CHICAGO, IL—Women with the HER2-enriched biologic subtype of breast cancer may not need dual HER2-targeting or more aggressive chemotherapy, a study of gene expression signatures from samples of the CALGB 40601 study concluded at the 2014 American Society of Clinical Oncology (ASCO) Annual Meeting.

Results of the study, in which 305 patients with stage 2-3 HER2-positive breast cancer were randomly assigned to receive 16 weeks of preoperative paclitaxel plus trastuzumab, trastuzumab plus lapatinib, or docetaxel, trastuzumab, and lapatinib and followed for pathologic complete response (pCR), were reported at last year’s ASCO Annual Meeting, said Lisa A. Carey, MD, Alliance for Clinical Trials in Oncology, The University of North Carolina at Chapel Hill, Chapel Hill, NC.

In this analysis, Dr. Carey and colleagues determined gene expression by mRNA sequencing on pretreatment and matched post-treatment samples to categorize response to chemotherapy by molecular subtype.

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The RNA sequencing “was normalized to HER2-positive tumors in The Cancer Genome Atlas Project, and genomic signatures applied, including intrinsic subtype and immune cell features,” she reported.

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Of the pretreatment specimens, 156 were hormone receptor–positive, including luminal A (34%), luminal B (48%), HER2-enriched (17%), and basal-like (1%); none were normal-like or Claudin-Low. The pretreatment subtypes for samples that were hormone receptor–negative were luminal A, 24%; luminal B, 5%; HER2-enriched, 51%; basal-like, 12%; Claudin-low, 3%; and normal-like, 5%. The difference between these two groups was statistically significant (P < 0.001).

The pCR varied by proliferation signature, she noted: high (53%), medium (43%), and low (30%; P = 0.005). RNA sequencing on pretreatment and post-treatment pairs demonstrated a change in subtype prevalence to 49% luminal A, 5% luminal B, 4% basal-like, 4% Claudin-Low, 9% HER2-enriched, and 29% normal-like.

The subtype frequency was found to change with therapy, with luminal A dominating the post-treatment tumor subtypes, she said, illustrating that tumors become more normal-like and luminal A-like with therapy.

Dr. Carey pointed out that these findings show that genomics (intrinsic subtype, proliferation), genetics (TP53 mutation), and microenvironment (immune cells) all contribute to response. The benefit of dual HER2-targeting, however, appears to be limited to the HER2-enriched subtype, with very high pCR rates across all arms in HER2-enriched tumors. The shift noted towards luminal A in residual disease may reflect increased stroma, decreased proliferation, intratumoral heterogeneity, and/or decreased HER2 signaling.

“Confirmation of these findings will require a pooled analysis,” she concluded.


  1. Carey LA, Barry WT, Pitcher B et al. Abstract 506. Presented at: 2014 American Society of Clinical Oncology (ASCO) Annual Meeting; May 30-June 3, 2014; Chicago, IL.