Study provides new insight on how HER2-low tumors may evolve in breast cancer patients

The finding that breast tumors can evolve to express low HER2 potentially widens the number of patients who can benefit from new investigational agents, typically novel antibody-drug conjugate therapies, that are currently in clinical trials for HER2-low tumors.

The first study of its kind exploring how breast cancers change from the primary to the recurrent tumor has revealed that nearly 30% of breast cancer patients convert from, or to, human epidermal growth factor receptor (HER)2-low status. Specifically, the study found that 14% of triple-negative breast cancers with HER2-negative expression (also referred to as HER2-0) in the primary tumor converted to HER2-low expression in the recurrent tumor possibly offering an option to such hard-to-treat tumors.

Traditionally, breast cancers are categorized as: hormone receptor positive (HR+)/HER 2-negative, (also known as luminal-like), HER2-positive, or triple negative (negative for estrogen receptors, progesterone receptors, and excess HER2 protein). HER2-low refers to HER2-negative tumors with low HER2 biomarker expression. About half of breast cancers classified as HER2-negative show low HER2 expression.

Presenting the findings at this year's ESMO Breast Cancer Virtual Congress is Dr Federica Miglietta, School of Oncology, University of Padua, Italy.

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. Our findings stress the importance of re-testing HER2 expression on tumor relapse since it might provide the option of new therapeutic opportunities, currently in a trial, and hopefully in the near future, in the clinic."

Dr Federica Miglietta, School of Oncology, University of Padua, Italy

Several clinical trials are ongoing in HER2-low breast cancer.

In total, 29% of recurrent breast cancer biopsies showed conversion either from, or to, HER2-low expression. In primary tumors and relapse tumors, HER2-low expression was seen in 34% and 38% of tumors, respectively. A total of 15% HER2-negative tumors switched to HER2-low tumors, and 14% HER2-low switched to HER2-negative.

The study also confirmed that HER2-low expression was more frequent in HR+/HER2-negative tumors compared to triple negative tumors (47% vs 36% on primary tumor samples, 54% vs 36% on relapse samples). Plus, the switch from HER2-negative to HER2-low in primary to recurrent tumors was 21% vs 14% in luminal-like and triple negative, respectively.

Commenting on the findings, Professor Aleix Prat, Head Medical Oncology, at the Hospital Clinic of Barcelona, Spain said: "These changes on HER2-low levels are substantial. There could be a 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."

"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 Prat.

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