HER2-associated Lung Cancer: Mutations and Amplifications Result in Different Cancers

Two distinct causes of HER2 activation in lung cancer were demonstrated in a recent study: HER2 mutation and HER2 gene amplification. These findings, published in the Journal of Thoracic Oncology, imply that HER2-positive lung cancer may need different targeted therapies to combat these related but possibly distinct diseases.1

This joint study, by University of Colorado (CU) Cancer Center and Memorial Sloan Kettering Cancer Center, found that 3% of patient samples of lung adenocarcinoma had HER2 amplification and another 3% had HER2 mutation. Among the tumor specimens from 175 patients with lung adenocarcinoma and no prior targeted therapy, no samples had both HER2 amplification and HER2 mutation.

The study used FISH to assess amplification, while mutation was assessed by fragment analysis, mass spectrometry genotyping, and Sanger sequencing.

"The question we wanted to answer was if these two genetic alterations tend to be found together. The fact that they are not overlapped means that we must test lung tumors separately for both amplification and mutation of HER2 or risk missing patients who might benefit from HER2-targeted therapy," said Marileila Garcia, PhD, CU Cancer Center investigator and professor of Medicine at the CU School of Medicine in Aurora.

An opposite result has been found with the closely related gene EGFR, which drives approximately 10% of lung cancers in the United States and 35% of lung cancers in East Asia. Garcia explained that EGFR and HER2 are in the same family, and she stated that EGFR is also called HER1. In non-small cell lung cancer that is EGFR associated, both mutation and amplification occur together an estimated 80% of the time.

This study shows that the opposite is true in HER2; apparently amplification and mutation do not commonly occur together, thereby expanding the potential number of patients carrying a HER2-dependent lung tumor.

The role of HER2 has been explored in breast cancer, where approximately 20% of breast cancers harbor the HER2 amplification and are susceptible to treatment with therapies that target HER2, including trastuzumab and lapatinib. Some oncologists choose to prescribe targeted therapies such as these, which are FDA approved to target HER2-associated breast cancer, to patients with HER2-associated lung cancer.

"However, it may be that gene amplification is more susceptible to treatments based not on TKIs but on antibodies," Garcia said. Tyrosine kinase inhibitors (TKIs) include lapatinib, and these drugs reduce the ability of a target gene to manufacture the protein it encodes.

In other words, knowing that whether HER2-associated lung cancer is due to amplification or mutation may point to different treatment options.

The paper concluded that "HER2-positive lung cancer may not be an adequate term." The research suggests that knowing the mechanism that creates HER2 involvement is key to determine patient cohorts to study HER2-targeted agents.

"Whether the overexpression of HER2 in these lung cancers is due to mutation or to amplification may make help us conceptualize what we now call HER2 lung cancer as 2 related but distinct diseases," Garcia said.

REFERENCE

1. Li BT, Ross DS, Aisner DL, et al. HER2 amplification and HER2 mutation are distinct molecular targets in lung cancers [published online ahead of print]. J Thorac Oncol. doi:10.1016/j.jtho.2015.10.025.

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