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D. Morgensztern
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MO16 - Prognostic and Predictive Biomarkers IV (ID 97)
- Event: WCLC 2013
- Type: Mini Oral Abstract Session
- Track: Medical Oncology
- Presentations: 1
- Moderators:S. Toyooka, J.C. Yang
- Coordinates: 10/29/2013, 16:15 - 17:45, Parkside Auditorium, Level 1
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MO16.04 - Analysis of HER2 amplification in non-small cell lung cancers (NSCLCs) with acquired resistance (AR) to Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitors (TKIs) (ID 2951)
16:30 - 16:35 | Author(s): D. Morgensztern
- Abstract
- Presentation
Background
Recent studies have demonstrated the feasibility of rebiopsy in patients (pts) with EGFR mutant NSCLC at the time of AR to the EGFR tyrosine kinase inhibitors (TKIs) erlotinib or gefitinib, and provide estimates of the prevalence of well described mechanisms of AR including the EGFR T790M mutation, MET amplification and small cell lung cancer (SCLC) transformation. HER2 amplification has also been described in cases of AR to EGFR TKIs, however, its exact frequency is still unclear. Moreover, comprehensive analysis of paired pre- and post-treatment samples to establish whether HER2 amplification is acquired during treatment with TKIs have not been performed. This prompted us to further investigate HER2 amplification in EGFR mutant NSCLC cases.Methods
Pts with metastatic or recurrent NSCLC who developed AR while on a molecularly targeted agent were enrolled on an IRB approved repeat biopsy protocol. Tumor biopsies were obtained at the time of AR, and histopathological and molecular analyses of the tumors were performed. Known mechanisms of AR to EGFR TKIs were analyzed (T790M mutation, MET amplification and SCLC transformation) as well as amplification of HER2. The presence of T790M was assessed either by Taqman or pyro-sequencing (unless T790M status was available from an outside institution). HER2 and MET amplification were determined using fluorescence in situ hybridization (FISH).Results
41 pts with AR to EGFR TKIs (erlotinib or gefitinib) were enrolled at YCC between Jan 2012 and May 2013. Histological analysis of all specimens revealed transformation of adenocarcinoma to SCLC in 3 cases (7%). Depending on the availability of tissue, samples were prioritized for T790M analysis followed by MET and HER2 amplification. T790M was identified in 36% of pts; MET and HER2 amplification were found in 11% and 10% of samples respectively. In the two cases with HER2 amplification, analysis of the pre-treatment specimen revealed that amplification of this receptor tyrosine kinase preceded treatment with EGFR-TKIs, however, the amplification level was lower pre-treatment in both cases. Specifically the ratio of HER2 to CEP17 probes was 2.8 pre-treatment in both cases and increased to 4.3 and 8 following TKI treatment. HER2 amplification was mutually exclusive with the other tested mechanisms of resistance.Conclusion
T790M was the most commonly identified mechanism of AR to EGFR TKIs in the YCC cohort consistent with other studies. MET amplification, HER2 amplification and SCLC transformation were also observed. The observation that HER2 was amplified pre-treatment warrants further investigation of HER2 amplification in AR and pre-treatment specimens. Whole exome sequencing of specimens without known resistance mechanisms is ongoing.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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PL05 - Genomics: From Research Tool to the Lung Cancer Clinic (ID 76)
- Event: WCLC 2013
- Type: Plenary Session
- Track: Pathology
- Presentations: 1
- Moderators:P. Goldstraw, T. Mok
- Coordinates: 10/30/2013, 16:15 - 17:45, Plenary Hall, Ground Level
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PL05.3 - Challenges for the Clinician (ID 798)
17:10 - 17:35 | Author(s): D. Morgensztern
- Abstract
Abstract
. Although EGFR mutations and fusions involving ALK and ROS1 are targetable by currently approved agents, these alterations are present in less than a fifth of patients with non-squamous NSCLC. Treatment options for the majority of patients remain largely empirical. The urgent need to develop therapies capable of targeting cancers without these alterations can only occur with a better understanding of the molecular biology and cytogenetic alterations. Recently, the lung cancer mutation consortium reported longer survival in patients with adenocarcinoma who underwent multiplexed genomic testing for the detection of alterations in 10 genes, and subsequently received matched targeted treatments. [Johnson et al J Clin Oncol 31, 2013 (suppl; abstr 8019)]. A total of 1,007 patients were screened for at-least one genetic alteration, and an actionable alteration that led to the use of targeted therapies was detected in 28% of these patients. The median survival in these patients was 3.5 years, while patients whose tumors did not harbor actionable alterations had a median survival of 2.1 years. It would be reasonable to assume that adapting NGS technologies, which allow comprehensive screening of the entire genome at a higher resolution, will result in improved outcomes in patients whose tumors do not harbor targetable mutations identifiable by commercially available assays. NGS has allowed a better characterization of lung cancer, with the identification of novel mutations and copy number alterations. Preliminary results from TCGA demonstrated that a significant percentage of patients with lung cancer harbor a targetable abnormality. It is still possible that additional less common mutations or alterations will be discovered once the sequencing of 1000 lung cancer samples is completed by TCGA. The next challenge is the development of novel drugs based on specific targetable abnormalities. Although this strategy may require extensive evaluation and multiple trials targeting distinct molecular subtypes of tumors, this departure from the empirical treatment of lung cancer, probably represents the best hope towards achieving meaningful progress.
