HER2-negative primary breast tumors may evolve to express low HER2 upon relapse, highlighting the need to retest recurrent tumors for HER2 expression, according to new research. "The results provide a whole new insight on how HER2-low tumors might evolve as a subgroup, possibly challenging the current dichotomy between HER2-positive and HER2-negative breast cancer," Dr. Federica Miglietta of the University of Padua School of Oncology, in Italy, said in a statement from the ESMO Breast Cancer Virtual Congress, where the findings were presented. Based on the results, "biopsy of locoregional relapses or distant metastases is strongly encouraged, since it may open new therapeutic opportunities in a not-negligible proportion of patients and better assist in patient selection for novel anti-HER2 antibody-drug conjugates," Dr. Miglietta said in her conference presentation. More than half of HER2-negative breast cancers harbor low HER2 expression that can be targeted with novel anti-HER2 antibody-drug conjugates. Discordance in HER2 status from the primary tumor to relapse has been demonstrated, but there have been no data on the evolution of HER2-low status from primary tumor to relapse, Dr. Miglietta explained. To investigate, the research team studied matched samples of primary and relapse breast cancers from 547 women. HER2 status was assessed according to ASCO/College of American Pathologists recommendations in place at the time of diagnosis (2007-2013), with a 10% cutoff for IHC applied. HER2-negative cases were sub-classified as HER2-low (IHC score 1+ or 2+ and ISH not amplified, negative) and HER2-negative (score 0 by IHC or HER2-0). Sixty-one percent of women had a primary-tumor phenotype that was luminal-like (HR-positive/HER2-negative), 25% were HER2-positive, and 14% were triple negative; corresponding percentages on relapse were 54%, 24% and 22%. The overall rate of HER2 discordance between primary and relapse samples was 39%. HER2-low expression was observed in 34% of primary tumors and 38% of relapse tumors. Notably, 15% of HER2-negative primary tumors switched to HER2-low tumors on relapse, while 14% of HER2-low primary tumors switched to HER2-negative on relapse. Overall, 29% of recurrent breast cancers converted either from, or to, HER2-low expression, Dr. Miglietta reported. In addition, the rate of conversion from HER2-negative primary tumor to HER2-low recurrent tumor was 21% for HR-positive/HER2-negative tumors and 14% for triple negative tumors. "These changes on HER2-low levels are substantial," Dr. Aleix Prat, head of medical oncology at the Hospital Clinic of Barcelona, in Spain, said in the statement. "There could be biological rationale for this, or a technical one, given that there is currently no standardization of how to determine levels of the HER2 biomarker in metastatic biopsies, which could be biopsied from skin, liver, or bone and give different results." "We need to work out how the HER2 status determines response to therapies. Is it the HER2 status in the primary tumor, or in the metastatic biopsy that is important? Maybe some patients have HER2-low expression in metastatic tumors and now respond when they didn't previously, and this might change again over time and further relapses," Dr. Prat said. "This all speaks to a much greater need to biopsy metastatic tumors. Importantly, we need to determine who will benefit from treatments for HER2-low, because patients will be asking about this in the clinic soon if trial results are positive," said Dr. Prat. The study received no specific funding. —Megan Brooks Source
