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M. Zakowski
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MINI 27 - Biology and Other Issues in SCLC (ID 152)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Small Cell Lung Cancer
- Presentations: 1
- Moderators:P.A. Bunn, Jr, J. Sage
- Coordinates: 9/09/2015, 16:45 - 18:15, 605+607
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MINI27.11 - Comprehensive Mutation Analysis of Never-Smokers with Small Cell Lung Cancer (SCLC) (ID 3135)
16:45 - 18:15 | Author(s): M. Zakowski
- Abstract
- Presentation
Background:
Although most patients with SCLC are current or former smokers, this disease has been reported in never-smokers. In our prospective genomic profiling of SCLC patients, we have identified four never-smokers. Here, we report next generation sequencing (NGS) results for these four SCLC patients and describe how they differ from those of smokers.
Methods:
We are evaluating pathologically confirmed SCLC tumors in patients undergoing treatment. Formalin-fixed, paraffin-embedded surgical resections, core biopsies, and fine needle aspirates are being evaluated using a targeted, hybrid capture-based, NGS assay, MSK-IMPACT, which identifies single nucleotide variants, indels, and copy number alterations in 341 cancer-associated genes. We determined never-smoking status prospectively: all smoked <100 cigarettes in their lifetime. Clinical data on stage [extensive (ES), limited (LS)], treatment, and response were collected.
Results:
Four never-smokers have been identified within the 50 patient samples that have undergone NGS evaluation thus far. The median age at diagnosis of the four never-smokers is 58 (range, 47-75); 50% are male; and one presented with LS-SCLC. None of these four patients developed SCLC as acquired resistance to EGFR tyrosine kinase inhibitors after treatment for EGFR-mutant lung cancers. The tumors from the four never-smokers displayed a median of 3 non-synonymous somatic mutations, while those from moderate (<20 pack years) and heavy (20+ pack years) smokers contained 4.5 and 8 mutations, respectively (P<0.05). None of the four never-smoker samples contained smoking associated G-to-T transversions (see Table). Inactivation of RB1 and TP53 occurred in 75% and 50% of the samples, respectively. Only patient 4 had platinum-refractory disease. The median survival of these patients was 20.7 months (range, 17 to 25).Sample Gene altered Alteration Present Protein Alteration Base Pair Alteration Patient 1 PHOX2B Missense Mutation P82L G-to-A NOTCH1 Frame-Shift Insertion P2485fs RB1 Splice Site R500_splice G-to-A TP53 Frame-Shift Deletion V218fs TP53 Frame-Shift Deletion V73fs TERT Amplification Patient 2 CBL Missense Mutation C401S G-to-C GNAS Missense Mutation M102V A-to-G MYCL Amplification Patient 3 TP53 Nonsense Mutation R342 G-to-A RB1 Frame-Shift Insertion T197fs CDKN2C Amplification MYCL Amplification Patient 4 RB1 Nonsense Mutation C666 ETV1 Amplification
Conclusion:
Using a targeted NGS assay, we have shown that the molecular characteristics differ between never-smokers and smokers, while the majority of the tumors demonstrate RB loss. Whole exome sequencing of the tumors from these never-smokers is underway. Ongoing comprehensive, multiplexed genotyping is needed to fully characterize the molecular diversity of SCLC in this unique population.
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P2.03 - Poster Session/ Treatment of Locoregional Disease – NSCLC (ID 213)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Locoregional Disease – NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.03-032 - Prognostic Impact of EGFR and KRAS Mutations in Patients with Lung Adenocarcinoma Treated with Definitive Radiation Therapy (ID 2422)
09:30 - 17:00 | Author(s): M. Zakowski
- Abstract
Background:
An association of EGFR and KRAS mutations with radiation sensitivity has been postulated in preclinical studies. Recent clinical studies reported longer local control and survival in patients (pts) harboring EGFR mutations treated with definitive radiotherapy (RT). Here, we sought to evaluate the prognostic impact of EGFR and KRAS mutations in 223 adenocarcinoma pts treated with definitive RT at our institution.
Methods:
Between 2004 and 2013, 466 inoperable pts with non-squamous lung cancer were treated with definitive RT ± chemotherapy. Mutational testing was performed in 223 pts. 44% were male, 56% female. 65% were former, 13% never, and 22% current smokers. Clinical stage was II in 5%, IIIA in 37% and IIIB in 58%. Median size of tumor was 3.8 cm (range 0.5-12.2 cm). 60% received concurrent, 31% sequential chemo-RT and 9% RT alone. The median RT dose was 63Gy (range 50-80Gy). OS was estimated by the Kaplan-Meier method. Cumulative incidence functions were used to estimate local failure (LF) and distal failure (DF), using death without failure as a competing risk. Association of factors with OS was analyzed by Cox regression and association with LF and DF by competing risk regression.
Results:
EGFR status was wild-type in 205 pts (92%) and mutated in 18 (8%). The most common EGFR mutations were exon 19 deletion (8 pts), followed by exon 21 L858R (7 pts), and exon 20 insertion (3 pts). KRAS status was wild- type in 142 pts (64%), mutated in 63 (28%), and not performed in 18 (8%). The most common mutations were G12C (13%), followed by G12V (5%) and G12A and G12D (3% each). With a median follow-up among survivors of 32.7 months (range 0.6-114), the median OS was 38 months for pts with EGFR mutation versus 26 months for pts without (p=0.96); 21 months for patients with KRAS mutation versus 31 months for pts without (p=0.24). 2-year LF was 37% and 46% for pts with and without EGFR mutation, and 48% and 46% for pts with and without KRAS mutation, respectively. 2-year DF was 80% and 64% for pts with and without EGFR mutation, and 62% and 64% for pts with and without KRAS mutation, respectively. On univariate analysis, factors significantly associated with improved OS included KPS ≥ 80 (p=0.01), increasing RT dose (p=0.04) and use of concurrent chemotherapy compared to RT alone (p=0.001). Factors associated with higher risk of LF included stage IIIB (p=0.04) and sequential rather than concurrent chemotherapy (p=0.05). Factors associated with a higher risk of DM included stage IIIB (p=0.03) and lower RT dose (p=0.003). Association of EGFR and KRAS mutations did not reach statistical significance on univariate analysis, thus we did not further investigate their effects by multivariable analysis.
Conclusion:
Despite analyzing the largest patient population to date, we did not identify a significant prognostic impact by EGFR or KRAS mutational status. The lack of an observed association could be related to the low rate of EGFR mutations identified. RT dose and use of concurrent chemotherapy were significantly associated with overall survival.
