The following article features coverage from the American Society of Clinical Oncology 2019 meeting. Click here to read more of Cancer Therapy Advisor‘s conference coverage.

According to results of a phase 2 study ( Identifier: NCT02326974) presented at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, Illinois, the presence of HER2 intratumor heterogeneity prevented achievement of a pathologic complete response (pCR) in women receiving neoadjuvant therapy with 2 anti-HER2 agents without chemotherapy for operable HER2-positive breast cancer.

Although neoadjuvant HER2-targeted therapy is a standard of care for patients with HER2-positive operable breast cancer, tumors may have a significant amount of heterogeneity with respect to HER2 gene amplification or HER2 protein expression (ie, the presence of 2 or more clones with different levels of HER2 amplification within a tumor). Hence, suboptimal response rates are likely in tumors with HER2 intratumor heterogeneity treated with HER2-targeted agents only.

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In this single-arm, open-label trial, patients with stage II/III breast cancer that was centrally confirmed as HER2-positive were treated with 6 cycles of neoadjuvant trastuzumab emtansine plus pertuzumab. The primary end point of the study was the association of the rate of pCR, defined as a residual cancer burden (RCB) of 0, with the level of HER2 intratumor genetic and/or regional heterogeneity, stratified according to tumor estrogen receptor (ER) status.

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The level of HER2 intratumor heterogeneity was determined centrally using 6 specimens obtained through baseline core biopsies of 2 separate sites (ie, 3 at each site). Intratumor heterogeneity was considered to be present if 1 of the following 2 criteria were met:

  • HER2 positivity by fluorescence in situ hybridization (FISH) in more than 5% and less than 50% of tumor cells
  • An area of tumor that tested negative for HER2

Baseline tumor characteristics of the 163 patients enrolled in the study who received study drug included a median tumor size of 2.8 cm and estrogen receptor-positive disease in 68.7% of patients.

Of the 157 patients evaluable for response, 141 (90%) had tumors classified as HER2 nonhetergeneous, whereas 16 (10%) met the definition of HER2 intratumor heterogeneity.

A key finding of the study was that 55% of patients with HER2 nonheterogeneous disease achieved a pCR, whereas the pCR rate in patients with HER2 intratumor heterogeneity was 0% (P =.001).

For patients with minimal residual disease (RCB-0 or RCB-1), the pCR rates for patients with disease characterized by HER2 nonheterogeneity and HER2 intratumor heterogeneity were 67% and 25%, respectively (P =.004).

In addition, pCR rates determined according to hormone receptor (HR) status were 65% (HR-positive disease) and 42% (HR-negative disease), (P =.01).

“Our study met its primary endpoint by demonstrating a significant association between HER2 heterogeneity and pCR, and this effect was independent of ER status and HER2 protein expression by immunohistochemistry,” concluded Otto Metzger Filho, MD,

Dana-Farber Cancer Institute, Boston, Massachusetts, who presented the study results.

He noted that the use of a clinical definition of HER2 heterogeneity (defined by FISH) should facilitate efforts to validate this association across other studies.

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Filho OM, Viale G, Trippa L, et al. HER2 heterogeneity as a predictor of response to neoadjuvant T-DM1 plus pertuzumab: Results from a prospective clinical trial. Presented at: 2019 American Society of Clinical Oncology (ASCO) Annual Meeting; May 31-June 4, 2019; Chicago, IL. Abstract 502.