Refining Therapy for Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer: T Stands for Trastuzumab, Tumor Size, and Treatment Strategy

The clinical importance of breast cancer subsets is now well established; we know that one size won’t fit all. In fact, we are well into the era of parsing subsets of subsets, and the major challenges are to refine therapies within each tumor subtype to tailor treatments based on tumor risk, treatment benefit, and likely adverse effects of therapy. For patients with estrogen receptor (ER) –positive/human epidermal growth factor receptor 2 (HER2) –negative breast cancers, the current challenge centers on defining which patients benefit from the addition of chemotherapy to endocrine therapy. For those with triple-negative (or basaloid) tumors, the challenge is to optimize our chemotherapy regimens while searching for targeted drugs that might dramatically improve outcomes. Finally, for the 15% to 20% of patients with HER2-overexpressing tumors, the success of trastuzumab has fastforwarded our efforts and has led to a dramatic improvement in clinical outcomes. The thoughtful and thorough review by Spector and Blackwell outlines several important ongoing areas of investigation that should better elucidate the precise mechanisms of action for trastuzumab and clarify which tumors markers besides HER2 overexpression most clearly predict benefit from trastuzumab; it also suggests related signaling pathways, such as PI3K and hsp90, that may account for trastuzumab resistance in both the adjuvant and metastatic settings and that can be targeted with newly available pharmacologic agents. Meanwhile, clinicians wrestle with practical day-to-day questions of how best to use trastuzumab, questions that remain unanswered from the landmark clinical trials of adjuvant trastuzumab therapy. The pivotal studies generally concentrated on patients with relatively high-risk, HER2-positive breast cancers and node-positive tumors. There has been only limited information on node-negative cancer outcomes, although the results have suggested comparable proportionate risk reduction as in node-positive patients. The randomized trials provided no data on small tumors (ie, cancers 1 cm) with negative lymph nodes. Although almost all of the data reported are with 1 year of trastuzumab administration, one study (Finland Herceptin [FinHER] study) delivered only 9 weeks of treatment, whereas another study (Herceptin Adjuvant Trial [HERA]) studied up to 2 years of trastuzumab. Three reports in this issue of Journal of Clinical Oncology raise questions about who should receive trastuzumab and how best to administer this drug.