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Intratumoral HER2 heterogeneity in breast cancer.

MP No general consensus exists regarding the definition of human epidermal growth factor receptor 2 (HER2) heterogeneity. That being said, Dr Otto Metzger Filho and colleagues at the Dana-Farber Cancer Institute presented a definition of HER2 heterogeneity, used in a phase 2 trial of neoadjuvant ado-trastuzumab emtansine (T-DM1; Kadcyla, Genentech) plus pertuzumab (Perjeta, Genentech) in patients with HER2-positive breast cancer, at the 2019 annual meeting of the American Society of Clinical Oncology (ASCO). The trial investigators defined intratumoral HER2 heterogeneity as at least 1 of 6 areas of a biopsied tumor demonstrating either (1) HER2 positivity by fluorescence in situ hybridization (FISH) in more than 5% and fewer than 50% of tumor cells or (2) an area of tumor testing negative for HER2. As is frequently the case when attempts are made to define cutoffs for variables that are continuous rather than dichotomous, a concern regarding the first part of the definition is that in a rapidly proliferating tumor (eg, with a high Ki67 level), some percentage of the cells may be undergoing DNA synthesis in S phase in which the DNA at the HER2 locus has been copied but the chromosome 17 centromere (control probe sequences) DNA replication is incomplete. In this situation, one might see a fraction of cells (perhaps >5% and <50%) with HER2/ CEP17 ratios that are slightly greater than 2, and approximately 4 copies of HER2 by FISH. This finding is clearly not an example of HER2 heterogeneity, but rather of pathophysiologic DNA synthesis during S phase in non– HER2-amplified tumor cells that are proliferating rapidly. A precise definition of intratumoral HER2 heterogeneity probably must await further technological breakthroughs. One example of such a breakthrough would be the application of single-cell sequencing technologies when or if this breaks the cost threshold. Nearly all oncologists who treat patients with breast cancer have seen cases in which the HER2 gene is focally (geographically) amplified in some of the tumor cells but not all—a classic example of heterogeneity in HER2 alteration. This more general descriptive definition that we see on pathology reports from time to time, however infrequently, falls within the second part of the definition of HER2 heterogeneity used in the Dana-Farber study.