HER2-Amplification, Mutation Do Not Overlap in Lung Adenocarcinoma

The term “HER2-positive lung cancer” may actually refer to two distinct entities, according to a new study. HER2 mutations and HER2 amplifications were found in similar numbers of lung adenocarcinoma cases, but they did not occur in the same samples, suggesting HER2-targeted agents should differentiate between mutation and amplification.

Though previous research has reported on HER2-driven lung cancers, “the molecular associations of HER2 protein overexpression, HER2 gene amplification, and HER2 mutation in lung cancers have not been distinctly defined,” wrote study authors led by Bob T. Li, MBBS, MPH, of Memorial Sloan Kettering Cancer Center in New York.

The new study analyzed tumor specimens from 175 patients with lung adenocarcinoma who had not received any prior targeted therapy. The study used fluorescence in situ hybridization, various sequencing methods, and immunohistochemical staining to assess mutation and amplification status. Results were published online ahead of print in the Journal of Thoracic Oncology.

A total of five cases out of 175 (3%) were found to have HER2 amplification. Similarly, HER2 mutations were found in four of 148 evaluable patients (3%), with three identical 12-base pair insertions and one 9-base pair insertion, all in exon 20. “In the 148 cases tested for both HER2 amplification and mutation, no overlap was found,” the authors wrote. In other words, mutation and amplification appeared to be completely distinct drivers of lung cancer.

In contrast, EGFR-associated lung cancers harbor mutation and amplification of the gene (which is closely related to HER2) about 80% of the time.

Interestingly, three of the five HER2-amplified cancers were men, and three of five were former smokers. Three out of the four HER2-mutant patients, however, were women, and all of them were never-smokers.

“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 another study author, Marileila Garcia, PhD, of the University of Colorado Cancer Center, in a press release.

The authors concluded that “HER2-positive lung cancer” is not an adequate term given the lack of overlap, and that clinical trials of HER2-targeted therapies should differentiate between the mutated and amplified patients.