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e-Poster Display Session

17P - Effects of tumour mutation burden on the antigen presentation pathway

Date

09 Dec 2020

Session

e-Poster Display Session

Presenters

Enrique Garcia-Rivera

Citation

Annals of Oncology (2020) 31 (suppl_7): S1417-S1424. 10.1016/annonc/annonc389

Authors

E. Garcia-Rivera1, J. Park1, C. Truntzer2, F. Ghiringhelli2, A. Mansfield1

Author affiliations

  • 1 Mayo Clinic, Rochester/US
  • 2 Platform of Transfer in Biology of Cancer, Georges Francois Leclerc Cancer Center, Dijon/FR
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Abstract 17P

Background

Tumor mutation burden (TMB) can be a predictor of benefit from treatment with immune checkpoint inhibitors (ICIs); however, some patients whose tumors have high TMBs do not benefit from treatment with ICIs. Loss of beta2-microglobulin (B2M) is a mechanism of acquired resistance to ICIs. We hypothesized that a potential mechanism of inherent resistance to ICIs is the inactivation of B2M and other antigen presenting genes (APGs) resulting from increasing TMBs.

Methods

We identified APGs by expert selection and use of the nferX knowledge synthesis platform. We profiled 9,418 tumors of 33 types in TCGA for somatic mutations and their involvement with APGs. Cohen’s d was used to determine the effect of TMB on mutations in APGs. Whole exome sequencing results from 62 patients with non-small cell lung cancer (NSCLC) treated with nivolumab in second or later lines of therapy were evaluated to determine the effect of mutations in APGs on survival using the log-rank test (Dijon Cohort).

Results

In TCGA, mutations in APGs were associated with increasing TMBs across 33 solid tumors (Cohen’s d=0.731, t-test p=8.476 × 10-199), and specifically in lung adenocarcinoma (n=508, Cohen’s d=0.552, t-test p=8.726 × 10-10). In non-small cell lung cancer (NSCLC) adenocarcinomas, ITGAX and CD1B were some of the most commonly mutated APGs (respectively 8.66%, Cohen’s d=1.132, t-test p-value=5.484 × 10-13; 2.56%, Cohen’s d=1.10, t-test p=2.150 × 10-5). In the Dijon Cohort, there was a mild association of increased TMB with mutations in APGs (Cohen’s d=0.870, t-test p=0.002). Mutations in one or more APGs were associated with improved progression-free survival (PFS; HR=0.54, log rank test p-value=0.04) but not overall survival (HR=0.78, log rank test p=0.49).

Conclusions

Increasing TMBs are strongly associated with mutations in genes essential to antigen presentation, specifically including ITGAX and CD1B in NSCLC. Contrary to our hypothesis, mutations in APGs were associated with improved PFS with nivolumab, possibly due to the involvement of single alleles rather than complete loss. Although bi-allelic loss of APGs may be a mechanism of inherent resistance to ICIs, mutations in these genes may more commonly serve as a surrogate for high TMBs and potential benefit of treatment with PD-1 inhibitors in NSCLC.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

J. Park: Full/Part-time employment: nference. F. Ghiringhelli: Honoraria (institution), Oral Communication: Lilly, Sanofi & Amgen; Honoraria (institution), Advisory Board: Merck Serano, Amgen, Sanofi. A.S. Mansfield: Honoraria (institution), Advisory Board: AbbVie; Honoraria (institution), Advisory Board: AstraZeneca; Honoraria (institution), Advisory Board: BMS; Honoraria (institution), Travel/Accommodation/Expenses, Advisory Board: Genentech/Roche; Research grant/Funding (institution): Novartis; Research grant/Funding (institution): Verily; Leadership role, Non-Renumerated Director: Mesothelioma Applied Research Foundation. All other authors have declared no conflicts of interest.

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