Looking Deep Into the Heterogeneity of Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer: Can We Understand It Better?
Authors: Sherene Loi, Peter Savas
Journal: Journal of Clinical Oncology (2016)

The success of trastuzumab when combined with cytotoxic chemotherapy to alter the previously aggressive natural history of humanepidermalgrowthfactor receptor2 (HER2)–positive disease has been remarkable. Despite intensive research, understanding the biologic factors that lead to resistance in some patients and the integration of such factors into the clinical setting has been slow. The relevance of estrogen receptor (ER) signaling in terms of response in the neoadjuvant setting and prognosis in the adjuvant setting is recognized but does not yet influence the way we manage anti-HER2 therapy. The identification of both prognostic and predictive factors becomes particularly critical as we seem to be moving into an era of dual anti-HER2 therapy. The Cancer Genome Atlas subjected 510 primary breast tumors to mutation, transcript, copy number, methylation, and protein analyses. Only 50% of clinical HER2-positive tumors were characterized as HER2 enriched at the mRNAand protein level, and the rest were predominantly luminal HER2 positive with a mutation profile similar to that of luminal HER2-negative tumors. 1 The HER2-enriched subgroup was also characterized by aneuploidy and by high levels of the genes in the HER2 amplicon, and it also had the highest average number of somatic mutations often including TP53. Despite this comprehensive moleculardescription of theheterogeneityofHER2-positive disease, the clinical relevance of these findings remains unclear. In the article accompanying this editorial, Carey et al 2 discuss the Cancer and Leukemia Group B (CALGB) 40601 (Paclitaxel and Trastuzumab With or Without Lapatinib in Treating Patients With StageIIorStageIIIBreastCancerThatCanBeRemovedbySurgery) study, a prospective randomized phase III trial of 295 patients with operable HER2-positive breast cancer ($ 1 cm). That study evaluated trastuzumab, lapatinib, and the combination with paclitaxel chemotherapy for 16 weeks to determine how different gene expression subtypes within HER2-positive tumors affect rates of pathologic complete response (pCR) in the breast only after neoadjuvant chemotherapy and HER2-targeted therapy. First, the investigators are to be commended for taking on the complex and difficult task of collecting prospective samples suitable for generating wholetranscriptome gene expression. Aside from caveats about the suitability of pCR as a surrogate end point for improvement in survival, the setting of a neoadjuvant trial seems ideal for testing the added value of gene expression profiling for a clinically meaningful end point,with allthe benefitsof randomizedassignment,complete clinical annotation, and consistent treatment administration. Correlative biomarker results from a clinical trial are more likely to be robust and reproducible for these reasons. 3 In the study by Carey et al, 2 the trastuzumab and lapatinib combination arm produced a numerically higher but not statistically significant increase in the rates of pCR in the breast, which was the primaryend point of the study. The trastuzumab-alone controlarmwas observed to have a higher pCR rate relative to that in other comparable studies. 4,5 This may be partly explained by the inclusion of smaller tumors ($ 1c m). Notably, however, only 64% of patients in the lapatinib arm and 85% in the combination arm (even after lapatinib dose reduction) compared with 92% in the control arm completed the entire protocol-specified neoadjuvant therapy, which may have contributed to the lack of statistical significance for the combination arm and the poor performance of the lapatinib-alone arm. The major conclusion of the correlative analyses was that intrinsic subtype, ER, HER2 signaling, and immune genes were significantly associated with pCR and that some cases of residual disease switched intrinsic subtypes compared with the primary tumor. These results further highlight the clinically important biologic heterogeneity within the HER2-positive subtype. Does the intrinsic subtype of HER2-positive breast cancer now have clinical utility? The primary correlative end point of pCR rates varied significantly by intrinsic subtype. Response was the highest (70%) in the HER2-enriched compared with the HER2luminal A and -luminal B subtypes (34% and 36%, respectively), independent of treatment arm (P,.001), similar to a previous report. 6 When the samples were classified by using traditional ER immunohistochemistry, pCR rates were also higher in the hormone receptor–negative patients in the trastuzumab and lapanitib combination arm (79%), with a nonsignificant trend toward an interaction by receptor status and treatment arm. Increasing levels ofESR1and ERBB2 single-gene transcripts were also significantlyassociated with lower and higher pCR rates, respectively, on a continuous scale, notably providing discriminatory information that also remained significant in themultivariateanalyses. Thesedataareallsupportiveofthenotion that the HER2-enriched subtype is enriched for ER-negative tumors as well as higher levels of HER2 amplification, and these tumors are the most responsive to HER2-targeted therapies.