Editor’s Note
	The path ahead

In the next five to 10 years, which breast cancer clinical research strategy is most likely to result in tangible improvements in patient care?

This is one of my favorite questions to ask during interviews with research leaders for the Breast Cancer Update audio series. It has gotten to the point where I generally can predict the answer. Targeted therapy based on tumor tissue markers is clearly the mantra for current clinical trials, and in this issue, Dr Harry Bear discusses plans for a new NSABP neoadjuvant study that fully embraces this paradigm.

The new trial is very different from the two prior NSABP neoadjuvant studies (B-18 and B-27), which were very large, randomized, Phase III efforts attempting to determine both short-term tumor responses and long-term impact on disease-free and overall survival. In contrast, the new NSABP trial, as described by Dr Bear, will attempt to compare four different chemotherapy regimens and will focus on short-term clinical response rates and changes in various markers within the tumor. Because disease-free and overall survival are not endpoints, the trial will require far fewer patients and will be completed in a much shorter time than trials like B-18 and B-27.

Everywhere in cancer medicine, researchers refer to breast cancer as the model for targeted therapy. This message is reinforced in our current issue. Dr Tony Howell discusses fascinating new research data from the ATAC trial, presented at the 2003 San Antonio Breast Cancer Symposium, demonstrating that while all patients with ER-positive cancers had lower relapse rates with adjuvant anastrozole than tamoxifen, the difference was particularly significant in women with ER-positive, PR-negative tumors. A similar observation has not previously been reported and, therefore, requires confirmation, but Dr Howell speculates that these tumors may also have HER2 overexpression.

Another related trial reported in San Antonio was the IMPACT study, which is essentially a neoadjuvant version of ATAC. The data document a significantly greater rate of breast conservation in women receiving preoperative anastrozole compared to tamoxifen. These patients also exhibit a greater reduction in Ki67 — a marker of tumor proliferation. For patients with HER2-positive tumors, improved response was also seen, and this helps confirm other studies demonstrating greater antitumor effect of aromatase inhibitors versus tamoxifen in this subset. Dr Howell is now spearheading a major effort to collect tissue blocks from patients enrolled in the ATAC trial so other factors can be studied.

Dr Edith Perez comments on another critical tissue factor that is rapidly increasing in importance — HER2, which can be evaluated both by immuno-histochemistry and fluorescence in situ hybridization (FISH). We have long known that women with HER2-overexpressing primary breast cancer have a worse prognosis and respond differently to systemic agents. A new generation of clinical trials is evaluating adjuvant trastuzumab, and for these studies, it is critical that patients are selected appropriately.

Dr Perez chairs one of the largest of the adjuvant trastuzumab trials, an Intergroup study being run out of the North Central Cancer Treatment Group (NCCTG). In this interview she chronicles her efforts, and those of the NSABP to ensure quality control in HER2 testing. The simple message that has emerged so far is that all primary breast cancers should be evaluated for HER2 overexpression, and that this testing should be performed in relatively high volume laboratories.

Many of us remember the “pre-ER” days of the 1970s when we administered endocrine agents like tamoxifen without really knowing whether our patients would benefit or not. We have now entered a new era in which many critical treatment decisions are determined by tissue testing. It is imperative that our patients receive state-of-the-art quality in these assays.

—Neil Love, MD

Bear HD et al. The effect on tumor response of adding sequential preoperative docetaxel to preoperative doxorubicin and cyclophosphamide: Preliminary results from National Surgical Adjuvant Breast and Bowel Project Protocol B-27. J Clin Oncol 2003;21(22):4165-74. Abstract

Boccardo F et al. Anastrozole appears to be superior to tamoxifen in women already receiving adjuvant tamoxifen treatment. Breast Cancer Res Treat 2003;82(Suppl 1);Abstract 3.

Dowsett M, on behalf of the ATAC Trialists’ Group. Analysis of time to recurrence in the ATAC (arimidex, tamoxifen, alone or in combination) trial according to estrogen receptor and progesterone receptor status. Breast Cancer Res Treat 2003;82(Suppl 1);Abstract 4.

Dowsett M, on behalf of the IMPACT Trialists. Greater Ki67 response after 2 weeks neoadjuvant treatment with anastrozole (A) than with tamoxifen (T) or anastrozole plus tamoxifen (C) in the IMPACT trial: A potential predictor of relapse-free survival. Breast Cancer Res Treat 2003;Abstract 2.

Perez EA et al. N98-32-52: Efficacy and tolerability of two schedules of paclitaxel, carboplatin and trastuzumab in women with HER2 positive metastatic breast cancer: A North Central Cancer Treatment Group randomized Phase II trial. Breast Cancer Res Treat 2003;82(Suppl 1);Abstract 216.

Smith I, Dowsett M, on behalf of the IMPACT Trialists. Comparison of anastrozole vs tamoxifen alone and in combination as neoadjuvant treatment of estrogen receptor-positive (ER+) operable breast cancer in postmenopausal women: The IMPACT trial. Breast Cancer Res Treat 2003;82(Suppl 1);Abstract 1.

Wolmark N et al. Preoperative chemotherapy in patients with operable breast cancer: Nine-year results from National Surgical Adjuvant Breast and Bowel Project B-18. J Natl Cancer Inst Monogr 2001;(30):96-102. Abstract

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