Subtypes of HER2-positive breast cancer with varying sensitivities identified

Research has not only shown that human epidermal growth factor receptor 2 (HER2)-positive breast cancer can be classified into four different subtypes, but has also unmasked a subtype showing both a greater response to and increased benefit from chemotherapy and anti-HER2 therapy. Such newly refined classification of different tumor subtypes will ultimately facilitate more effective treatment tailored to a specific tumor as well as will advance targeted therapy against HER2-positive breast cancer.

The study was led by Aleix Prat, MD, PhD, principal investigator of the Translational Genomics Group at Vall d'Hebron Institute of Oncology (VHIO) in Barcelona, Spain, in collaboration with José Baselga, physician-in-chief of the Memorial Sloan Kettering Cancer Center, New York, New York, and was published in Clinical Cancer Research (2014; doi:10.1158/1078-0432.CCR-13-0239).

The research centers on the fact that not all HER2-positive tumors respond in the same way to anti–HER2 targeted therapy. Although tumors disappear in many patients, others show no response or become resistant to anti-HER2 therapy in combination with chemotherapy. This observation led to this present retrospective study of patients treated in the phase 3 NOAH clinical trial, with the objective of establishing the genomic differences of both treatment-sensitive and treatment-resistant tumors.

Determining the molecular subtype of any breast cancer is fundamental. Until recently, breast cancer had been classified into three groups according to the presence or absence of hormone receptors and the HER2 receptor: hormone-sensitive, HER2-positive, and triple-negative (when not included in either of these first two groups).

Over recent years however, largely thanks to the stunning advancements in genomic technologies, this classification has been finely tuned and subsequently shown that there are at least four major breast cancer subtypes—luminal A, luminal B, HER2-enriched, and basal-like. Last year, this very group of researchers refined the classification of hormone-sensitive tumors by genomics.

In this study, the group focuses on HER2-positive disease by evaluating the response of the different molecular subtypes after treatment with anti-HER2 therapy. The study reveals that these subtypes are also found in HER2-positive breast cancer, and they affect treatment response.

"Specifically, we have found that HER2-positive tumors in the HER2-enriched subtype have a highly activated HER2 signaling pathway, thereby making them especially sensitive to anti–HER2-targeted therapies such as trastuzumab. Therefore, among the four defined subtypes, HER2-enriched benefits most from specific anti-HER2 therapy" explained Prat.

Establishing the genomic and clinical particularities between each of the subtypes may first drive more individually tailored treatment strategies, leading in turn to more robust treatment for those who stand to benefit from it. Second, more effectively targeted treatments may also be facilitated for those patients who may benefit from this strategy and thus ultimately receive a more personalized, precise therapy, resulting in better and longer survival.

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