HER2 or Not HER2: That Is the Question

It is becoming increasingly apparent that the longappreciated clinical heterogeneity in breast cancer arises in large part from intrinsic biologic heterogeneity within the tumor. In other words, there is more than one type of breast cancer. Different tumor types are not merely arbitrarily defined subsets, but rather different diseases. Underlying this revised taxonomy are different identifiable growth factors and receptors, reflecting the different molecular and cellular features of these distinct tumor types. Hormone receptor–positive and –negative breast cancer and human epidermal growth factor receptor 2 (HER2) –positive and –negative breast cancer are as different from one another as pneumococcal and staphylococcal pneumonia or acute myeloid leukemia and acute lymphoblastic leukemia. The preliminary but provocative results from the preoperative treatment of HER2-positive breast cancer using chemotherapy with or without trastuzumab, reported in this issue by Buzdar et al, provide the opportunity to reflect on the challenges clinicians and clinical researchers face in acknowledging and responding to the biologic heterogeneity of breast cancer. In particular, these findings have led us to imagine a time, probably not far from now, when different breast cancers are treated along distinctive pathways that target their intrinsic biologic features. At a minimum, it is likely that treatment will vary depending on hormone receptor expression and HER2 expression and that other novel molecular targets will be identified in years to come. The dilemma that will confront clinically oriented thinking is that many recent lessons regarding optimal breast cancer therapy have been derived from treating patients without prior selection of tumors based on biology. It is not clear how such lessons will apply to biologically defined classes of breast tumors. The trial from the M.D. Anderson Cancer Center randomly assigned women with HER2-positive, operable breast cancer to either preoperative chemotherapy alone or to chemotherapy and trastuzumab. There was a substantial improvement in pathologic complete response (pCR) rate with trastuzumab-based therapy. The chosen end point of pCR has been widely used in preoperative treatment trials because of the reproducibility of the measurement and because it may be a surrogate for long-term treatment outcomes. It is not all that surprising that trastuzumab improved pCR because randomized trials in the metastatic setting have demonstrated that trastuzumab-based treatment substantially increases response rate, progression-free survival, and overall survival for patients with HER2positive breast cancer compared with chemotherapy alone. It is critical to articulate what the M.D. Anderson data do not tell us about a standard approach to breast cancer therapy. The study, with approximately 20 patients per arm, is too small to demonstrate with confidence the safety of preoperative trastuzumab administered with or without anthracycline-based chemotherapy. In particular, the study cannot exclude the possibility of clinically important risks of heart failure. The study was not designed to demonstrate, nor did it report, whether trastuzumab would improve long-term results, such as recurrence-free or overall survival, and we await the data from the many randomized trials in the adjuvant setting to define such benefits. The study does not suggest that trastuzumab-based treatment facilitates breast-conserving surgery; the rates of mastectomy were the same in each treatment arm, at approximately 55%, based on the high clinical response rate. For all these reasons, the use of preoperative trastuzumab remains an investigational approach for HER2overexpressing, early-stage breast cancer. Notwithstanding these limitations, this small trial confirms previous reports of preoperative trastuzumab-based treatment in early-stage breast cancer. Moreover, the M.D. Anderson data suggest that it may not be too soon to begin to anticipate the era when HER2-positive breast cancer (20% to 25% of all cases) is treated as a separate disorder, and then to assess the implications for how we will care for the remaining three quarters of breast cancer patients. Consider first the impact of winnowing the HER2positive breast cancer cases out of the pool of unselected tumors. HER2 overexpression is widely appreciated to have JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 23 NUMBER 16 JUNE 1 2005