In a molecular profile analysis of 2,271 cases of non–small cell lung cancer (NSCLC), EGFR was mutated in 12% and KRAS in 32% of cases. HER2 gene amplification was confirmed as a rare event in NSCLC (4%). Coexistence of HER2 gene amplification and EGFR mutation was identified in three cases, while KRAS was mutated in seven HER2-amplified cases. Double EGFR mutations were found in only two cases. NSCLC with HER2 amplification were frequently (39%) associated with KRAS-activating mutation. A rare A859T mutation was found in one case and was associated with HER2 gene amplification. This mutation was previously associated with resistance to tyrosine kinase inhibitors.
This novel molecular insight in a large sample of NSCLC cases was presented by Zoran Gatalica, MD, DSc, Adjunct Professor of Pathology at Creighton University School of Medicine, Omaha, and Director of Oncologic Pathology at Caris Life Sciences International, at the European Multidisciplinary Conference in Thoracic Oncology in Lugano, Switzerland.1
Underlying Mechanisms
HER2 is a member of the EGFR family of receptor tyrosine kinases. It forms heterodimers with other family members enhancing kinase-mediated activation of the downstream signaling pathways. HER2 amplification has been implicated as a mechanism of acquired resistance to EGFR–tyrosine kinase inhibitors, occurring in a subset of tumors that do not show the acquired, somatic resistance EGFR T790M mutation.
Activating mutations in the tyrosine kinase domain of HER2 have been described in a subset of lung adenocarcinomas and as mutually exclusive with EGFR and KRAS mutations. Arcila et al previously reported2 that HER2 mutation was significantly associated with NSCLC patients who were never smokers but not associated with sex, race, or disease stage. They concluded that HER2 mutations identify a distinct subset of lung adenocarcinomas.
Given the high prevalence of lung cancer worldwide and the availability of standard and investigational therapies targeting HER2, they advocated that routine clinical genotyping of lung adenocarcinoma should include HER2. However, no association between HER2 mutation and HER2 overexpression was shown in their study or in results reported by Stephens et al,3 who determined the prevalence of HER2 mutations in primary NSCLC to be 4.2%, with prevalence increasing to 9.8% in patients with adenocarcinoma.
Current Study
In this latest analysis, Dr. Gatalica headed a team of investigators from Caris Life Sciences, Phoenix, Arizona, and Basel, Switzerland, in characterizing the molecular profiles of 2,271 patients with NSCLC. They used the Molecular Intelligence technique to evaluate samples for HER2 protein expression (immunohistochemistry), HER2 gene amplification (FISH), and EGFR and KRAS gene mutations (sequencing). Their goal was to analyze the frequency of the simultaneous occurrence of EGFR mutations and HER2 gene amplifications.
As determined by sequencing, EGFR was mutated in 12% and KRAS mutations were seen in 32% of NSCLC patients. Consistent with earlier reports, HER2 gene amplification was detected by FISH in 22 (4%) of 589 tested cases, associated with 3+ protein expression. There was no evidence that HER2 amplification associated with T790M mutation.
Coexistence of HER2 gene amplification and KRAS mutations were seen in seven cases. Simultaneous HER2 gene amplification and EGFR mutation was demonstrated in three cases. Double EGFR mutations were found in only two cases. The most frequent association was seen between HER2 amplification and KRAS-activating mutation, which occurred with a frequency of 39%.
One sample showed the rare A859T mutation, which had been reported by Han et al4 to be associated with resistance to tyrosine kinase inhibitors (HER2 status was unknown). However, this mutation was associated with HER2 gene amplification in the current analysis. The authors speculated that previously reported resistance to tyrosine kinase inhibitors may have been due to HER2 gene amplification rather than an effect of the EGFR-mutated protein. ■
Disclosure: All study authors are employed by Caris Life Sciences, which funded this study.
References
1. Gatalica Z, Gupta P, Ghazalpour A, et al: HER2 in non-small cell lung carcinomas. European Multidisciplinary Conference in Thoracic Oncology. Abstract 650. Presented May 10, 2013.
2. Arcila ME, Chaft JE, Nafa K, et al: Prevalence, clinicopathologic associations, and molecular spectrum of ERBB2 (HER2) tyrosine kinase mutations in lung adenocarcinomas. Clin Cancer Res 18:4910-4918, 2012.
3. Stephens P, Hunter C, Bignell G, et al: Lung cancer: Intragenic ERBB2 kinase mutations in tumours. Nature 431:525-526, 2004.
4. Han SW, Kim TY, Hwang PG, et al: Predictive and prognostic impact of epidermal growth factor receptor mutation in non-small-cell lung cancer patients treated with gefitinib. J Clin Oncol 23:2493-2501, 2005.
