From BMT Newsletter May1994 Issue # 23 - Breast Cancer Reprinted by NYSERNet with Permission from BMT Newsletter
Breast cancer is the most frequently diagnosed cancer in women. The American Cancer Society estimates that in 1994, 182,00 new cases of breast cancer and 46,000 deaths will be reported. One thousand new cases and 300 deaths due to breast cancer will occur in men.
Most cases of breast cancer are diagnosed at an early stage of the disease while the tumor is still small and breast cancer cells are not detectable in other parts of the body. If diagnosed early, breast cancer is treatable and often curable. However, once there's evidence that the cancerous cells have "metasta-sized" or spread to the Iymph nodes, liver, lungs, bone marrow or brain, treatment is more difficult and cure less likely.
Symptoms of breast cancer include a lump in the breast, or a persistent thickening, swelling or dimpling of the breast. In some cases there may be skin irritation, scaliness, pain, nipple tenderness or nipple discharge.
Women over the age of 40 are at greater risk of developing breast cancer than younger women. Other risk factors include a family history of breast cancer, early age at menarche (beginning of menstrual periods), late age at menopause, no children or late age at the birth of the first child.
Breast cancer may be localized (detectable in the breast only), regional (observed in the Iymph nodes under the arm as well as the breast) or metastatic (detectable in other major organs such as the brain, lungs, bone marrow or liver). Ninety three percent of patients diagnosed with disease confined to the breast will be alive 5 years after diagnosis, up from 78 percent in the 1940s. For those diagnosed with breast cancer limited to the breast and draining Iymph nodes. the 5-year survival rate is 72 percent. Only 18 percent of women with metastatic breast cancer at the time of diagnosis survive 5 years.
Four stages are used to describe the extent of disease in breast cancer patients. In Stage I, the tumor is small (less than 2 cm) and there's no evidence that the cancer has spread beyond the breast. Patients with Stage II breast cancer include those with larger tumors (2-5 cm) and those whose disease has spread to the axillary Iymph nodes under the arm. In Stage III, the tumor is larger than 5 cm or is adhering to the wall of the chest. Metastatic breast cancer - cancer that has spread to the liver, lungs, bone marrow and/or brain - is classified as Stage
More than 80 percent of breast cancer patients are initially diagnosed when the disease is in an early and treatable stage. The tumor is removed by a lumpectomy or mastectomy, depending on the size of the tumor and breast, the location of the tumor, and patient and physician preference. If a patient has poor prognostic features, i.e., clinical and laboratory test results that indicate the disease will probably recur, follow-up with "adju- vant" or "consolidation" chemotherapy is recommended. Traditionally this has consisted of several rounds of combina- tion chemotherapy administered over a 4 to 12 month period on an outpatient basis. If tamoxifen is recommended, therapy usually continue for at least 5 years.
More than 80 percent of breast cancer patients are initially diagnosed when the disease is in an early and treatable stage.
Even after consolidation chemotherapy, more than 50 percent of women with poor prognostic features will relapse. Those at greatest risk of relapse are women with ten or more cancerous Iymph nodes, and those with inflammatory breast cancer which is evidenced by a diffuse redness or dimpling of the breast. Other less significant risk factors include a tumor size greater than 2 cm and tumor cells that are estrogen receptor negative (i.e., the cells do not have receptors on their surface that bind estrogen). If the breast cancer is "node negative", i.e., has not infiltrated the Iymph nodes, the risk of relapse is greater if the tumor cells have an "S-phase" greater than 6 percent (a measure of the frequency with which cells produce DNA and protein) or "abnormal ploidy" (a measure of DNA content in tumor cells).
Once breast cancer has spread or metastasized to the liver, lungs, brain or bone marrow, it is usually not considered curable. Thus, researchers have been investigating whether administering very high doses of chemotherapy followed by an autologous bone marrow transplant (ABMT) or a peripheral stem cell trans- plant (PSCT) (see box on page 2) can cure or prolong survival for Stage IV metastatic breast cancer patients, as well as Stage II and Stage III breast cancer patients at high risk of relapse.
In the early 1980s, several research teams noted a relationship between the amount of chemotherapy administered to breast cancer patients and the length of disease-free survival. Clinical trials were initiated to determine whether very high doses of chemotherapy followed by a BMT could increase the remission rate and duration of long term survival in Stage IV metastatic breast cancer patients for whom standard therapy was unlikely to provide a cure.
Each of the early trials involved only a small number of patients, many of whom had refractory cancer - cancer that did not respond to prior chemotherapy. The results of trials were encouraging in that many patients, including some who previously did not respond to chemotherapy, achieved a complete or partial remission of their disease. However, the remissions were short-lived and the incidence of fatal complications such as infection or liver disease was high.
Further trials followed, testing various combinations of chemotherapy and an autologous bone marrow transplant on a larger number of Stage IV metastatic breast cancer patients. The risk of treatment-related death fell significantly during this period due to better infection control procedures, and the use of colony-stimulating factors and peripheral stem cells to speed the recovery of bone marrow. Although 50-75 percent of patients in the studies achieved a remission of their disease, long term complete remissions were observed in only 10 to 25 percent of patients.
It is clear from these studies that a small, but definite subset of patients with metastatic breast cancer can achieve prolonged disease-free survival following high dose combination chemotherapy and an autologous bone marrow transplant. Which patients are most likely to benefit has yet to be determined.
In an effort to improve upon early results, researchers are currently exploring two strategies: (a) giving Stage IV breast cancer patients an "induction" or preliminary round of standard dose chemotherapy before administering high dose chemotherapy and a bone marrow transplant and (b) treating high risk Stage II and Stage III breast cancer patients with high dose chemotherapy and an autologous bone marrow transplant before the disease metastasizes. The theory behind both approaches rests on the widely accepted principle that cancer is more responsive to chemotherapy when the "tumor burden" or number of cancerous cells in the body is small. If the tumor burden can be decreased with an initial round of chemotherapy or treated at Stage II or III when it is still small, researchers theorize that the high dose chemotherapy will be more effective against the remaining cancerous cells. Preliminary study results have been very encouraging.
A recent analysis of 604 women with Stage IV metastatic breast cancer who were treated with standard dose chemotherapy before undergoing high dose chemotherapy and an ABMT found 39 percent of "chemosensitive" patients (those whose tumor size decreased following standard chemotherapy) alive and in remission 3 years post transplant. For those whose cancer was "chemoresistant" (their tumor size did not decrease appreciably following standard chemotherapy) only 10 percent remained alive and disease free 3 years post transplant.
A similar retrospective analysis was performed of 662 Stage II and Stage III breast cancer patients who were treated with high dose chemotherapy and an ABMT at 33 institutions. Seventy-eight percent of the women were high risk patients with ten or more cancerous Iymph nodes. The actuarial overall survival at 5 years is 77 percent, with 68 percent disease free. The longest survivor is more than 7 years post-transplant. The National Cancer Institute is now sponsoring two clinical trials to determine whether similar results can be achieved in a randomized patient population.
Deciding whether or not to opt for high dose chemotherapy and a bone marrow or peripheral stem cell transplant is difficult for many women with breast cancer. There's no one "right" answer for every woman, but a number of factors should be considered when making the decision.
On the plus side is the very real possibility that a patient may have a longer period of disease-free survival than is possible with standard dose chemotherapy and perhaps be cured. High dose chemotherapy and a bone marrow transplant may also offer the patient a better quality of life during her remaining months or years. Although patients undergoing HDC and an ABMT may experience intense, unpleasant side-effects and a major disruption of their lifestyle for 4 to 6 weeks, they can usually resume a normal lifestyle after transplant and avoid or delay the continuous nausea, vomiting, infections and disruption of lifestyle associated with standard dose chemotherapy administered over many months.
On the negative side is the uncertainty that a cure or extended survival will be achieved, and the possibility of treatment related death from infection, bleeding or organ failure. Although the risk of treatment related death has fallen dramatically in recent years and is now only 1-5 percent at most institutions, it is still a possibility that must be weighed against the potential benefits of the procedure.
This document was created by NYSERNet, Inc. through a grant funded by the New York State Science and Technology Foundation as part of the Breast Cancer Infomation Clearinghouse.