EMCTO 2013 News: A study of simultaneous occurrence of EGFR mutations and HER2 gene amplifications in large series of NSCLC

Recently, HER2 amplification was recognised as a mechanism of acquired resistance to EGFR-TKI that occurs in a subset of tumours lacking the acquired, somatic resistance EGFRT790M mutation

Coexistence of HER2 amplification and EGFR mutations in NSCLC.

Coexistence of HER2 amplification and EGFR mutations in NSCLC.
Credit for image: Dr Zoran Gatalica gave permission for publishing the images in the ESMO web news and post-EMCTO Scientific report.

In a molecular profile analysis of 2271 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 3 cases, while KRAS was mutated in 7 HER2-amplified cases. Double EGFR mutations were however found in only 2 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 (TKIs). This novel molecular insight in large sample of NSCLC cases was presented by Dr Zoran Gatalica, Adjunct Professor of Pathology at Creighton University School of Medicine, Omaha, USA and Director of Oncologic Pathology at Caris Life Sciences International at the European Multidisciplinary Conference in Thoracic Oncology (EMCTO), held 9-11 May, 2013 in Lugano, Switzerland.

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-TKIs that occurs in a subset of tumours that do not show the acquired, somatic resistance EGFRT790M 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 reported (CCR 2012) that HER2 mutation was significantly associated with NSCLC patients who were never smokers but did not associate 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. (Nature 2004) who determined the prevalence of HER2 mutations in primary NSCLC to be 4.2%, with prevalence increasing to 9.8% in patients with adenocarcinoma.

In this latest analysis, Dr Gatalica headed a team of investigators from Caris Life Sciences, Phoenix, USA and Basel, Switzerland in characterising the molecular profiles of 2271 patients with NSCLC. They used the Molecular Intelligence™ technique to evaluate samples for HER2 protein expression (immunohistochemistry), HER2 gene amplification (FISH), EGFR and KRAS gene mutations (sequencing). Their goal was to analyse 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 (HER2/CEP17>2.2) 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 7 cases. Simultaneous HER2 gene amplification and EGFR mutation was demonstrated in 3 cases (L858R, A859T and E746_A750del, respectively). Double EGFR mutations (L858R/T790M and E746_A750del/T790M) were also rare and found in only 2 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 al. (JCO 2005) to associate with resistance to TKIs (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 TKIs may have been due to HER2 gene amplification rather than an effect of the EGFR mutated protein.

Since earlier studies have suggested that HER2 amplification may cause resistance to erlotinib and gefitnib, NSCLC patients with HER2 amplification and activating EGFR mutation may respond better to afatinib, which inhibits both HER2 and EGFR activity. In January afatinib was granted priority review by FDA for treatment of patients with advanced NSCLC harbouring EGFR (HER1) mutations. The study authors advocate for using a comprehensive biomarker evaluation in formulating a targeted treatment strategy for patients with NSCLC to obtain the maximum treatment benefit together with minimum side effects. All authors are employed by Caris Life Sciences which funded this study.

Besides this recent recognition that HER2 amplification may be a mechanism of acquired resistance to EGFR-TKI that occurs in a subset of tumours lacking the acquired, somatic resistance EGFRT790M mutation, the amount of research dedicated to HER2 in NSCLC is increasing. At the recent ESMO Signalling Pathways Symposium entitled “Targeting the HER/EGFR family: Focus on breast, lung and colorectal cancers” and data publication in the JCO (2013), it has been acknowledged that HER2 mutated NSCLC represent a small distinct subgroup of oncogene addicted cancers with specific demographics and potentially outcomes. Results of that largest analysis to date in patients with NSCLC and HER2 mutations, despite limitations of studying data retrospectivelly, provide important insights into HER2-driven NSCLC. Furthermore, this largest study in HER2-mutated NSCLC reinforced the importance of screening for HER2 mutations in lung adenocarcinomas and suggests the potential efficacy of HER2-targeted drugs in this population.

EMCTO is organised in partnership between the European Society for Medical Oncology (ESMO), The European Society for Radiotherapy and Oncology (ESTRO), the European Society of Thoracic Surgeons (ESTS) and the European Respiratory Society (ERS), and the European Thoracic Oncology Platform (ETOP). The five partners have created a programme that integrated perspectives from the different disciplines and demonstrated how the multidisciplinary team can combine knowledge for personalised treatment of the whole range of thoracic oncology tumours.