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N. Dorvault



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    MA11 - Novel Approaches in SCLC and Neuroendocrine Tumors (ID 391)

    • Event: WCLC 2016
    • Type: Mini Oral Session
    • Track: SCLC/Neuroendocrine Tumors
    • Presentations: 1
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      MA11.02 - Mutational Burden in Pulmonary Neuroendocrine Tumors (puNETs) (ID 6099)

      14:26 - 14:32  |  Author(s): N. Dorvault

      • Abstract
      • Presentation
      • Slides

      Background:
      Tumor mutational load (TML) by whole-exome sequencing (WES) is a potential determinant of response to immune checkpoint blockers. The use of PD-L1 as a predictive biomarker for use of PD-1/PD-L1 inhibitors is limited. To date, there are few data concerning TML in puNETs.

      Methods:
      WES was performed in fresh-frozen tumor-normal pairs from 35 typical carcinoid (TC), 4 atypical carcinoid (AC) and 9 large-cell neuroendocrine carcinoma (LCNEC) consecutively collected. Exome enriched libraries were sequenced on an Illumina HiSeq 2000 with a paired-end 2 x 100 bp protocol. Reads were aligned to the reference hg19 using an implementation of the Burrows-Wheeler Aligner, and a BAM file was produced for each tumor and normal sample using the Picard pipeline. The MuTect algorithm was used to identify SSNVs in WES data. We used a minimal allelic fraction cutoff of 0.1. Patients' characteristics and TML were described (median and interquartile for quantitative variables and frequencies for qualitative variables). To evaluate the effect of some factors on the TML, an analysis of variance was used. A log transformation was performed according to the distribution of the TML. The median follow-up was estimated using the Schemper's method. The number of relapses and deaths was reported.

      Results:
      Cohort included 24 male and 24 female. Median age at diagnosis was 57 [Q1= 46; Q3= 70] years, 38% of carcinoids (TC+AC) and 89% of LCNEC were smokers, 26 (54%) stage I, 16 (34%) stage II, 3 (6%) stage III and 3 (6%) stage IV. All patients underwent surgery and 5 (10%) received neoadjuvant treatment. Median follow-up was 32.6 (min= 4.4; max= 179.9) months; there were 8 (17%) relapses (6/9 LCNEC, 2/39 carcinoids) and 10 deaths. On average, 11.6 Gb of sequence were produced per sample, aiming a mean coverage of 72X. Overall median TML was 0.31/Mb [Q1= 0.22; Q3= 0.67], significantly lower in carcinoids tumors than LCNEC (0.28 [Q1= 0.20; Q3= 0.38]/Mb vs. 2.98 [Q1= 1.20; Q3= 4.84]/Mb, respectively, p<0.0001). Similar findings were observed among smoker vs. non-smoker patients (0.28 [Q1= 0.18; Q3= 0.38]/Mb vs. 0.60 [Q1= 0.28; Q3= 2.98]/Mb, respectively, p=0.04). Both variables were found to be independently correlated with TML within the ANOVA test (p=0.0016).

      Conclusion:
      Our findings provide a unique portrait of puNETs, revealing different histotype mutational burden. Continued work in harnessing immunological data in puNETs are needed for better understanding immunotherapy-treatment option in this orphan disease.

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