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Expert Point of View: Mark Pegram, MD, and Sandra Swain, MD, FASCO


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Mark Pegram, MD

Mark Pegram, MD

Mark Pegram, MD, the Susy Yuan-Huey Hung Professor of Medical Oncology and Director of the Stanford Breast Oncology Program, said the Dana-Farber study “independently confirms that HER2 heterogeneity is a distinct clinical entity with lower levels of HER2 expression and pathologic complete response rates (from treatment with T-DM1 [trastuzumab emtansine] plus pertuzumab).”

Dr. Pegram indicated that similar observations at the protein level were reported in another study presented at the 2019 ASCO Annual Meeting, from the I-SPY 2 study investigators.1 In that study, quantitative measurement of HER2 protein positively associated with response to T-DM1/pertuzumab in patients already identified as HER2-positive. A number of clinical trials have also now shown that higher HER2 levels are associated with more favorable outcomes, vs lower levels of transcript expression.

“Taken together, these data make a compelling argument that HER2 expression levels are important in the action of T-DM1 in the metastatic and neoadjuvant settings,” said Dr. Pegram. “The fact that this has been observed across trials by independent groups adds more strength to that conclusion.”

Future Directions

“Future directions in addressing the heterogeneity issue may include use of antibody-drug conjugates with activity in HER2-low states, antibody-drug conjugates whose payloads have bystander effects (T-DM1 does not), and combinations of antibody-drug conjugates targeting epitopes expressed in heterogeneous tumor cell populations,” Dr. Pegram suggested.

Sandra Swain, MD, FASCO

Sandra Swain, MD, FASCO

Sandra Swain, MD, FASCO, Associate Dean for Research Development at Georgetown University Medical Center and the Lombardi Comprehensive Cancer Center, Washington, DC, said the study is “fantastic,” although the findings should be further explored in larger prospective studies. If validated, she added, “Then we need better therapy for patients with HER2 heterogeneity.” 

DISCLOSURE: Dr. Pegram has consulted or advised for Daiichi Sankyo, Genentech/Roche, MacroGenics, and Seattle Genetics. Dr. Swain has served as a consultant or advisor for Cardinal Health, Daiichi Sankyo, Genentech/Roche, Genomic Health, Inivata, Lilly, Pieris Pharmaceuticals, and Tocagen; has received honoraria from Novartis and travel expenses from Caris Centers of Excellence, Daiichi Sankyo, Genentech/Roche, Inivata, Lilly, and NanoString Technologies; has received institutional research funding from Genentech; and reports other relationships with AstraZeneca and Roche.

REFERENCE

1. Wulfkuhle JD, Wolf DM, Yau C, et al: HER family protein expression and activation predicts response to combination T-DM1/pertuzumab in HER2+ patients in the I-SPY 2 trial. 2019 ASCO Annual Meeting. Abstract 3133. Presented June 1, 2019.


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