HER2 Heterogeneity Impacts Response Rates in HER2-Positive Breast Cancer

Intratumor HER2 heterogeneity was associated with a poor response rate to T-DM1 and pertuzumab compared to patients with no such heterogeneity in a phase II trial of HER2-positive breast cancer, meaning heterogeneity may need to be incorporated into treatment decisions in the future.

HER2 heterogeneity is defined by the presence of at least two distinct clones of cells that have differing levels of HER2 amplification within a tumor.

“In fact, the estimates of the prevalence of HER2 heterogeneity from retrospective series varies from 10% to 30%, depending on the definition and population being studied,” said Otto M. Filho, MD, of the Dana-Farber Cancer Institute in Boston. He presented results of the single-arm trial at the American Society of Clinical Oncology (ASCO) 2019 Annual Meeting, held May 31-June 4 in Chicago (Abstract 502).

The study included a total of 164 patients with HER2-positive breast cancer; all patients had stage II or III disease and were treated with T-DM1 and pertuzumab in the neoadjuvant setting. All patients underwent ultrasound-guided core biopsies of two distinct sites within the tumor, comprising three cores from each site. Heterogeneity was defined as at least one of the six areas demonstrating either HER2 positivity by fluorescence in-situ hybridization in more than 5% and less than 50% of tumor cells; or an area of tumor that tested HER2-negative.

The median tumor size in the trial was 2.8 cm, and 68.7% of patients had estrogen receptor- and/or progesterone receptor-positive disease. One patient withdrew consent, and heterogeneity testing failed in 5 patients, leaving 157 patients for the primary analysis.

A total of 16 patients (10%) were classified as HER2 heterogeneous; of those, 13 had hormone receptor-positive disease (81%)

The study met its primary endpoint, demonstrating a significant association between HER2 heterogeneity and pathologic complete response (pCR) rate. The pCR rate in non-heterogeneous patients was 55%; in the 16 patients with HER2 heterogeneity, there were no pCRs (P < 0.001).

In the non-heterogeneous patients, 67% had minimal residual disease (residual cancer burden class 0 or 1), compared with 25% of heterogeneous patients for an odds ratio of 5.6 (P = 0.004). The associations between HER2 heterogeneity and response to therapy were maintained when patients were stratified based on estrogen receptor status and immunohistochemistry HER2 results (2+ vs. 3+).

“HER2 heterogeneous cancers may represent a distinct subset of HER2-positive breast cancer, associated with lower rates of pCR, lower levels of HER2 protein expression,” Filho said. “And these are probably a subset of breast cancer patients that may need different therapies.”

Mark D. Pegram, MD, of Stanford University School of Medicine, discussant for the abstract, noted that similar results have been found in at least one other trial. The new data, he said, “independently confirm that HER2 heterogeneity is a distinct clinical entity.” Future directions for research might include testing the use of antibody-drug conjugates with activity in HER2-low states, as well as conjugates with bystander effects.

“Combinations of antibody-drug conjugates targeting different epitopes on different heterogeneous tumor cell populations might also be a possibility to address the severe heterogeneity problem and could be a consideration as a future direction,” he said.