional recurrences, the risk of distant metastasis increased significantly with increasing BMI. For instance, the ov/ob patients (BMI ≥ 25 kg/m2) had a 42-46% increased risk in the period of time 5-10 years after diagnosis, but not in the first 5 years (9). This finding confirms earlier data which detected risk increases of 72% for distant BCa recurrences and of 78% for BCa death in patients with excessive weight (BMI > 27.8 kg/m2 compared to normal weight BMI 21.9 - 24.5 kg/m2) (10). Overall, these findings suggest that adjuvant treatment is less effective in women with excessive weight. As a consequence, they will suffer from more long-term recurrences such as metastasis appearing later than 5 years after diagnosis (11).
In contrast, the After Breast Cancer Pooling Project (ABCPP) that followed 14 938 BCa patients for a median of 7.8 years after diagnosis observed a U-shaped association between the BMI at diagnosis and overall mortality with a 81% increased risk in survivors who were morbidly obese and a 59% increased risk in those who were underweight (BMI < 18.5 kg/m2). However, the patients who were overweight, obese and even the severely obese had no statistically significant increased mortality risk after adjustment for the above-mentioned risk factors. Moreover, the risk of BCa recurrence and BCa –specific mortality was not related to BMI, which indicates the poorer survival in the two extreme ranges of BMI was mainly due to non-cancer causes (12).

The few studies using waist-hip ratio to define abdominal obesity or suprailiac/thigh ratio to define android obesity confirm the poorer prognosis in patients with high central adiposity at the time of cancer diagnosis (7;8;13).
Most studies reveal a U- or J-shaped relationship between BMI and BCa prognosis with clearly worse outcomes at both the extremes of BMI who are either the severely obese or the underweight. However, for the middle and overweight range of BMI there is no or inconsistent evidence of increased risk (10;12;14) in contrast to the above-mentioned DBDG study (9). These inconsistencies may in part be due to differences in the definition of “non-obese” (15).  Some studies pool various degrees of obesity as “obese” (BMI > 30 kg/m2) and do not distinguish between underweight, normal weight or overweight subjects within the group defined as “non-obese” (BMI < 30 kg/m2). Indeed, there is still not enough evidence to set a BMI threshold value above which the risk of recurrence and mortality increases significantly.

In the 2014 Continuous Update Project (CUP) Report on “Diet, nutrition, physical activity and breast cancer survivors”, the evidence from 85 studies (on 164 416 women ) investigating the relationship between body fatness, BCa and mortalitywas analyzed taking into account the timing of assessment of body fatness. By making a distinction between three periods (before diagnosis, < 12 months after diagnosis and ≥ 12 months after diagnosis) the impact of body fatness on either incidence of the primary breast cancer or on prognosis after diagnosis could be separately assessed. It concluded that the evidence was limited but generally consistent of a positive association between greater body fatness (which the CUP Panel interprets to be marked by BMI) and all-cause mortality, breast cancer mortality in postmenopausal women, and development of second primary breast cancer (16).

• Change in weight and body composition during treatment and after

Weight gain during and after systemic adjuvant chemotherapy has been described since the early days of cancer treatment (17). This unbalanced increase in weight results in a change in body composition with a relative increase of central (abdominal) fat mass, and decrease in lean mass especially in legs and lower trunk (sarcopenic obesity). With the improvement of therapy regimens and better evidence-based dietary and lifestyle advice, the large gains of up to 7 kg body fat that were seen in the first 6 months after diagnosis in the earlier studies (18) have gradually been reduced. Now more recently, typical increases of 2-4 kg in body weight and of 2% in body fat mass are being reported (17;19). This is equivalent to an additional 2.89 kg gain in weight when compared to the same age group in the general population (20). In the Life After Cancer Epidemiology (LACE) study, the gain in weight was more pronounced in the younger (premenopausal) patients. For example, in the period encompassing the year before and the year after diagnosis, the proportion of women who gained > 8 kg was 20% in the group less than 50 years old and 6% in those older than 70 years (20). In a group of 72 patients aged 40-55 years and receiving chemotherapy, the increase in weight and in fat mass in torso and extremities was evident in patients with normal weight at diagnosis, but not in ov/ob patients (21).

Several studies reported that a gain in weight during and after cancer treatment was associated with a higher mortality. In the Nurses’ Health Study (NHS) that followed 121 700 women for a median of 9 years, an increase in BMI  of > 2kg/m2 in the first year after diagnosis was associated with a 64% increase in BCa death and recurrence in patients with normal weight at diagnosis, but not in ov/ob women (22). In the Shanghai cohort (n 5 042) followed for 46 months, increases of ≥5 kg in the 6 months after diagnosis worsened survival by 31%, and by 90% if the weight gain was extended for 18 months (23).

Furthermore, in the Healthy Eating Activity Lifestyle study (HEAL, n 471), BCa survivors with sarcopenia within one year of diagnosis had a 2.86-fold higher overall mortality. The risk of BCa-specific mortality was also 95% higher, but not statistically significant (24).

It should be noted that decreases in weight of more than 1 kg also worsened prognosis in the Shanghai cohort (23). Similarly, in the 7-year follow-up of the LACE study, obese women who lost ≥ 10% of weight unintentionally in the period between pre-diagnosis and study-entry had a 2.5 and 2.8-fold higher risk of recurrence and overall mortality respectively, whereas weight gain did not confer any additional risk (25). However, there is still not enough evidence discriminating between the impact of intentional (weight-losing diets) and unintentional (caused by disease in general) weight loss.


WHICH FACTORS CAN MODULATE THE IMPACT OF EXCESS WEIGHT ON BREAST CANCER PROGNOSIS?

• Menopausal status/Hormone replacement therapy/Hormone receptor status

The latest World Cancer Research Fund (WCRF) update reports that in postmenopausal women there is convincing evidence that excess weight increases the incidence of BCa. In premenopausal women, in contrast, BCa incidence decreases with excess weight, but the evidence is weaker and designated as probable by the WCRF (26). In contrast, for cancer survivors, it is uncertain how menopausal status affects the impact of obesity on prognosis. For instance, in the Nurses’ Health Study (NHS), the impact of a high BMI at diagnosis and of increasing weight after diagnosis was stronger in premenopausal women (22). Among Japanese BCa survivors, obesity (Asians are classified as obese when BMI > 25.8  kg/m2 and have normal weight when BMI 21.2-23.3 kg/m2)  increased overall and BCa-specific mortality only in premenopausal women (27). Premenopausal women also gained more weight in the LACE study (19). In the meta-analysis by Protani, obesity tended to have a more pronounced impact in pre-menopausal women (47% versus 22% in postmenopausal). Yet due to the heterogeneity of the participants in the different studies, this meta-analysis was underpowered to detect a statistical difference (7). However, a more recent meta-analysis of 21 studies shows that the impact of obesity on overall or BCa-specific survival does not differ significantly by menopausal status (28).
Interestingly, a 10-year follow-up of 2 640 postmenopausal patients in the Swedish Breast Cancer Study found that obesity doubled BCa mortality only in those who had ever used estrogen-progestin therapy (29).
Among obese BCa patients in China, those who were estrogen/progestin receptor negative had a fourfold higher risk of relapse and mortality from BCa than the receptor-positive obese patients (23). Correspondingly, the impact of a >10% weight loss on mortality and recurrence was more pronounced in estrogen and progestin receptor negative patients (25). However, the most recent meta-analysis did not find any significant differences between obese survivors who were either hormone receptor positive or negative (28).

 

• AJCC Stage/Tumor grade/ Nodal status

At diagnosis, overweight and obese patients have a more unfavorable prognostic profile in terms of older age, more menopause, larger tumors, more ductal grade 3 histology and more positive nodes (9).
The impact of obesity on BrCA-specific mortality and recurrences was seen in node-positive patients (who are more at risk of metastases) (9) (14), but was not evident in node-negative study populations in the National Surgery Adjuvant Breast and Bowel Project (NSABP B14) trial (30) nor in the International Breast Cancer Study Group (IBCSG) (31).

• Type of adjuvant Chemo-Hormonal therapy/ Surgery/Radiation

In the Arimidex Tamoxifen Alone or in Combination (ATAC) trial the increased mortality and recurrence associated with obesity (BMI > 35 kg/m2compared normal weight: BMI <23 kg/m2) was found with aromatase inhibitor treatment (a 53% higher risk), whereas with tamoxifen the 18% higher risk was not statistically significant (32). Similar results were observed in the Austrian Br Ca trial (ABCSG-12) (33). Likewise, the impact of Tamoxifen on prognosis was not affected by the degree of ov/ob or underweight (30).

• Diabetes/Co-Morbidities

Part of the increased overall mortality in ov/ob cancer survivors is explained by their fourfold increased risk of co-morbidities (type 2 diabetes mellitus, asthma, back pain, osteoporosis and cardiovascular disease) (6). In the ABCPP, co-morbidities were already present in 44% of the overweight, and in 60% of the obese at the time of diagnosis (12). In fact, cancer survivors are equally likely to die from cardiovascular disease as from BCa (34). A meta-analysis involving 13 019 patients shows that suffering from diabetes at diagnosis increases the all-cause mortality of BCa patients by 61% (35).

• Smoking/Alcohol/ Physical activity

Few studies adjust for lifestyle factors, which could modulate the pathophysiologic changes that are induced by an increase in adiposity. In the Nurses’ Health Study (NHS), the unfavorable impact of ov/ob at diagnosis on BCa recurrence and death was only seen in never smokers (22).

• Race /Socio-economic factors

There is little data from non- Caucasian cancer survivors, despite the well-known fact that African Americans have higher BCa mortality and obesity rates as well as lower socio-economic status (36). Data from the Multiethnic Cohort (MEC) study on 3842 ethnically diverse postmenopausal BCa survivors in the USA did not find any significant evidence of between- race differences in the impact of obesity on overall or BCa-specific mortality (37).  Since the African Americans have higher obesity rates and more aggressive BCa tumors, they suffer from a heavier BCa burden with more serious overall health implications (36).


PREVALENCE OF CANCER SURVIVORS AFFECTED BY EXCESS WEIGHT

Survival rates have gradually improved since 1975. The most recent 5-year relative survival rate for all cancers in the US is 67% (38) and for BCa specifically 89% (ranging from 99% for localized disease to 23% for distant-stage disease (36). This means that the population of cancer survivors is steadily increasing.
In the USA, there were 11.9 million survivors in 2008 (39), 13.7 million in 2012 and there will be an estimated 18 million in 2022 (40). Twenty-two percent of these are BCa survivors (36) (39). Therefore, the current 2.97 million BCa survivors in the USA in 2012 will increase to an estimated 3.79 million in 2022 (40).
Worldwide, the number of cancer survivors within five years of diagnosis has been estimated to be almost 28.7 million for 2008 with over 5 million BCa survivors (41).
In the USA about 50% are ov/ob at diagnosis and 20% are obese, as reported in LACE study (20). Therefore in 2012, in the USA alone, more than 600 000 obese BCa survivors could have a worse prognosis as a direct consequence of their excessive adiposity. As for the overweight survivors, there is still no consensus on the BMI threshold value above which BCa prognosis worsens significantly. Nevertheless, the pooled data allows us to estimate that maintaining a BMI of < 25 kg/m2 could prevent 11 to 18 thousand BCa deaths per year in the USA (11).


Mechanisms of action


WHY/HOW DO BREAST CANCER SURVIVORS GAIN WEIGHT DURING AND AFTER TREATMENT?

 

Caloric intake does not increase significantly, and cannot explain the weight gain seen in the first year after diagnosis. For example, in the HEAL (Healthy Eating Activity and Lifestyle) cohort, patients even decreased daily caloric intake by 137kcal, but still gained 1.5 kg in body weight in the first year after diagnosis (42). Pioneering work by Demark-Wahnefried showed that during adjuvant BCa chemotherapy, weight gain was mainly due to reduced energy expenditure. At the mid-point of a chemotherapy cycle, resting metabolic rate decreased by 322 kJoules /day, and by the end of the cycle returned to pre-treatment levels (43) or remained lower (18). Addition of chemotherapy to local treatment such as radiation and surgery also decreased the energy expended in physical activity during the first year after diagnosis. This is possibly related to the more sedentary lifestyle and longer sleeping hours during treatment (17;18).
During the first year of adjuvant treatment body fat mass increased from 33.5% to 35.8%. This increase is in the same range as the difference between an average pre-menopausal 40 year-old and a menopausal 50-year old. This suggests that therapy-induced premature amenorrhea can also play a role in weight and body fat gain in BCa survivors (17).

 

HOW DOES EXCESS WEIGHT AND AN INCREASE IN ADIPOSE TISSUE WORSEN PROGNOSIS?

 

Several potential pathophysiologic alterations have been proposed to explain how the poorer BCa prognosis in obesity and weight gain is associated with both more biologically aggressive tumors that progress more rapidly, as well as a poorer response to cancer treatment.

• Regarding cancer progression

As summarized in a recent overview by Patterson and illustrated in Figure 1, the mechanisms linking excess adiposity to cancer risk and progression are based on the following evidence (44).

 

Figure 1:

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

The presence of the metabolic syndrome in patients undergoing chemotherapy is an unfavorable prognostic factor and high blood glucose predicts more rapid disease progression (45). The underlying insulin resistance reflected by the high insulin (Highest quartile >51.9 pmol/L compared to the lowest quartile <27 pmol/L plasma insulin) at diagnosis increased the risk of BCa recurrence two-fold and the risk of death due to BCa three-fold in a cohort of 512 patients followed up for 7 years (10;46). This unfavorable impact of high insulin is strong in the first 5 years after diagnosis and decreases progressively in the next 6 to 12 years of follow-up (47 ). These findings suggest that patients with high insulin levels should be preferably targeted for more aggressive anti-cancer treatment (46).

The pro-mitogenic effects of insulin are amplified by the (over)expression in cancer cells of receptors to insulin (in particular the more sensitive isoform A) and to other growth factors such as IGF-I and II, as well as hybrid Insulin/IGF-I receptors. In addition, high insulin levels by occupying the binding sites in circulating hormone binding globulins will increase the bioavailability of IGF-I and estrogens, thus further stimulating growth and proliferation in the tumor (11). Furthermore, in postmenopausal BCa patients with obesity there is a higher synthesis of estrogens in the expanded adipose tissue, including the breast tissue. This is mainly due to up-regulation and higher activity of the enzyme aromatase, which transforms androgens into estrogens. The impact of higher estrogen levels in obesity is especially relevant in estrogen receptor positive tumors of postmenopausal patients.

Breast cancer survivors with body fat mass ≥ 35% in the first year post-diagnosis and those who gain ≥ 5% in weight have higher acute phase proteins such as C-reactive protein (CRP) and serum amyloid A (SAA) that are biomarkers of low-grade chronic inflammation (48). The higher adiposity causes an imbalance of adipokines (lower adiponectin, higher leptin) and a pathologic expansion of macrophages in the adipose tissue, including the cancerous breast tissue of obese women. This leads to an excess of pro-inflammatory cytokines (prostaglandin PGE2, interleukins IL-6, IL-1ß, IL-8 and IL-10, tumor necrosis factor TNF and macrophage inflammatory, monocyte chemo attractant protein 1)(8;49). These will further aggravate the prognosis by cross-talking with the hormonal alterations. For example, they will synergistically enhance VEGF (vascular endothelial growth factor) production in the adipose tissue, and thus promote angiogenesis (50). In fact, elevated inflammation markers (CRP and SAA) 31 months after diagnosis, predicted a 2 to 3-fold increase in overall mortality (51).

• Regarding the response to cancer treatment

 

Higher BMI is associated to a poorer histopathological response to neoadjuvant chemotherapy before surgery (52). There are several potential explanations. A survey conducted in the USA showed that mammography screening is less frequent in obese than in normal weight women (53). This may result in delayed detection, and consequently in a worse response to therapy. Moreover, overweight and obese women can be under-dosed in case chemotherapy dosages are calculated based on ideal weight instead of on actual body weight for fear of toxicity (54). Under-dosing of adjuvant hormonal treatment may also be inadequate to suppress the enhanced aromatase activity and excess production of estrogens completely (11).

 

How could intermittent fasting, caloric restriction or voluntary weight loss after diagnosis improve cancer prognosis?

 

In view of the clear harmful consequences of a weight gain before and/or after diagnosis, one would expect that dietary interventions limiting caloric intake with the purpose of losing or preventing weight gain would have a favorable impact on BCa prognosis. The rationale underlying the potential beneficial effects of caloric restriction or fasting is based on several experimentally proven mechanisms.

 

MODULATION OF THE TOXICITY OF ANTI-CANCER DRUGS BY FASTING

Cell cultures exposed to fasting conditions (such as lowering glucose and serum concentration in the culture medium) and mice exposed to short-term starvation (48 hours) develop a so-called “differential stress resistance” that protects normal, but not cancer cells, against the toxic and oxidant effects of drugs such as cyclophosphamide, doxorubicin and etoposide (55;56). Fasting or dietary restriction can modulate the Keap-Nrf2 (Kelch like ECH associated protein-Nuclear related factor E2) pathways, and thus enhance transcription of phase II detoxification and antioxidant enzymes. As a result, the resistance of non-cancerous cells to the toxic effects of chemotherapy improves (57).


IMPROVEMENT OF CELLULAR ENERGY SIGNALING BY FASTING

The longer survival and protection against the toxicity of chemotherapy observed after a 72-hour fast in mice was associated to a 70% decrease in IGF-I with a concomitant increase in its binding protein IGFBP-1 (58). This leads to a downstream down-regulation of mitogenic signaling pathways mediated by the insulin/IGF-I-axis such as MAPK/Ras, PI3K/AKT /mTOR and other proto-oncogenes (57). A 36-120 hour fast in humans also results in decreases of blood glucose and IGF-1 (59). But so far, there are no human studies reporting an enhanced efficacy of chemotherapy in response to fasting.

Known as the Warburg effect, cancerous cells are extremely avid for glucose that is channeled towards the biosynthesis of cell components for the proliferating cells. Restricting glucose availability leads to a shift in nutrient signaling in non-cancerous cells, which involves activation of the “cellular energy sensor” AMPK (adenosine 5-monophosphateactivated kinase) and SIRT1 (sirtuin 1). These enhance PGC1α (peroxisome proliferator-activated receptor-γ-coactivator)-dependent transcription. PGC1α activation protects the cell by shutting down growth signals while maintaining repair mechanisms and conserving mitochondrial function (60). Malignant cells are unable to block the growth signals in response to glucose restriction and as a result remain or become even more vulnerable to chemotherapy (57).longer survival and protection against the toxicity of chemotherapy observed after a 72-hour fast in mice was associated to a 70% decrease in IGF-I with a concomitant increase in its binding protein IGFBP-1 (57).


HORMONAL AND METABOLIC EFFECTS OF CALORIC RESTRICTION

Even modest weight and body fat losses -achieved by restricting caloric intake in various dietary regimens- lead to an improvement in insulin sensitivity and a lowering of insulin and leptin levels, which reverses the growth -factor imbalances that worsen prognosis in BCa survivors (61;62). Restricting caloric intake by modifying the dietary pattern, for example by increasing fiber intake, can also affect the bioavailability of estrogens and other growth factors, as well as improve insulin sensitivity (63). In addition, an intervention resulting in a 7% in weight loss in CA survivors lowered pro-inflammatory cytokines (64).


Does it work? What is the quality of the evidence that dietary interventions to maintain or lose weight have an impact on breast cancer prognosis?

Neither Neither the data on the impact of increased adiposity from the prospective observational studies nor the pathophysiological mechanisms described above provide enough evidence to prove that a loss in weight or preventing weight gain after diagnosis improves the prognosis of BCa patients. In order to address this question, several intervention trials have been set up and are summarized here.

The 2011 updated systematic review by Davies on nutritional interventions specifically for cancer survivors (65;66) and the evidence-based nutritional guidelines compiled by Robien (67) and the ACS (68), noted that there is a high heterogeneity with regard to the type of dietary intervention, combination with or without other lifestyle changes such as physical activity, and the baseline characteristics and tumor status of the patients enrolled. Notably, the different outcomes investigated to determine the prognosis of cancer survivors ranged from overall or all-cause mortality or survival, cancer-specific mortality, disease-free survival (referring to any cancer or specifically to BCa), recurrence, relapse, second primary cancer, contralateral or ipsilateral BCa and recurrence-free or relapse-free survival.

Apart from the review by Patterson that reports on the effect of dietary patterns and macronutrients in both observational and intervention studies (69), there is at the present no meta-analysis focusing specifically on dietary interventions that involve a change in caloric intake in cancer survivors. Therefore, it is relevant to describe the individual trials separately. They all address weight management but target different aspects of the diet. These trials are summarized in Table 1.


TYPE OF CONTROLLED DIETARY INTERVENTIONS AFFECTING CALORIC INTAKE IN BREAST CANCER SURVIVORS:

• Caloric restriction by short-term fasting during & after treatment

In a case series report, 10 patients fasting for 48-140 hours prior to and for 5-56 hours following chemotherapy reported fewer side effects but no differences in tumor reduction markers (70). Current ongoing trials are summarized in the section Perspectives.

• By restricting fat intake

In the Women’s Intervention Nutrition Study (WINS, n=2437), the intervention group succeeded in decreasing fat intake (from a baseline 30% to 20% of total energy intake) and maintaining it for 5 years. This was accompanied by a slightly lower caloric intake (a difference of 167 kcal/day) and resulted in a loss of 2.7 kg (4%) of body weight and a 1.1 kg/m2 reduction in BMI. After 5 years, the risk of a BCa relapse was 24% lower (borderline statistical significance) in the whole intervention group and 42% significantly lower in the subgroup who were estrogen receptor negative (71).

• By changing the proportion of dietary carbohydrates and fat

Several trials are currently investigating the effect of changing the proportion carbohydrates in weight-losing diets. Usually, a decrease in carbohydrate implies a higher proportion of fats, which is often accompanied by a moderate increase in protein intake. Such diets have proved effective to lose weight and normalize high insulin levels and could thus improve prognosis in cancer survivors (72). In the ongoing CHOICE trial the impact of a negative energy balance (700 kcal/day), achieved by caloric restriction in combination with increasing physical activity, is being studied in postmenopausal ov/ob BCa patients (n=370). The diets are balanced in protein (20% of energy), but contain either low fat (16% with 64% carbohydrate) or high fat (48% with 32% carbohydrate). After 6 months, the loss of weight (by 6 kg) and body-fat (by 2.4%) was similar in both groups and associated to beneficial changes in serum lipids and glucose (73;74). It also remains to be seen if the type of regimen to restrict carbohydrate and energy intake also influences prognosis.

• By intermittent restriction

Current trials have shown that hypocaloric diets where the caloric restriction is intermittent (for example, by decreasing energy intake by 70% and limiting carbohydrate to 40 g two days per week) are more effective than daily caloric restriction in improving prognostic factors such as insulin function and body fat, as well as enjoying better adherence by the patients (74). Longer-term trials are needed to investigate if these different dietary regimens are effective in improving BCa prognosis in the long-term.

• By changing dietary pattern: Increasing intake of fruits and vegetables, fiber, Mediterranean diet

In the Women’s Healthy Eating and Living study (WHEL, n=3088), the intervention group (9.2 servings of fruits and vegetables per day versus 6.2 in the control group) achieved 65%, 25% and 30% higher intakes of vegetables, fruit and fiber respectively, as well as a 13% lower intake of fat. However, after 7 years of follow-up, body weight had not changed significantly in either group and the survival curves and BCa events were identical (76). Subgroup post-hoc analyses revealed that hot flushes negative women (associated with higher circulating estrogens and with an overall worse prognosis) were significantly protected by the WHEL intervention (31% fewer BCa recurrences). Protection by the WHEL diet was even more pronounced in the postmenopausal hot flushes negative sub- group (47% fewer BCa recurrences) (77).

Interestingly in this study, among the 1765 tamoxifen users and irrespective of the study group, those with high intakes of vegetables before the intervention (> 4 servings per day) had a 44% reduced risk of BCa recurrences (78). Similarly, the patients with the highest average plasma carotenoid concentration over time (before and during the 7 years of the trial) had a 33% reduced risk of BCa recurrence. Their better prognosis was not influenced by the changes in fruit and vegetable intake during the relatively short trial period of 7 years (79). Both these observations support the claim that a lifelong consumption of a good quality diet, even before diagnosis, improves overall survival (68).

The protective effect of fiber is also supported by the results of the Healthy Eating Activity Lifestyle (HEAL, n=688) study where intakes above 9 gram per day conferred a 47% lower risk of BCa mortality (80). In this prospective observational study, the women with the highest quartile of the Healthy Eating Index-2005 score had an 88% reduced risk of death from BCa after 6 years of follow-up (81). The potential benefit of a Mediterranean diet on BCa recurrences and survival is currently being investigated in the ongoing DIANA-5 multicenter randomized controlled intervention trial (n 1208) (82).

• Alternative hypocaloric “anti-cancer” diets

The effect of alternative diets such as those named after Budwig, Buchinger, Gerson, Gonzalez and Breuss have not been investigated in randomized trials involving cancer survivors. Likewise, although the macrobiotic, CRON (caloric restriction optimal nutrition) and the Ornish diets involve dietary modifications that resemble dietary patterns associated with a lower cancer incidence, there is currently no evidence of any impact on BCa survival.


GUIDELINES

 

When & How should the dietary intervention start?

During the initial stage of diagnosis and treatment, current guidelines advise an individual symptom-focused approach aimed at meeting nutritional needs, maintaining lean body mass and addressing conditions such as vomiting and fatigue (68).

During the early post-treatment stage, enrollment of eligible patients in a nutritional intervention program occurs while they are more compliant for long-term dietary adaptation (67). For the long-term management of weight in the disease-free or stable disease phase, current guidelines encourage a 3-part approach consisting of dietary changes to maintain or reach a normal weight within 2 years, exercise to maintain energy expenditure as well as bone and muscle mass (prevent sarcopenia), and behavioral therapy (83). Safe weight loss should be achieved by caloric restriction by reducing energy dense foods (saturated fat and refined carbohydrates) while maintaining adequate intakes of all essential nutrients (68).

 
Subgroups at high-risk/ liable to benefit from dietary interventions involving caloric restriction

 

  • Patients with obesity (BMI > 30 kg/m2) at diagnosis (7)
  • Patients rapidly gaining weight and abdominal fat (83), especially if they are premenopausal and with normal weight at diagnosis (20;22)
  • Patients with alterations of the metabolic syndrome such as abdominal obesity, high insulin levels and insulin resistance, high circulating inflammatory markers (10;46;47;51).
  • Patients with conditions associated with high circulating estrogens, such as in the hot flushes-negative postmenopausal subgroup in the WHEL trial, might benefit more from a dietary increase in fruits and vegetables (77). (These conclusions from post-hoc analyses need to be confirmed by specific intervention trials).
  • Estrogen receptor negative patients who benefited more from a reduction in dietary fat in the WINS trial (71). (These conclusions from post-hoc analyses need to be confirmed by specific intervention trials).

 

DOSE RESPONSE TO DIETARY INTERVENTIONS

Most authors agree that in all individuals with excess weight, an intentional weight loss of 5-10% achieved by healthy eating, caloric restriction and physical exercise, and maintaining a BMI between 18.5 and 25 kg/m2 is likely to have significant health benefits. This approach also applies to cancer survivors who would benefit from the decrease in the risk of both BCa recurrences and of co-morbidities (68). In practice this can be achieved by a typical hypocaloric diet (decrease daily caloric intake by 500 kcal) (73) or by following the recommendations of the Diabetes Prevention Program (DPP) that also stressed moderate to intense physical exercise (at least 150 minutes/week) (84). Even small decreases in caloric intake (by little more than 150 kcal/day), achieved by adapting the dietary pattern, have significant beneficial benefits. The WINS data suggests that for every 38 patients with BCa who change their diet by eating less fat, one additional BCa recurrence would be prevented (71).
However, in order to retard cancer growth significantly, the mice studies indicate that substantial weight losses (for example a 30% lowering of body fat) are needed (56).


Is it safe? Potential adverse effects


LEAN & BONE MASS

Excessive weight loss with a drop in BMI values to less than 20 kg/m2 is a well-known risk factor for fractures especially if associated with aromatase inhibitor treatment (85). In overweight postmenopausal BCa survivors undergoing weight loss diets, a weight loss of 6 kg was achieved at the expense of a significant 0.7 kg loss of lean mass (73). Promoting physical activity to slow down loss of muscle and bone mass during weight loss regimens is thus indispensable to improve prognosis. It is currently incorporated in all the lifestyle guidelines for cancer patients (83;86).

 

Perspectives

 

LIMITATIONS OF THE INTERVENTION TRIALS

In order to propose clear guidelines to BCa patients, future trials will need to address the limitations found in the afore-mentioned trials. Some study design issues are small participant numbers and multiple interventions, heterogeneity and imbalance in the comparison groups in relation to confounding and other prognostic factors, lack of biomarkers of dietary compliance/adherence, drop-in in the control groups, short duration and variable time-frames and inconsistent definition of the endpoints. Moreover, It is not clear to what extent individual studies fully adjusted for potential confounders such as the tumour type, type of treatment, amount of treatment received, and the dissemination of the disease (16). Unbalanced quoting of study results, for example, by giving too much weight to non-RCT studies or not taking into account unpublished results, can also distort conclusions (65).
It should be stressed that any strategy derived from the conclusions of dietary intervention studies on cancer survivors will need to take into account that cancer is not a static disease and that the nutritional needs of each individual-and thus the impact of any diet change- can evolve in the course of the various phases of survivorship.
Moreover, dietary advice to manage weight -and thus influence prognosis -will be inadequate if not combined with appropriate recommendations on physical exercise.
And finally, though this is not the subject of this article, primary prevention to stop the incidence of cancer is still the best recommendation to improve the prognosis of individuals at risk. This implies that an optimal diet and lifestyle should be adopted since pregnancy and early age.
The 2014 CUP Report concludes that the above-mentioned limitations in study design reduce the strength of the evidence needed to make specific dietary recommendations for breast cancer survivors. Nevertheless, the following healthy lifestyle recommendations are given (16):

  • maintain a healthy body weight
  • be physically active
  • eat foods containing fibre
  • eat foods containing soy
  • lower the intake of total fat and, in particular, saturated fat.

 

ONGOING TRIALS ON BREAST CANCER PATIENTS

There are 3 ongoing Phase I trials on the safety and feasibility of short term fasting just before and/or during chemotherapy in several types of cancer, but no results are available yet (87). Another, potentially promising approach, is the use of energy-restriction mimetics, such as metformin, that activate the same metabolic pathways as during the cellular energy stress caused by glucose deprivation (88).  As for interventions to control weight in BCa survivors, there are 28 trials currently registered in the NIH Clinical Trials website (89). Three relevant trials still underway  are the Exercise and Nutrition to Enhance Recovery and Good Health in You (ENERGY) trial (90), the Lifestyle Intervention Study in Adjuvant Treatment of Early Breast Cancer (LISA )(91) and the lifestyle intervention arm of the European SUCCESS C trial (92) (the protocols are shown in Table 1). Several important considerations for the design of these trials were outlined in a 2006 NCI workshop. For example, in  a 5-year diet and physical activity controlled intervention trial -to achieve a 10% reduction of body weight in BCa survivors with BMI> 25 kg/m2, or to avoid weight gain in those with BMI≤ 25 kg/m2- an estimated sample size of 4400 to 5100 would be needed in order to investigate the impact of weight control on disease-free and BCa recurrence-free survival with sufficient power (93).


Addenda


SUMMARY OF THE EVIDENCE ON THE IMPACT OF WEIGHT ON PROGNOSIS IN PROSTATE CANCER SURVIVORS

Obesity is associated with a higher risk of dying from prostate cancer (PCa), but it is not clear whether this is the result of increased incidence, faster progression after diagnosis, or both (8).
Regarding incidence, the data from the Cancer Prevention Study II Nutrition Cohort (n=69 991 subjects followed for 11 years) reveals that obese patients have a higher risk of advanced PCa forms, but a lower risk of localized forms (94). A recent meta-analysis of prospective studies on more than a million subjects has confirmed this finding. It indicates that excess adiposity has an opposing etiologic impact depending on the PCa subtype (95;96). These conclusions are further supported by the 2014 Continuous Update Project Report on “Diet, nutrition, physical activity and prostate cancer” that updates the evidence on the risk of developing prostate cancer with data from 104 trials on 9 855 000 men (97). By discriminating between the different types of prostate cancer (fatal, advanced and early non-advanced) it can now conclude with that there is strong evidence that being overweight or obese increases the risk of advanced cancer.

It is important to note that no conclusion could be drawn for total or non-advanced prostate cancer and that no distinction could be made between the periods before and after diagnosis. These findings have obvious implications on the prognosis of these patients.

In addition, obesity at diagnosis and weight gain in the 25 years before diagnosis both increase the risk of biochemical recurrence (PSA increase) after prostatectomy or radiotherapy (98).  More specifically, an increase in weight of more than 2.2 kg in the period encompassing 5 years before diagnosis and 1 year after radical prostatectomy is associated with a 94% increase in the risk of recurrence (99).

Overall, a meta-analysis indicates that each 5 kg/m2 increase in BMI increases the risk of biochemical recurrence by 21% in treated PCa patients (n= 26 479), the risk of of PCa mortality by 20% in PCa survivors (n= 18 203) and by 15% in a population that was initially cancer-free (n=1 263 483) (100).

Dietary intervention trials with an impact on weight show that decreasing fat intake to 15% of total energy intake (with or without supplementation with fish oil) in newly diagnosed PCa patients resulted in the loss of around 2.5 kg in body weight after 4-6 weeks even though the intervention was designed to maintain body weight. Compared to the habitual Western diet (40% energy from fat), the low fat diet led to significant decreases in serum lipids and proliferation indexes in the prostate cancer cells, but no change in PSA or hormonal status (101;102). In PCa patients awaiting prostatectomy, a more moderate lowering of dietary fat intake (from 36 to 28% energy) resulted in a slight but significant decrease in BMI (from 29 to 28 kg/m2) after 3 weeks, but no effect on tumor proliferation rates (103). A more drastic lowering of fat intake to 10% energy by adhering to a vegan Ornish diet led to a decrease of 4.5 kg body weight, as well as a significant lowering of PSA levels after one year. There was also less recourse to conventional cancer therapy after two years (104;105).

The current guidelines on weight management in PCa patients do not differ from those for BCa survivors. The 2014 CUP recommendations stress the importance of maintaining a healthy weight, eating a healthy diet and being physically active (97). Since these patients are likely to lose bone and muscle mass as a result of androgen deprivation therapy, special emphasis is given to adequate exercise (68).


SUMMARY OF THE EVIDENCE ON THE IMPACT OF WEIGHT ON PROGNOSIS IN COLORECTAL CANCER SURVIVORS

There is convincing evidence that obesity increases the risk of developing colorectal cancer (CRC), more in men than women (96;106). In contrast, there are not enough studies investigating the impact of excess body weight and adiposity at and after diagnosis on CRC recurrence and survival (8). A systematic review of 20 observational studies reports a weak but inconsistent association between obesity and high visceral fat before/at diagnosis and mortality (all-cause and colorectal specific), and more in women than men and depending on the molecular subtype of tumor (107). The follow-up study of the Cancer Prevention Study II Nutrition Cohort (n= 184 000) demonstrated a significant association between mortality and high pre-diagnosis BMI in both men and women, but not with post-diagnosis BMI. Again, this association was stronger in the localized than in the regional tumors (108).


Table 1: Dietary intervention trials affecting weight control in breast cancer survivors

 

 

 

 

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