2000 NIH Consensus Conference on Adjuvant Therapy of Breast Cancer
Richard Kaderman, Ph.D.

On November 1-3, 2000, the fourth NIH Consensus Development Conference on adjuvant therapy for breast cancer was convened in Bethesda, Maryland, with over 1,200 attendees and simultaneous worldwide webcast. Previous meetings were held in 1980, 1985 and 1990, but the current conference seemed particularly meaningful in light of the recent report of sharp declines in breast cancer-related mortality in the United Kingdom and United States. The Consensus Statement, abstract book, and the National Library of Medicine's bibliography of over 2,200 citations from 1995-2000, may be read or downloaded as PDFs at:

http://odp.od.nih.gov/consensus/cons/114/114_intro.htm

New and promising strategies not addressed by the panel, but considered worthy topics for ongoing clinical research:

• Mapping and evaluation of sentinel lymph nodes
  
  
• Immunohistochemical evaluation of bone marrow biopsies
  
  
• Herceptin as a single agent or combined with cytotoxic or hormonal agents
  
  
• Bisphosphonates as adjuvant therapy
  
  
• Delayed use of chemotherapy or hormonal adjuvant therapy and "maintenance" adjuvant therapy
  
  
• Small molecule inhibitors, antisense gene constructs, antiangiogenesis compounds and vaccines

Selected Comments from the Final Statement

(Note: The entire Consensus Statement is reproduced in the appendix to the educational supplement binder.)

"Accepted prognostic and predictive factors include age, tumor size, axillary node status, histological tumor type, standardized pathologic grade, and hormonal-receptor status."

"Although overexpression/amplification of HER-2/neu is associated with an adverse outcome in node-positive patients and may predict the response to therapy, laboratory methods and the reporting of results require standardization before its predictive performance can be established."

"The development of immunohistochemical and molecular methods to identify occult cancer cells (i.e., micrometastases) in histologically tumor-free axillary lymph nodes or bone marrow has raised questions as to whether such findings should alter the clinical stage and become a further indication for systemic adjuvant therapy. At present, the clinical significance of these findings remains uncertain, and they require assessment in prospective clinical trials before they directly alter patient management."

"It is essential that the value of predictive and prognostic factors be evaluated in well-designed clinical studies that are based on standardized protocols and have sufficient statistical power. Because these standards are infrequently met, very few new prognostic or predictive factors have been validated in the last 10 years, and future progress will depend on greater attention to these standards."

"The decision whether to recommend adjuvant hormonal therapy should be based on the presence of hormone receptors, as assessed by immunohistochemical staining of breast cancer tissue. If the available tissue is insufficient to determine hormone receptor status, it should be considered as being positive, particularly in postmenopausal women. The small subset of women whose tumors lack hormone receptor protein but contain progesterone receptor also appear to benefit from hormonal therapy."

"Adjuvant hormonal therapy should be recommended to women whose breast tumors contain hormone receptor protein, regardless of age, menopausal status, involvement of axillary lymph nodes, or tumor size. While the likelihood of benefit correlates with the amount of hormone receptor protein in tumor cells, patients with any extent of hormone receptor in their tumor cells may still benefit from hormonal therapy."

"Randomized trials and a meta-analysis have shown that 5 years of tamoxifen are superior to 1 to 2 years of such treatment. Currently, there are no convincing data that justify the use of tamoxifen for longer than 5 years outside the setting of a clinical trial."

"Neither transvaginal ultrasonography nor endometrial biopsies are indicated as screening maneuvers for endometrial cancer in asymptomatic women taking tamoxifen."

"Ovarian ablation appears to produce a similar benefit to some chemotherapy regimens. Combining ovarian ablation with chemotherapy has not been shown to provide an additional advantage to date. The value of combining hormonal therapies has not yet been adequately explored."

"Available data indicate that adjuvant chemotherapy regimens that include an anthracycline result in a small but statistically significant improvement in survival compared to nonanthracycline-containing programs."

"Randomized trials have demonstrated threshold dose effects for two of the most active chemotherapeutic agents, doxorubicin (A) and cyclophosphamide (C). These two drugs are frequently administered together (AC) and appear to result in a comparable survival outcome, whether given preoperatively or postoperatively. However, AC has not been compared to cyclophosphamide/doxorubicin/5-fluorouracil (CAF) or cyclophosphamide/epirubicin/5-fluorouracil (CEF)."

"There is currently no convincing evidence to demonstrate that more dose-intensive treatment regimens (e.g., high-dose chemotherapy with peripheral stem cell support) result in improved outcomes compared to the administration of polychemotherapy programs at standard dose levels. Such stem cell-support treatment strategies should not be offered outside the setting of a randomized clinical trial."

"Taxanes (docetaxel, paclitaxel) have recently been demonstrated to be among the most active agents in the treatment of metastatic breast cancer. As a result, several studies have explored the clinical utility of adding these drugs to standard doxorubicin/cyclophosphamide treatment programs in the adjuvant treatment of node-positive, localized breast cancer. Although a number of such trials have completed accrual and others remain in progress, currently available data are inconclusive and do not permit definitive recommendations regarding the impact of taxanes on either relapse-free or overall survival. There is no evidence to support the use of taxanes in node-negative breast cancer outside the setting of a clinical trial."

"Available data demonstrate that chemotherapy and tamoxifen are additive in their impact on survival when employed as adjuvant treatment of breast cancer. Therefore, most patients with hormone receptor positive tumors who are receiving chemotherapy should receive tamoxifen."

"At the present time, there are no convincing data to support the use of any known biological factor in selecting a specific adjuvant chemotherapy regimen in breast cancer. Future prospective studies are needed to determine if such factors in an individual patient (e.g., HER-2/neu overexpression) should influence the choice of adjuvant cytotoxic therapy."

"On the basis of available data, it is accepted practice to offer cytotoxic chemotherapy to most women with lymph node metastases or with primary breast cancers larger than 1 cm in diameter (both node-negative and node-positive). For women with node-negative cancers less than 1 cm in diameter, the decision to consider chemotherapy should be individualized."

"There is evidence that women with a high risk of locoregional tumor recurrence after mastectomy will benefit from postoperative radiotherapy. This high-risk group includes women with four or more positive lymph nodes or an advanced primary tumor."

"At this time, the role of post-mastectomy radiotherapy for women with one to three positive lymph nodes remains uncertain and is being examined in a randomized clinical trial."

"Retrospective studies report that women may be willing to undergo treatment for as little as a 1 to 2 percent improvement in the probability of survival. Clear communication of benefits and risks is an essential component in enabling as informed a joint treatment decision as possible. Absolute and relative benefits and risks of therapy must be discussed openly."

"Communication between patients and their physicians is the primary vehicle through which complex treatment decisions are made. This communication will likely be facilitated through the use of decision aids, and well-designed patient information materials about the medical condition or procedure, treatment side effects, probabilities associated with health outcomes, and impact on quality of life."

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