BREAST CANCER

INTRODUCTION

Cancer, also known as a malignant tumor or malignant neoplasm, is a group of disease involving abnormal cell growth with the potential to invade or spread to other parts of the body.

Six characteristics of cancer have been proposed:

  • Self-sufficiency in growth signaling
  • Insensitivity to ant-growth signals
  • Enabling of a limitless replicative potential
  • Evasion of apoptosis
  • Induction and sustainment of angiogenesis
  • Activation of metastasis and invasion of tissue

Breast cancer is a form of cancer that develops from breast tissue.

SIGNS AND SYMPTOMS

The first noticeable symptom of breast cancer is typically a lump that feels different from the rest of the breast tissue. The earliest breast cancers are detected by a mammogram. Lumps found in lymph nodes in the armpits can also indicate breast cancer.

Other indications include:

  • Thickening difference of one breast tissue from the other
  • One breast becoming larger or lower
  • A nipple changing position, shape or becoming inverted
  • Skin puckering or dimpling
  • A rash on or around a nipple
  • Discharge from the nipple(s)
  • Constant pain in part of the breast or armpit
  • Swelling beneath the armpit or around the collar bone.

Occasionally, breast cancer presents as metastatic disease. The symptoms caused by metastatic breast cancer will depend on the location of metastasis. Common sites of metastasis include: bone, liver, lungs, and brain. Unexplained weight loss can occasionally herald an occult breast cancer, as can symptoms of fevers or child. Bone or joint pains can sometimes be manifestations of metastatic breast cancer, as can jaundice or neurological symptoms. These symptoms are called non-specific, meaning they could be manifestations of many other illnesses.

RISK FACTORS

The primary risk factors of breast cancer are female sex and older age. Other potential risk factors include;     

  • Genetics
  • Lack of childbearing or lack of breast feeding
  • Higher levels of certain hormones
  • Certain dietary patterns
  • Obesity
  • Recent studies have indicated that exposure to light pollution is a risk factor for the development of breast cancer.
  • Smoking tobacco appears to increase the risk of breast cancer. The greater the amount smoked and the earlier in life that smoking began, the higher the risk.
  • Lack of physical activity has been linked to about 10% of cases.

  DIAGNOSIS

Most types of breast cancer are easy to diagnose by microscopic analysis of a sample or biopsy of the area of the breast.

The two main commonly used screening methods, physical examination of the breast by a healthcare provider and mammography, can offer an approximate likelihood that a lump is cancer, and can also detect some other lesions such as a simple cyst.

When these examinations are inconclusive, a healthcare provider can remove a sample of the fluid in the lump for microanalysis (a procedure known as fine needle aspiration, or fine needle aspiration and cytology) to help establish the diagnosis.

Other options for biopsy include a core biopsy or vacuum assisted breast biopsy, which are procedures in which a section of the breast is removed; or an excisional biopsy in which the entire lump is removed

CLASSIFICATION

Breast cancer is classified by several grading systems. Each of these influences the prognosis and can affect treatment response. Description of breast cancer optimally includes all these factors;

  • Histopathology
  • Grade
  • Stage
  • Receptor status
  • DNA assays

PREVENTION

Women may reduce their risk of breast cancer by;

  • Maintain a healthy
  • Drinking less alcohol
  • Being physically active
  • Breast feed their children
  • Marine omega-3 polyunsaturated fatty acids appear to reduce the risk.
  • Removal of both breasts (prophylactic bilateral mastectomy) may be considered in people with BRCA1 and BRCA2 mutations.

BRCA testing is recommended in those with high family risk after genetic counseling.

MANAGEMENT OF BREAST CANCER

The management of breast cancer depends on various factors; including the stage of the cancer and the age of the patient. Increasingly aggressive treatments are employed in accordance with the poorer the patient’s prognosis and the higher the risk of recurrence of the cancer following treatment.

Breast cancer is usually treated with surgery, which may be followed by chemotherapy or radiation therapy or both. A multidisciplinary approach is preferable.

Hormone receptor-positive cancers are often treated with hormone blocking therapy over courses of several years. Monoclonal antibodies or other immune modulating treatments may be administered in certain cases of metastatic and other advanced stage of breast cancer.

SURGERY

Surgery involves the physical removal of the tumour, typically with some of the surrounding tissue. Standard surgeries include;

  • Mastectomy
  • Quadrantectomy
  • Lumpectomy

Once the tumour has been removed, if the patient desires, breast reconstruction surgery may be performed to improved the aesthetic appearance of the treated site.

Alternatively, women use breast prostheses to stimulate a breast under clothing, or choose a flat chest. Nipple/areola prostheses can be used at any time following mastectomy.

MEDICATION

Drugs used after and in addition to surgery are called adjuvant therapy. Chemotherapy or other types prior to surgery are called neo adjuvant therapy.

There are 3 main groups of medications used for adjuvant breast cancer treatment.

  • Hormone blocking agents
  • Chemotherapy
  • Monoclonal antibodies

HORMONE BLOCKING AGENTS

Some breast cancers require oestrogen to continue growing. They can be identified by the presence of oestrogen receptors (ER+) and progesterone receptors (PR+) on their surface (sometimes refrred to together as hormone receptors). This ER+ can be treated with drugs that either block the receptors, e.g tamoxifen, or alternatively block the production of oestrogen with an aromatase inhibitor, e.g anastrozole, letrozole.

Aromatse inhibitors, however, are only suitable for post menopausal patients.

This is because the active aromatase in postmenopausal women is different from the prevalent from in premenopausal women and therefore these agents are ineffective in inhibiting the predominant aromatase of premenopausal women.

Tamoxifen (nolvadexm istubal, valodex, genox)   

Tamoxifen is an antagonist of oestrogen receptor in breast tissue via its active metabolite, 4-hydrotamoxifen. However, it behaves as an agonist in the endometrium, and thus may be characterized as a selective oestrogen receptor. It is also approved by the FDA for the prevention of breast cancer in women at high risk of developing the disease. It has been further approved for the reduction of contra lateral (in the opposite breast) cancer.

Mechanism of action

Tamoxifen itself is a prodrug, having relatively little affinity for its target protein the oestrogen receptor. It is metabolized such as hydroxytamoxifen (afimoxifen) and N-desmethyl-4-hydroxytamoxifen 9endoxifen) which have 30-100 times more affinity with the oestrogen receptor that tamoxifen itself.

These active metabolites compete with oestrogen in the body for binding to the estrogen receptor. In breast tissue, 4-hydroxytamoxifen acts as an estrogen receptor antagonist so that transcription of oestrogen-responsive genes is inhibited.

Side effects

  • Some cases of lower limb lymphedema have been associated with the use of tamoxifen, due to the blood clots and deep vein thrombosis (DVT) that can be caused by this medication.
  • A beneficial side effect of tamoxifen is that it prevents bone loss by acting as an oestrogen receptor agonist (i.e. mimicking the effects of oestrogen) in this cell type.
  • It has been linked to endometrial cancer in women.
  • Tamoxifen treatment of postmenopausal women is associated with beneficial effects on serum lipid profiles. However, long term data from clinical trials have failed to demonstrate a cardio protective effect. For some women tamoxifen can cause a rapid increase in triglyceride concentration in the blood. Tamoxifen is also a cause of fatty liver, otherwise known as steatorrhoeic hepatosis or steatosis hepatis.
  • Tamoxifen treatment breast cancer patiens show evidence of reduced cognition, a major side effect of tamoxifen and semantic memory scores. However, memory impairment in patients treated with tamoxifen was less severe compared with those treated with anastrozole.

A significant number of tamoxifen treated breast cancer patients’ experience a reduction of libido.

Pharmacogenetics and drug interaction      

Patients with Variant forms of the gene CYP2D6 may not receive full benefits from tamoxifen because of too slow metabolism of the tamoxifen, as these drugs can compete metabolite 4-hydroxytamoxifen.

Recent studies suggest that taking SSRIs antidepressants paroxetine, fluoxetine and setraline can decrease the effectiveness of tamoxifen, as these drugs can compete for the CYP2D6 enzyme which is indeed to metabolized tamoxifen into the active form.

ANASTRAZOLE   

It’s a non steroidal aromatic inhibiting drug approved for the treatment of breast cancer after surgery, as well as metastasis in both pre and post menopausal, as sex hormones cause hyperplasia, and differentiation at oestrogen receptor sites. Anastrazole works by inhibiting the synthesis of oestrogen.

Mechanism of action

Anastrozole binds reversibly to the aromatase enzyme through competitive inhibition, inhibits the conversion of androgens to oestrogen in peripheral tissues.

Bone weakness has been associated with anastrozole. Women who switched to anastrazole after 2 years on tamoxifen reported twice as many fractures as those who continued to take tamoxifen (2.1% compared to 1%).

Biphosphates are sometimes prescribed to prevent the osteoporosis induced by aromatase inhibitors.

CHEMOTHERAPY

Chemotherapy is predominantly used for cases of breast cancer in stages 2-4, and is particularly beneficial in oestrogen receptor negative (ER+) disease. The chemotherapy medications are administered in combinations, usually for periods of 3-6 months. One of the common requirements known as ‘AC’ combines cyclophosphamide with doxorubicin. Sometimes a taxane drug, such as docetaxel is added and the regimen is then known as ‘CAT’.

Another common example is cyclophosphamide, methotrexate and fluorouracil (or CMF). Most chemotherapy medications work by destroying fast growing and/ or fast replicating cancer cells, either causing DNA damage upon replication or other mechanisms. However, the medications also damage fast growing normal cells, which may cause serious side effects. Damage to the heart muscle is the most dangerous complication of doxorubicin.

CYCLOPHOSPHAMIDE

The main effect of cyclophosphamide is due to its metabolite phosphoramide mustard. The metabolite is only formed in cells that have low levels of ALDH. Phosphoramide mustard forms DNA crosslinks both between and within DNA strands at guanine N-7 positions. This is irreversible and leads to cell apoptosis.

Side effects

Adverse drug reactions from cyclophosphamide are related to the cumulative medication dose and include;

  • Chemotherapy
  • Bone marrow suppression
  • Stomach ache
  • Hemorrhagic cystitis
  • Diarrhea
  • Darkening of the skin/nails
  • Alopecia

DOXORUBICIN

Mechanism of action

Doxorubicin acts by interacting with DNA by intercalation and inhibition of macromolecular bio-synthesis.

Side effects

The most serious adverbs effect being life-threatening heart damage. Others include hair loss, myelosuppression, oral muositis, oesteophagitis, diarrhea, skin reactions and localized swelling and redness along the vein in which the drug is delivered. Less common yet serious reactions include hypersensitivity reactions (including anaphylaxis), radiation recall, heart damage and liver dysfunction.

Methotrexate

Mechanism of action

It cats by inhibiting the metabolism of folic acid.

Side effects

Hepatotoxicity, ulcerative stomatitis, low white blood cell count and thus predisposition to infection, nausea, abdominal pain, fatigue, fever, dizziness, acute pnemonities and kidney failure.

FLUOROURACIL

5-Fluorouracil acts in several ways but principally as a thymidlate synthase inhibitor. Interrupting the action of this enzyme blocks synthesis of the pyrimidine thymidine, which is a nucleoside required for DNA replication.

MONOCLONAL ANTIBODIES

Trastuzumab, a monoclonal antibody to HER 2 (a cell receptor that is especially active in some breast cancer cells), has improved the 5 years disease free survival of stage 1-3 HER2 –positive breast cancer to about 87%. When stimulated by certain growth factors, HER 2 causes cellular growth division; in the absence of stimulation by the growth factor, the cell will normally stop growing. Between 25-30% of cancers over express the HER2 gene or its protein product and over expression of HER2 in breast cancer is associated with increased disease recurrence and worse prognosis. When trastuzumab binds to prevents growth factors from being able to bind to and stimulate the receptors, effectively blocking the growth of the cancer cells. Trastuzumab, however, is very expensive and its use may cause serious side effects (approx 2% of patients who receive it suffer significant heart damage). Further, transtuzumab is only effective in patients with HER2 amplification/over expression.

RADIATION      

Radiology is given after surgery to the region of the tumour bed and regional lymph nodes, to destroy microscopic tumour cells that have escaped surgery. Radiation therapy can be delivered as external beam radiotherapy or as brachytherapy (internal radiotherapy). Conventionally radiotherapy is given after the operation for breast cancer. Radiation can also be given at the time of operation on the breast cancer intra operatively.

PALLIATIVE CARE   

Palliative care refers to treatment that attempts to make the person feel better  and  may not be combined with an attempt to treat the cancer. Palliative care includes action to reduce the physical, emotional, spiritual and psychosocial distress experienced by people with cancer. Unlike treatment that is aimed at direct killing cancer cells, the primary goal of palliative care is to improve the person’s quality of life.

People at all stages of cancer treatment should have some kind of palliative care to provide comfort. In some cases, medical specialty professional organizations recommend that people and physicians respond to cancer only with palliative care and not with cure-directed therapy. This includes;

  • People with low performance status, corresponding with limited to care for themselves.
  • People who received no benefit from prior evidence – based treatments.
  • People who are not eligible to participate in any appropriate clinical trial
  • People for whom the physician sees no strong evidence that treatment should be effective.

   PSYCHOLOGICAL ASPECTS

The emotional impact of cancer diagnosis, symptoms, treatment and related issues can be severe. Larger hospitals are association with cancer support groups which provide a supportive environment to help patients cope and gain perspective from cancer survivors.

Not all breast cancer patients experience their illness in the same manner. Factors such as age can have a significant impact on the way a patient copes with a breast cancer diagnosis. Premenopausal women with oestrogen receptor positive breast cancer must confront the issues of early menopause induced by many of the chemotherapy regimens used to treat their breast cancer, especially those that use hormones to counteract ovarian function.

HORMONES

CONTRACEPTION

In breast cancer survivors, non-hormonal contraceptive methods should be used a first line options. Progestogen-based methods depot meddroxyprogesterone acetate, IUD with progestogen or progestogen only pills have a poorly investgated but possible increases risk of cancer recurrence, but may be used if positive effects outweigh this possible risk.

MENOPAUSAL HORMONE REPLACEMENT

In breast cancer survivors, it is recommended to first consider  non-hormonal options for menopausal effects, such as biphosphonates or selective oestrogen recptor modulators (SERMs) for osteoporosis and vaginal oetrogen for local symptoms. Observational studies of systemic hormone replacement therapy after breast cancer are generally reassuring. If hormone replacement is necessary after breast cancer oestrogen only therapy or oestrogen therapy with an intrauterine device with progestogen may be option than combined systemic therapy.

 

 

 

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