In their article, "Trastuzumab and Beyond: New Possibilities for the Treatment of HER2-Positive Breast Cancer," Drs. Morris and Carey provide an excellent summary of therapeutic progress in this disease, and also turn their attention to the challenge now facing us—that of understanding the heterogeneity of HER2-positive breast cancer and mechanisms of resistance to trastuzumab(Drug information on trastuzumab) (Herceptin)-based therapy. Despite significant progress, important questions remain regarding the optimal management of this previously poor-prognosis breast cancer subtype.

Defining HER2-Positive Breast Cancer

Before exploring the heterogeneity of HER2-positive breast cancer, it is important to optimize the definition of HER2-positive disease. Most of the initial clinical trials in this setting used immunohistochemistry (IHC) for HER2 cell surface protein assessment. However, a retrospective analysis of the pivotal metastatic trials used fluorescence in situ hybridization (FISH) to determine HER2 gene amplification status in the treated cancers. In this study by Mass et al, the benefit from trastuzumab was restricted to patients with FISH-positive disease.[1] In the North Central Cancer Treatment Group (NCCTG) N9831 trial, central and local laboratory assessments for HER2 status correlated poorly in the first 119 patients enrolled. Only 67% of those classified as HER2-positive by local FISH could be confirmed by central FISH testing, and the overall concordance rate between local and central IHC testing was 74%.[2]

Further evaluation of this issue recently reported by Perez et al supports the principle that central laboratories with large-volume testing for HER2 status are essential.[3] While FISH has been held up as the clinical gold standard, a recent consensus panel from the National Comprehensive Cancer Network (NCCN) acknowledged the ambiguous HER2 status of tumors with an average HER2 gene/chromosome ratio of 1.8 to 2.2, or an average number of HER2 gene copies/cell ranging from greater than 4 to less than 6.[4] More specific molecular methodologies for defining tumor subtype would therefore be useful for dissecting treatment resistance and developing new agents targeting this biologic feature.

Advanced Breast Cancer Trials With Trastuzumab

The promise of trastuzumab-based therapy was first noted in the pivotal phase III trial by Slamon et al, as cited. The observation of high response rates with trastuzumab in combination with chemotherapy has been replicated in numerous phase II trials. However, a common feature of these trials is the high percentage of subjects who did not receive adjuvant chemotherapy. For example, in the anthracycline/cyclophosphamide arms of the Slamon study, 131 (47%) of 278 subjects had not received adjuvant chemotherapy. Even in more recently reported studies, this percentage of chemotherapy-naive patients holds. In a study of pegylated liposomal doxorubicin(Drug information on doxorubicin) (Doxil) with trastuzumab, 37% of patients had not received adjuvant chemotherapy.[5] In a phase III trial comparing docetaxel(Drug information on docetaxel) with or without carboplatin(Drug information on carboplatin) in first-line treatment, 44% of patients were chemotherapy-naive.[6]

With the greater appreciation of the poor prognosis of untreated early-stage HER2-positive breast cancer, and the widespread use of adjuvant trastuzumab, the nature of advanced metastatic breast cancer is likely to change. Patients with metastatic HER2-positive disease should, fortunately, become less common. However, when they develop recurrence, these patients will also be more heavily pretreated and selected for having a different biology. Therefore, the response rates to trastuzumab-based therapies seen in these earlier trials are unlikely to hold, highlighting the need for novel agents such as those discussed in the Morris and Carey article.

Controversies in Early-Stage Adjuvant Therapy

The poor prognosis of HER2-positive cancer raises questions about the appropriate treatment of node-negative lesions, particularly those less than 1 cm in diameter. Although the adjuvant trials have included high-risk node-negative cancers, fewer of these cases were enrolled. None of the trials allowed lesions smaller than 1 cm. Nevertheless, clinicians have become wary of HER2-positive breast cancer, leading many to treat aggressively despite current guidelines. Adjuvant trials to study therapy in this group of patients are needed.

HER2 Status and Endocrine Therapy

A relatively unexplored area clinically is the interaction of HER2 positivity and endocrine therapy. Concurrent expression of HER2 and hormone receptors is not uncommon. Indeed, in all the landmark adjuvant trastuzumab trials, ~50% of the cancers were hormone receptor-positive. A similar percentage is seen in most of the metastatic trastuzumab-based therapy trials. HER2 positivity is thought to be associated with some degree of resistance to endocrine therapy.