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BREAST CANCER

 The most prevalent type of cancer in females but it is the  second leading cause of death.

 Risk Factors

  1. Family history - two to four fold increase in risk for breast cancer among women with one or more first-degree relatives with the disease. First degree families could be paternal or maternal
           1. Hereditary Breast/Ovarian Cancer Syndrome (BRCA1) gene:        found on the longer arm of chromosome 17

    a. BRCA2 Gene:
    - localized to the long arm of Chromosome 13
    - Also associated with male breast cancer
    - prostate and pancreatic cancers

    b. Li-Fraumeni Syndrome:
    - associated with breast cancer (1%)
    - childhood sarcomas
    - brain tumors
    - leukemias
    - adrenocortical carcinomas.
    - Inheritance is autosomal dominant

    c. Cowden Syndrome:
    1. Associated with skin manifestations
    2. Breast cancer
    3. Gastrointestinal cancers
    4. Thyroid disease
    5. Caused by mutation in the PTEN (Protein Tyrosine Phosphates with homology to tensin) gene located on chromosome 10

  2. Previous history of breast , ovarian and endometrial cancers
  3. Geographical location - highest incidence in N. America
  4. Age - Over age 45 common in whites; under age 40 common in blacks
  5. Early menstruation and late menopause. Abortion does NOT increase risk of breast cancer.
  6. Oral contraceptives and breast cancer have no known association with the development of this cancer
  7. Obesity also increases risk
  8. Exposure to radiation
           a. Patients treated for Hodgkins's disease using mantle radiation tend to have medial breast cancer lesions
  9. Diet - high fat diet increases breast cancer risk
  10. Alcohol - There are conflicting reports on this issue
  11. Short duration of breast feeding or none at all increases risk.

 
 Screening Guidelines National Comprehensive Cancer Network  Guidelines for Familial Breast Cancers

  1. Annual mammography starting at age 20-25 (30 years in patients with Cowden Syndrome)
  2. Semi-annual clinical breast exam starting at 20-25 years.
  3. Training in self-breast examination starting at age 25
  4. Prophylactic care to be discussed with patients on a case by case basis
  5. Annual comprehensive examination starting at age 20-25 years (18 years in patients with Cowden's Syndrome)
  6. Target surveillance based on family histories
  7. Prophylactic mastectomy/oophorectomy confers about 90% reduction in the incidence of breast cancer.
  8. Male patients require annual mammogram and clinical breast examinations.

 
 Presentation

  1. 85% of newly diagnosed cases are detected as breast lumps
  2. Some breast cancers are detected on routine mammography
  3. Bloody breast discharge, skin dimpling, nipple refractions are other forms of presentations
  4. Some breast cancers present with metastases at diagnosis
  5. General screening guidelines include
    a. Self breast examinations
    b. Clinical examinations
    c. Radiological imaging techniques, e.g., mammography (especially useful in reducing breast cancer mortality in women over 50 years).

 
 Pathologic Classification of Breast Cancer

  1. Two broad terms
    d. Non-invasive breast cancer
    e. Invasive breast cancer

     Non-invasive Breast Cancer

    1. Two main sub-divisions:
      f. Lobular carcinoma in-situ (LCIS)

      i. Cancer is confined to one or more mammary lobules without basement membrane invasions
      ii. Common in pre-menopausal women
      iii. It is usually multi-centric
      iv. Risk of bilateral breast involvement is high
      v. May progress to invasive carcinoma

      g. Ductal Carcinoma in-situ (DCIS)

      i. Ductal proliferation of cancer cells without invasions
      ii. The "comedo" type of DCIS has a central tissue lesions and this histology portends a poorer prognosis (increased incidence of recurrence).
      iii. Maxillary lymph node involvement is lower

 Invasive Breast cancer

  • The most common type is invasive ductal cancer
  • Paget's disease of the nipple is a form of invasive DCIS in which case there is invasion of the ducts and the epidermis of the areola

     Poor Prognostic Factors in Breast Cancer

  • Lymph node involvement - the most important factor
  • Tumor size - prognosis is worse with increased tumor size
  • Vascular invasion o Negative estrogen and progesterone receptor status
  • Increased cell proliferation indices (S-phase, K1-67, Thymidine labeling index) Increased growth factors/receptors: Her2/neu, EGRF (epidermal growth factor), TGF (Tumor growth factor), however increased Her2/neu factor is predictive of response to anthracycline based regimen. Somatostation receptor, if present is indicative of better prognosis Angiogenesis: If there is increased density of microvessels in the malignant tissue, prognosis is worse.
  • The role of Ca15-3 (or CA27-29) if considered separately is not clear. It may be used as a baseline marker and when considered in conjunction with the other biological, clinical and pathological factors, could be important in making decisions in the follow-up of these patients.

 MANAGEMENT OF BREAST CANCER
  • Consists of the following treatment modalities:
  • Treatment in any patient may involve the use of one or more of these: i. Surgical Management
  • An initial biopsy is required to make a diagnosis
  • This could be in the form of fine needle aspiration (FNA), excisional biopsy of the breast or biopsy of metastatic sites
  • Definitive surgical procedures include:
    1. radical mastectomy, modified radical mastectomy
    2. axillary lymph node dissection (total).
    3. Sentinel node concept is fast gaining popularity
    4. Breast preservation procedures e.g. lumpectomy, tumorectomy, quandrantectomy.
    Note: Breast conservation procedures and mastectomy plus axillary lymph node dissection have equivalent end points in terms of survival in clinical trials. However, radiation therapy must be given in patients with breast conservation procedures In patients with mastectomy/lumpectomy margins of resection should be negative for tumor. If not, additional therapy will be required (e.g. mastectomy in a patient with previous lumpectomy, wider excision if cosmetically possible, radiation therapy, chemotherapy, hormonal therapy, etc.)
 1. Radiation Therapy (PT)
  • Necessary in patients with breast conservation procedures
  • May also be used in patients with local recurrence
  • The effect of RT in patients with multiple lymph node involvement on survival is yet to be seen but it reduces local recurrence
  • For palliative treatment of metastatic deposits in bones, soft tissues, brain
  • Cord compression requires RT in addition to the use of steroids and pain medications

 2. Chemotherapy

  • Upfront chemotherapy in patients with Stage III breast cancer before definitive surgery is performed
  • CMF (cyclophosphamide, methotrexate, 5-fluoruracil) is preferred in none-negative patients. Six cycles of CMF is equivalent to 4 cycles of CAF (Cyclophosphamide, Adriamycin and 5-Fluorouracil)
  • High dose chemotherapy with peripheral blood stem cell transplant is evolving but there is no effect on prolongation of survival , according to a recent report.
  • Taxanes are being increasingly used (paclitaxel and Docetaxel)
  • Taxanes are being used as single agents or in combination with antrhacyclines

 3. Hormonal Therapy

  • The first line hormonal agent is Tamoxifen
  • Used in ER/PR receptor positive post-menopausal and pre-menopausal patients
  • ER/PR receptor negative pre-menopausal patients should be given chemotherapy
  • Elderly patients benefit from hormonal therapy whether they are ER/PR receptor positive or negative.
  • Second line hormonal agents include: a. Aromatase inhibitors which may be -Reversible non-steroidal inhibitors of Aromatase e.g., Letrozole and Anastrazole -Irreversible aromatase inhibitors, e.g. Exemestane

 4. Other Agents

  • Angiogenesis inhibitors a. Thalidomide - given in low doses was tried in breast cancer patients in the United Kingdom
    b. AE-941 is another agent being tried in Canada
  • HER-2 Receptor Antibody (HERCEPTIN) produces a 15% response rate as a single agent. Use is indicated in patients who express HER-2 receptors Combinations of Herceptin + Taxol Carboplatin and Herceptin + Anthracyclines have to be evaluated in randomized, double blinded controlled trials.

 
 FOLLOW - UP

  • self breast examination
  • clinical breast examination.
  • annual chest xray, mammogram, pap smear ( in patients who are on hormonal therapy).