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R. Kurek
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MINI 13 - Genetic Alterations and Testing (ID 120)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:Y. Koh, R.K. Thomas
- Coordinates: 9/08/2015, 10:45 - 12:15, 205+207
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MINI13.06 - Mutation Prevalence for Oncogenic Drivers in Lung Adenocarcinoma (ID 3279)
11:15 - 11:20 | Author(s): R. Kurek
- Abstract
- Presentation
Background:
Identification of mutations which drive pulmonary adenocarcinomas (ADC) has rapidly moved from the research arena to clinical practice. The prevalence of these mutations has been suggested by a multitude of studies but here we describe the prevalence of mutations from a large study of patients with advanced ADC treated in the international phase III study INSPIRE (Lancet Oncology 2015) with all testing performed in one CLIA-certified laboratory under standardized conditions.
Methods:
Mutation testing was performed on 412 adenocarcinoma specimens using SNaPshot® methodology. Mutations were examined in the AKT, EGFR, KRAS, BRAF, NRAS, PIK3CA, TP53, PTEN, CTNNB1, and MEK1 genes. The relative frequencies of genetic alterations were calculated based on the total number of adequate specimens and specific consent for testing.
Results:
Of the 412 adenocarcinoma specimens tested, 372 (90.3%) had evaluable results from mutation testing. A single mutation was detected in 157 (42.2%) specimens, whereas mutations in two genes were detected in an additional 20 (5.4%). The overall prevalence of mutations for each specific gene was as follows: KRAS (34.2%), EGFR (12.2%), TP53 (4.9%), PTEN (2.8%), PIK3CA (2.2%), CTNNB1 (2.2%), NRAS (1.8%), BRAF (1.2%), MEK1 (0.3%), and AKT (0%). Figure 1 Evaluation of smoking status identified a substantially higher percentage of KRAS mutations in ex-light smokers and current smokers (38.2% and 40.5%) combined compared to never smokers (7.6%, p<0.0001) , and a lower proportion of EGFR mutations in ex-light and current smokers (10.9% and 4.9%) combined compared to never smokers (39.7%, p<0.0001). Patients ≥70 years old had a higher proportion of both NRAS (7.1% vs. 0.7%, p=0.009) and TP53 mutations (12.5% vs. 3.3%, p=0.010). In addition, males had a lower incidence of EGFR mutation (8.6% vs. 19.0%, p=0.007) as compared to females. Patients from North America, Europe, and Australia/New Zealand demonstrated lower rates of mutation in CTNNB1 (1.4% vs. 8.6%, p=0.030) and PIK3CA (1.4% vs. 8.3%, p=0.032) compared to patients from Central/South America, South Africa and India. Finally, among specimens with two mutations, combinations involving KRAS were the most prevalent (70%, 14/20) followed by TP53 (50%, 10/20).
Conclusion:
These results demonstrate the wide spectrum of mutations that can be detected in adenocarcinoma specimens, with high prevalence rates in the EGFR and KRAS genes. Most patients had only one identified driver mutation. The study revealed age and geographical associations in some mutations. The clinical relevance of the studied mutations in relation to chemotherapy and the human EGFR antibody, Necitumumab, will be studied.
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ORAL 32 - EGFR WT and MT Targeting (ID 144)
- Event: WCLC 2015
- Type: Oral Session
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:K.J. O'Byrne, D.R. Gandara
- Coordinates: 9/09/2015, 16:45 - 18:15, Four Seasons Ballroom F3+F4
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ORAL32.05 - EGFR IHC and FISH Correlative Analyses (SQUIRE Trial): Necitumumab + Gemcitabine-Cisplatin vs Gemcitabine-Cisplatin in 1st-Line Squamous NSCLC (ID 2651)
17:28 - 17:39 | Author(s): R. Kurek
- Abstract
- Presentation
Background:
SQUIRE, a randomized phase III study, demonstrated that the addition of necitumumab (N) (a second-generation, recombinant, human immunoglobulin G1 EGFR antibody) to gemcitabine-cisplatin (GC) improved overall survival (OS) in patients with stage IV squamous non-small cell lung cancer (NSCLC). Analyses of the relationship between efficacy and epidermal growth factor receptor (EGFR) protein expression using the immunohistochemistry (IHC) H-score=200 cut-point were previously reported (Thatcher et al. Lancet Onc, 2015; doi: 10.1016/S1470-2045(15)00021-2). Here we report additional exploratory analyses of the relationship with EGFR protein, as well as analyses of EGFR gene copy number.
Methods:
SQUIRE included mandatory tissue collection from archived tumor. EGFR protein expression was assessed by IHC in a central lab, using the Dako EGFR PharmDx kit. Analyses of the relationships between efficacy outcomes with EGFR across the range of protein levels were performed, using methodologies including subpopulation treatment effect pattern plot (STEPP) with a sliding window target size of 200 patients. An exploratory assessment of EGFR gene copy number gain was performed in tissue sections using fluorescence in situ hybridization (FISH) (J Clin Pathol; 2009;62(11):970-7). Efficacy outcomes were estimated using the Kaplan-Meier method and hazard ratios estimated using an un-stratified Cox model. .
Results:
A total of 982 patients (89.8% of the ITT) had evaluable IHC assay results. The large majority of these patients (95.2%) had tumor samples expressing EGFR protein; only 4.8% had tumors without detectable EGFR protein (H-score=0). The STEPP analyses showed no consistent trend or obvious cut-point for the relationship between either OS or PFS with EGFR protein across the range of IHC values when comparing treatment arms. Archived tumor tissue with evaluable results for exploratory EGFR FISH analysis was available for 51.0% of patients (557 of 1093 ITT patients). Of these patients, 208 patients (37.3%) had increased EGFR gene copy number (FISH positive). A trend for greater necitumumab benefit was observed in EGFR FISH positive patients. Treatment HR (95% CI) for FISH positive and negative patients were 0.70 (0.52, 0.96) and 1.02 (0.80, 1.29) for OS, and 0.71 (0.52, 0.97) and 1.04 (0.82, 1.33) for PFS. However, the interaction of EGFR gene copy number gain with treatment was not statistically significant for either OS or PFS (p=0.066 and 0.057, respectively).
Conclusion:
The analysis of EGFR protein expression did not identify consistent trends related to efficacy outcomes across the range of IHC values. EGFR gene copy number gain showed a trend for a more favorable HR, but did not appear to be strongly predictive. However, both markers showed some evidence of potential trends that will be investigated further in future trials.
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