| 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 (ClinicalTrial.gov 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.
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.
Read more of Cancer Therapy Advisor‘s coverage of ASCO’s annual meeting by visiting the conference page.
Reference
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.
