Section A
by Dr. D. Tsiftsis, Surgical Oncologist

Introduction

Breast cancer can be defined as the accumulation of cells in the form of a tumor in the mammary gland, that for some reason have transformed from normal to malignant.

It can happen at one single site of the breast but it can also happen at more than one sites of one of the sections (quadrants) of the mammary gland (multifocal), or at more than one site anywhere in one breast (multicentric). Less often primary tumors can develop in both breasts simultaneously (bilateral breast cancer).

Under the general term “breast cancer” we include a number of malignant tumors of the mammary gland which is harbored in the human breast. It affects mostly women but men are not spared.

The normal mammary gland consists of lobules that produce the milk and tubes that carry the milk to the nipple. The transformation of a normal ductal or lobular cell to malignant does not happen overnight like turning a switch. It can take a considerably long time and cells go through an almost predetermined process. This process takes the cells through the following stages:

  1. normal
  2. hyperplasia
  3. dysplasia (mild, moderate, or severe)
  4. carcinoma in situ
  5. invasive carcinoma.

The invasive carcinoma at a later stage may acquire the ability to metastasize.

 

Incidence

In 2013, and taking into account only the USA, 232,000 women and about 2,000 men are expected to be diagnosed with breast cancer. During the same year we expect about 40,000 women and 410 men will lose their life due to the disease. These figures make breast cancer the leading malignancy in women, making up almost 1/3 of all female cancer cases. In women, breast cancer accounts for 14% share of all deaths due to malignant tumors, preceded only by lung cancer. The picture is similar in most western and developed countries. The incidence is low in the Far East and in the developing and third world countries. It increases though in parallel with the improvement of the standards of living, to a point that it is considered a disease of the westernized way of life.

The probability of a newborn female developing invasive breast cancer throughout her lifetime is 12.38% or 1 in 8.

 

Breast Cancer types

If the carcinoma originates from the cells of the mammary ducts it is named invasive ductal carcinoma (IDC). It represents the great majority of breast cancer. A special form of ductal carcinoma is the inflammatory carcinoma and derives its name from the appearance of the breast being hot, swollen and red due to the obstruction of the dermis lymphatic vessels by malignant cells. Variants of ductal carcinoma include medullary, mucoid, tubular, adenoid etc. If the transformed cells grow and multiply confined inside the duct without breaking (invading) through the ductal wall it is called ductal carcinoma in situ (DCIS), meaning that it remains “in its place” not spreading. Therefore, it is not a true carcinoma in the narrow sense of the term because a carcinoma is characterized by invasion of the neighboring tissues and metastases to other organs, properties that DCIS does not possess. On the other hand DCIS has a propensity to transform to the invasive form of the same type (ductal). It is not known exactly why and how this transformation happens, nor how much time it takes or how to distinguish the DCIS that has this potential from another that will never transform. Therefore DCIS is considered as a premalignant lesion and often is overtreated.

If the carcinoma stems from the milk producing lobules it is termed invasive lobular carcinoma (ILC). It is similar to ductal carcinoma but has distinct histology and clinical course. If the lobular carcinoma has not invaded the lobule it is growing inside in the same sense as DCIS then it is termed lobular carcinoma in situ (LCIS). Although similar to DCIS there is a major difference between the two. DCIS transforms to the invasive form of the same histology (ductal) at the site where it is located. LCIS rarely transforms to invasive lobular carcinoma at the site where it has developed. It signals an elevated risk for the woman to develop an invasive carcinoma ductal usually or lobular at any site of either of her breasts. Therefore, if DCIS is considered a premalignant lesion, LCIS is a marker of high risk for invasive carcinoma of any histology.

Sometimes the nipple develops a condition described as Paget’s disease of the nipple that in essence is a carcinoma of the nipple and/or the areola. Often develops in tandem with an invasive or in situ ductal carcinoma in the same breast. 

Rarely the breast develops primary tumors that usually occur in other organs or tissues like sarcoma, lymphoma etc.

Finally a tumor of borderline malignancy is the cystosarcoma phyllodes a tumor that resembles fibroadenoma but with a higher mitotic rate and a tendency to recur if not excised properly. At the other end of the spectrum it can behave as true sarcoma.

 

Risk Factors

The causes of breast cancer are not known. It more likely has multiple factors, and the process of tumor creation probably takes many years.

We have identified a number of conditions that are connected with an increased breast cancer risk. These factors can be divided into two major categories: familial and personal.

 

Familial or inherited risk factors

We now know that in two chromosomes (Nr 17 & 13) one of their genes (BRCA1 & BRCA2), if mutated, confer a high risk mainly for breast and ovarian cancers. The mutation is dominantly inherited (by father or mother) but has low penetrance i.e. not all of the carriers of the mutation will exhibit the disease. Another characteristic of familial breast cancer is that the disease appears at a younger age (<50 years old), with more than one cases in more than one generations. The responsible genes are linked to other malignancies like prostate, pancreas etc.

There is a genetic test that can reveal mutation of the referred genes. Since only less than 10% of cases have familial connection, it is imperative before a woman takes the test to have genetic consultation that will determine whether she has a probability to be a mutation carrier.

At increased risk are also members of families affected by inherited syndromes like Li-Fraumeni, Peutz-Jegher, ataxia-telangiectasia and Crowden’s disease known to be associated with breast cancer.

 

Personal history

A number of conditions have been associated with an increased risk for breast cancer. The connection is established from the study and statistical analysis of the habits and practices of lifestyle in large series of patients. Some of these factors seem to have a strong relation to the disease and some less so, but none exhibit the uniform and strong association of the familial category of breast cancer.

A woman cured of an in situ or invasive breast cancer has a higher probability than the general population to develop a second primary breast cancer. Age is also important since the majority of cases appear after the age of 50 and the risk increases with age advancement. Age at menarche and menopause plays a role: the earlier the start and the later the cessation of the periods, the greater the risk. Age also matters as to the first full term pregnancy as does the number of births. Nulliparity and age of first birth after the age of 30 confers risk.

First birth before the age of 20 lessens the risk. The risk is also reduced for births of twin, triplets etc. Also, it seems as a woman with fewer menstrual cycles is protected.

A number of benign conditions like papilloma, florid or atypical hyperplasia, sclerosing adenosis, increase the risk 2 to 5 times. This can be reflected to the number of previous breast biopsies for benign conditions the woman has had.

There are also other risk factors of lesser importance such as lactation, diet, weight, the birth control pill, hormone replacement treatment, alcohol, smoking, exercise etc. The National Cancer Institute has on its site a risk calculator of free access if a woman wants to have an estimate of her risk.

 

Prevention and risk reduction

Prevention from breast cancer can be approached in two ways:

  1. Prevent the disease from developing by eliminating all causative factors (primary prevention)
  2. If the patient cannot achieve that, the second way is to be able to diagnose it at a very early stage of its course that renders the disease curable (secondary prevention).

A risk reduction strategy is adopted for women with calculated high risk, aiming to reduce it by deploying the best primary or secondary preventive measures.

Primary prevention is difficult in a disease like breast cancer because we know that the cause is multifactorial and the carcinogenetic period probably spans several decades. A preventive strategy would have to commence at an early age (before puberty) and be so demanding that would make it incompatible with most aspects of western lifestyle. For the familial type of breast cancer, we still do not possess the technology for replacement of the mutated genes in every day clinical practice.

Secondary prevention (early diagnosis) is feasible thanks to mammography. It is well established that regular mammography screening improves survival rates up to 40%. State and scientific bodies have issued guidelines concerning the age group and frequency of screening taking into account the cost of such mass action. My recommendation would be a risk assessment by her doctor and for an average risk establish a routine of a mammography yearly with physical examination starting at the age of 40.

Risk reduction strategies take various forms. For women with both genes mutated, a safe choice would be prophylactic mastectomy and/or oophorectomy. Although it is clearly a radical and amputative procedure, especially at an early age, it offers maximum protection. The physical and psychological effects are sometimes great and its recommendation must be given after careful evaluation of the patient’s needs and expectations. In cases of one mutated gene mastectomy or oophorectomy alone can be proposed depending on the mutated gene and the racial profile of the patient.

Another way to reduce risk is close follow-up through breast Magnetic Resonance Imaging (MRI) that has proved safe and effective in diagnosing a suspicious breast lesion at a very early stage, reducing unnecessary biopsies.

Finally, another approach is called chemoprevention. A number of drugs called selective estrogen modulators (SERM) like tamoxifen and raloxifene have been shown to offer protection to high risk pre- and postmenopausal women, in some cases up to 50%. The same effect is shown by another group of drugs, aromatase inhibitors or inactivators (AI), of the same magnitude in postmenopausal women.

 

Manifestation and symptoms

Breast cancer can manifest itself as:

  • A lump in the breast
  • Abnormal mammogram results
  • Altered shape or contour of the breast or of the skin and nipple.

In rare cases it manifests itself as:

  • Bloody nipple discharge
  • A metastasis to other site(s)

Symptoms are few and non-specific. Most of the time the patient reports a palpable mass in her breast or a dimple in the skin or the nipple. Pain is almost always absent. In cases of inflammatory breast cancer, the breast appears red, hot, swollen and painful symptoms that resemble those of acute mastitis.

 

Diagnosis

The cornerstone of diagnosis of any breast problem is the triple assessment. It consists of

  1. physical examination
  2. mammography, and
  3. tissue sampling.

In a patient with a palpable mass in her breast or with an abnormal non-palpable mammographic finding, a pressing question that has to be answered swiftly and confidently is: Benign or Malignant?

Also, in a patient with a diagnosed breast cancer there is always the need to know the status of the axillary lymph nodes.

The ability to take material from a breast lesion and achieve a tissue diagnosis without resorting to a formal surgical biopsy has been a great advance in the management of breast problems. It allows outpatient investigation, with substantially lower cost, with lesser inconvenience for the patient and with the potential to diagnose the majority of breast lesions at the patient’s first visit.

Such procedures include:

  • Fine Needle Aspiration Cytology (FNAC). It is performed with an ordinary needle syringe. The lesion is punctured and the material is aspirated. The obtained material is smeared onto microscope slides and air-dried or fixed. Today the cytologist can also classify the tumor and perform specialized studies. The sensitivity and specificity of FNAC is 95% and the positive predictive value 99.8%.
  • Core Biopsy. The goal is to remove a small core from the mass using a cutting needle technique (Tru-cut). It requires local anesthesia and extra care to avoid the formation of a hematoma. Multiple specimens can be obtained. The sensitivity of the technique is over 90%.

In non-palpable, mammographically detected lesions, these techniques can be applied with the guidance of ultrasound, Mammography, MRI or a dedicated stereotactic vacuum-assisted apparatus (Mammotome). If sampling is unsuccessful or not feasible, a J-wire or a tracer is left in place for a guided open biopsy.

In a woman with a confirmed breast cancer, the axillary nodes can be evaluated before any operation, through ultrasound examination, and a node that looks suspicious can be sampled with the FNAC technique mentioned above. This way we can have the full picture of the disease and plan the treatment in the best possible way.

As part of good clinical practice, a tissue diagnosis of a breast lesion is necessary before definitive surgery because the patient and doctor can discuss her treatment options and arrive to a decision that best suits her needs. If the lesion is benign the patient avoids an unnecessary surgery.

 

Breast Cancer spread and staging

The cancer (primary tumor) resides for some time in the mammary gland of the breast (local disease) growing in size and invading surrounding tissues. At a later stage its cells will acquire the ability to leave the primary tumor and spread to other parts of the body. It seems that at the beginning of this process the cancer cells prefer to spread via the lymphatic channels that from the breast will lead them to the axilla (armpit) where they will be trapped in the axillary lymph nodes (regional disease). This lymphatic spread takes place in an orderly anatomically way and the lymphatics from the breast will always reach first one node in the armpit that is responsible for “guarding” the breast. This node, the first to receive the cancer cells, is termed “sentinel node” and plays an important role in the breast cancer treatment. From this node if the cancer cells escape will invade other nodes at a higher level of the axilla. Therefore, if the sentinel node is free of malignant cells then we can assume with a certainty of 92% that the patient is free of axillary node metastases.

The cells from the primary tumor can also invade the blood stream and reach distant organs of the body and grow there what is called metastases (systemic disease). Organs most often affected are the lung, liver and the bones.

Staging is the process that immediately follows the histological diagnosis of breast cancer. The objective is to evaluate the size of the problem by measuring the volume of the tumor in the breast, if it has spread to the regional lymph nodes or to distant organs. The components of this evaluation are: the diameter of the primary tumor (T), the involvement of the axillary lymph nodes (N) and the presence of metastases (M). This process is referred to by the acronym TNM system and determines the stage of the disease.

Today more sophisticated biological factors are in use, that are called molecular prognostic and predictive factors. These can reveal accurately the biologic behavior of the tumor and foresee the patient’s response to treatment. Such factors are the estrogen (ER), progesterone (PR) and HER-2 receptors, the Ki-67 antibody, the p-53 oncogene and the cathepsin-D protease. The wide clinical use of these factors and their importance in making therapeutic decisions has affected the classification of breast cancer. We have subtypes based on molecular and not histological characteristics. They are Luminal A (ER+, PR+), Luminal B (ER+, PR-), HER-2 +/ER-, Basal like (triple negative) and Claudin low.

 

Breast Cancer treatment

The treatment modalities against breast cancer include:

  • Surgery
  • Radiation
  • Chemotherapy
  • Hormonal
  • Biological (molecular)

The choice of one of them or the combination of more than one and the sequencing of treatments is based on the patient’s preference and the characteristics of the disease (histology, molecular profile, extend). Every treatment has risks and side effects. The patient has the right to be fully informed of the condition, the advantages and disadvantages of the proposed treatment, and to be assisted in making the best choice. If the patient participates in the decision making process the collaboration with the treatment team will be better.

 

Surgery

The aim of surgery is to remove the tumor with a margin of normal tissue and at the same time maintain or restore the appearance of the breast. It is a fact that nowadays surgery is becoming less disfiguring but more efficacious. It is directed against the primary tumor in the breast, the lymph nodes in the axilla and occasionally metastases to other organs.

 

Surgery of the breast

Depending on the extent of the resection it is termed as mastectomy when the whole of the breast is removed or wide local excision (segmental mastectomy) if a part of the mammary gland (where the cancer is located) and/or skin is excised. Other terms for the same procedure are tumorectomy and quadrectomy. Although surgery becomes less radical, there are cases where mastectomy is clearly indicated, as when there is a big tumor in a small breast, when dealing with multicentric disease or if the cancer has recurred in the same breast after breast conserving surgery.

None of the above applies to the treatment of lobular carcinoma in situ (LCIS) which is usually an incidental finding in a breast biopsy done for another reason. Since it is a marker of high risk the choice is between close follow-up with or without chemoprevention and bilateral prophylactic mastectomy.

Following surgery, the breast may need cosmetic reshaping or reconstruction. This can be done on the same session with the excision or at a later stage.

 

Surgery of the axillary nodes

We have the means by injecting a radioisotope tracer (or a blue dye) in the breast to visualize and identify the node that first receives lymph from the breast (sentinel node). This one node can be excised and send to the lab for an immediate result whether it has cancer cells or not. If the sentinel node is negative no further surgery to the axilla is indicated. If it is infiltrated by cancer cells the rest of the lymph nodes of the axilla have to be removed.

 

Surgery of metastases

In carefully selected cases the removal of a breast cancer metastasis from an organ (liver, lung, brain) can offer survival or better quality of life.

In most cases surgery has to be complemented by another form of treatment.

 

 

 

Section B
by G. Lypas, M.D., Medical Oncologist

Medical Treatment for Breast Cancer

Breast cancer medical treatment may be given in women at various settings. Usual scenarios involve:

  • Before breast surgery: This is called neoadjuvant (or preoperative) therapy. It may be administered to make a large tumor smaller, in order to make surgery feasible. Neoadjuvant therapy may be an option for women who want to avoid removal of their whole breast, by shrinking their tumor so that they can have a lumpectomy. In special circumstances like “triple negative breast cancer”, neoadjuvant chemotherapy may benefit the patients more than any other treatment.
  • After breast surgery: This is usually called adjuvant (or postoperative) therapy. Even with the most extensive and more aggressive type of surgery, some breast cancer cells may remain in the body, not being detectable with the usual tests. The goal of adjuvant therapy is to kill those cells. Most women with breast cancer get some type of adjuvant therapy, in order to reduce the chances of their cancer recurrence.
  • Treatment for Metastatic/recurrent disease: It is administered in order to reduce the size and number of tumors in her body. Goal of such therapy is to prolong the patient’s life and/or improve her quality of life.

 

Chemotherapy

Most women with breast cancer receive chemotherapy. Chemotherapy is administered in order to kill cancer cells or prevent them from multiplying. There are several drugs, which have proved to be effective in breast cancer. These include doxorubicin, epirubicin, cyclophosphamide, paclitaxel, docetaxel, flourouracil, capecitabine, vinorelbin, gemcitabine, carboplatin, cisplatin, etc.

Such drugs can be given as single agents or more commonly as combinations.

Each chemotherapeutic drug has its own side-effect profile. Common problems caused by chemotherapy involve nausea (upset stomach) or vomiting, reduced blood counts (usually low white cells, corresponding to reduced defense against germs), infections, fever, headache, getting easily tired, hair loss, sore throat and mouth, diarrhea, etc.

 

Hormonal therapy

Hormonal therapy is given for breast cancers, which express hormonal receptors. Tamoxifene, letrozole, anastrozole, exemestane LHRH analogues are included in hormonal therapy medication.

Hormonal therapy is generally well-tolerated; however side effects include: osteoporosis, pain in the joints, hot flushes, blood clotting, increased risk for uterine cancer etc.

 

Targeted (or biological or molecular) therapy

Targeted (or biological or molecular) therapy involves more modern drugs, which have been designed to target only cancer cells which carry specific targets and spare healthy tissue. They do have side effects too, although they may be usually mild and manageable.

Common biological therapies for breast cancer include trastuzumab, lapatinib, TDM-1, bevacizumab, pertuzumab, everolimus etc. The strategy for medical treatment of breast cancer is different in early and metastatic stage.

 

Early Breast Cancer treatment

Adjuvant treatment (after an operation): The treatment choice will depend on several factors which will be determined after surgery. These factors include:

  1. The patient herself i.e. age, menopausal status, comorbidity, general health condition, lifestyle, preferences.
  2. Tumor biology and extent, which include:
  • The number of axillary lymph-nodes to which the breast cancer has spread.
  • The type of tissue where the cancer cells come from. Lobular breast cancer arises from breast cancer lobules (the cells which produce the milk in lactating women). Ductal breast cancer arises from the breast ducts, the small “tubes” leading the milk to the nipple. These are the most common types of breast cancer.  
  • Whether it is infiltrative or in an earlier form (called “in situ”).
  • Tumor grade: It ranges from 1 to 3. The lower the grade is, the more tumor looks normal breast gland cells. The higher it is, the more different it looks and more aggressive it is.
  • Ki-67: It is about the percentage of cancer cells that are actively multiplying.
  • Hormonal (Estrogen & Progesterone) Receptors: when tumor cells express many of these molecules, they may be sensitive to hormonal therapy (such as tamoxifen, anastrozole, letrozole, exemestane etc.)
  • HER2 (or c-erb-B2) Receptors: when breast cancer cells express many of these receptors, they may be more sensitive to special drugs (such as trastuzumab, lapatinib etc).
  • Other factors, routinely reported, include whether the tumor infiltrates blood vessels, lymphatic vessels, nerves and skin.
  • The Pathology report also provides information on “tumor margins”, i.e. how much healthy tissue surrounding the tumor was removed by surgery. When a layer of sufficient healthy tissue covers the removed tumor, the chances that cancers cells may be left back are lower.

 

Tumor genetic signature

During the last few years, sophisticated tests have been developed. These tests explore the tumor’s biology by looking into its genes. Such tests are called “gene signatures”, and are used to help the physician and the patient to select appropriate therapies and avoid unnecessary ones. For example, a 21-gene signature helps identify patients for whom hormonal therapy will be sufficient, and who will not get additional benefit from chemotherapy, thus they may avoid it. This test is usually done in patients with Hormonal Receptor positive, HER-2 negative and axillary nodes without infiltration.
The decision for treatment is taken based on these factors.

The most common chemotherapy drugs include Cyclophosphamide, Doxorubicine and Taxanes. For HER-2 positive cases, the monoclonal antibody Trastuzumab is added for one year after chemotherapy.

For patients with Estrogen Receptor positive tumors (ER+), hormonal therapy is given, following chemotherapy for several years. Hormonal treatment alone without chemotherapy is usually given in more indolent cases or more elderly patients.

 

Adjuvant radiotherapy

Depending on the tumor’s stage, most women who have their tumor removed, but not their whole breast, need radiotherapy. In some cases radiotherapy may be required for women who have had a mastectomy and have more than 3 infiltrated axillary lymph nodes.

 

Metastatic Breast Cancer

The case of metastatic breast cancer indicates that cancer has spread to other organs.
The type of treatment will depend on:

  • the patient’s age
  • time interval since the initial diagnosis
  • extent of disease
  • the visceral organs which have been involved.


The choice of the drugs, however, depends on the biological characteristics of the initial biopsy or the repeat biopsy from any metastatic site. Hormonal receptors and the presence of HER-2 will play an important role for the decision.
Therefore, hormonal treatment, chemotherapy and targeted therapy are all options available for the patients. These may be given alone or in combination.
Radiotherapy is very important for palliation. Additionally, bisphosphonates are helpful for bone metastasis and Epoetin for anemia.

 

Content on this site is not a substitute for professional medical advice. You should always consult your doctor.