Breast Cancer Facts

David Brown, MD
http://medical-library.com

Breast Cancer: Practical Considerations and Future Approaches

Breast cancer is the most common form of cancer in women. There are close to 200,000 new cases of breast cancer a year, and this results in about 47,000 deaths per year, although the mortality has fallen slightly in the 1990s.

The etiology of breast cancer remains unknown but at least two breast cancer genes have been cloned–the BRCA-1 and the BRCA-2 genes. Only about 10% of all breast cancers can be explained by hereditary mutations in these genes. Most of the sporadic cases, the other 90% of the cases of breast cancer, do not seem to have mutations in these genes so there does not seem to be a common pathway gene for both sporadic and hereditary cases.

The lifetime risk of breast cancer is one in eight for a woman who is age 20. Breast cancer is a disease that increases significantly with increasing age. Breast cancer in young patients under age 50 is still a relatively rare event compared to the cumulative lifetime risk. For patients under age 60, the chance of being diagnosed with breast cancer is 1 in about 400 in a given year.

Epidemiology and Risk Factors for Breast Cancer

A. Breast cancer is the most common cancer in women

B. Approximately 185,000 new cases this year and 47,000 deaths

C. Etiology is unknown

D. Most cases are sporadic; about 10% are apparently hereditary

1. BRCA-1 gene now localized on 17th chromosome, long arm

2. BRCA-2 gene (probable) on chromosome 13

3. It is unclear what role mutations in these genes play in sporadic cases

Risk Factors for Breast Cancer
Factor	Direction of association
Demographic features
Female gender	Increase
Increased age	Increase
Oriental heritage	Decrease
Occidental residence	Increase
Characteristics of the menstrual cycle
Early menarche	Increase
Late menopause	Increase
Oophorectomy	Decrease
Characteristics of pregnancy
Early first birth (age <25y)	Decrease
Further births at age <25y)	Decrease
Late first birth (age >30y)	Increase
Further births at age (>30y)	Increase
Other characteristics
Family history of breast cancer	Increase
History of benign breast disease	Increase
Increased height	Increase
Increased weight	Increase
Use of replacement estrogens |	Increase
Exposure to ionizing radiation |	Increase
Alcoholic beverage consumption	Increase

Breast Cancer - Screening

A. Mammography and physical examination are complementary

1. 1. Mammography is more sensitive, but false negative rate of approximately 15%.
2. 2. Physical examination is quite sensitive to lesions over 1 cm.
3. 3. Mammographic screening
   a. Decrease in mortality with mammography in women 50 and older is accepted.
   b. A similar impact on mortality in women ages 40-50 has not been established.
   c. No evidence for value of "baseline" study at age 35.
   d. Screening Guidelines
   
   • i. Begin physical examination at or before age 40.
   • ii. Mammography before 50 if: a) personal history of breast cancerb) family history of early breast cancerc) hard to examine
   • ii. Annual physical examination and mammography from age 50

4. Breast self-examination recommended monthly after age 20

Evaluation of a Palpable Mass

A. A palpable mass requires explanation, even if mammogram is negative.

B. Ultrasound may determine that lesion is a cyst, but strict criteria must be used.

C. Needle aspiration, needle bx, excisional bx are all acceptable procedures but the method used must establish specific diagnosis.

Management of Cancer in the Breast

A. Approximately 20% of breast cancers are non-invasive; incidence of non-invasive cancer is increasing with increasing application of mammography.

1. 1. These lesions are confined to the walls and lumens of ducts (ductal carcinoma in situ or DCIS) or of the lobules (small, terminal ducts) (lobular carcinoma in situ or LCIS).
2. 2. LCIS is more appropriately considered a pre-malignant condition, a marker of increased risk of developing ductal carcinoma anywhere in either breast at an approximate frequency of 1% per year. The management of LCIS is generally close follow-up without specific rx; the only rational alternative is bilateral mastectomy.
3. 3. DCIS is a pre-invasive malignancy with a risk of progression to invasive cancer in that anatomic region of the breast of at least 30%.

a. The NSABP trial suggests lumpectomy (excisional bx) and breast radiation may be an alternative to mastectomy, but follow-up is short (NEJM 1993; 328:1581-86).

b. Uncertain whether wide excision alone, with or without tamoxifen, is a safe and effective alternative that might avoid the need for mastectomy or breast radiation--presently under study.

B. Invasive ductal or lobular breast cancer (infiltrating ductal or lobular carcinoma)

1. Primary radiation therapy following lumpectomy is equivalent to mastectomy in disease-free and overall survival.
2. Patients with extensive DCIS in addition to invasive cancer, those with an occult primary tumor, and those whose potential for a good cosmetic outcome with breast conservation has been decreased by excisional bx (e.g. large tumor in a small breast) are better candidates for mastectomy, with or without reconstruction which may be done immediately.
3. Chest wall radiation after mastectomy will decrease local recurrence but does not improve overall survival. This is usually reserved for patients with 4 or more positive axillary nodes, in whom the risk of local recurrence despite mastectomy is high.

Breast Cancer - Adjuvant Systemic Therapy

A. Mortality from breast cancer results from systemic spread of disease prior to local treatment.

B. Axillary node involvement and certain features of the primary tumor can be used to predict risk of occult distant spread.

C. Meta-analysis of all published trials of adjuvant breast cancer treatment was performed in 1990; approximately 30,000 women had received tamoxifen and 9,000 received chemotherapy in this analysis (Lancet 1992;3391:1-5,71-85).

1. Chemotherapy produced a statistically significant reduction in recurrence and in mortality in women up to age 59.
2. Tamoxifen produced statistically significant reduction in recurrence and in mortality in women 40 and older.
3. The benefits observed for both forms of adjuvant therapy were greater during years 6-10 of follow-up than during the first 5 years.
4. The proportional reduction in recurrence and in mortality for both tamoxifen and chemotherapy was constant across all nodal subsets (0, 1-3, 4 or more positive nodes).

D. One half of all women with breast cancer are node negative; the overall survival in this group is approximately 70% at 10 years.

1. 1. Prognostic factors which suggest and adverse outcome in node negative women include larger tumors, high nuclear grade, vascular or lymphatic invasion, high mitotic activity (high S phase).

E. All node positive and most node negative women receive adjuvant therapy.

Follow-up after Primary Therapy

A. Most recurrences found by patients, not tests.

B. Routine bone scans, CT scans, chest x-rays are not indicated in patients without symptoms or signs; probably little value in routine blood tests--eg, liver function, tumor markers.

C. Annual mammography is important--new tumors in (either) breast may be curable as well as local breast recurrence after radiation therapy.

D. Suggest interval history and physical exam every 3-6 months.

Management of metastatic breast cancer

A. Cannot yet be considered curable; survival duration extremely variable, may be many years.

B. Hormone therapy in patients with positive estrogen receptor, long disease-free interval, and metastases to skin, nodes, bone.

C. Chemotherapy for ER negative, short disease-free interval, visceral involvement, refractory after hormone therapy.

D. Palliative X-ray therapy, especially to bone, is often very useful.

E. High dose chemotherapy with hematologic reconstitution using growth factors plus peripheral blood progenitor cells and/or marrow autografts.

1. Increasingly used but still lacking adequate controlled data on efficacy.
2. Is not indicated for refractory and/or heavily pretreated patients; essentially no long term disease-free survival in that setting.
3. Best results are as first treatment of metastatic disease after induction (proving responsiveness) with standard chemotherapy; young patients with minimal sites of disease, minimal volume of disease, no liver disease, no skeletal involvement are the best candidates.
   
   • Even in this most favorable small subset of metastatic breast cancer, continuing complete remissions achieved in only 20-40% of those transplanted.
   • It is unknown if whether "double transplants", marrow pursing can improve results.

F. On the horizon: clinical testing of compounds that specifically antagonize growth factors or block growth factor receptors.