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Poster display session

1613 - Analysis of POLE mutation and Tumor Mutational Burden (TMB) Across 80,853 Tumors: Implications for Immune Checkpoint Inhibitors (ICPIs)

Date

10 Sep 2017

Session

Poster display session

Presenters

Alexa Schrock

Citation

Annals of Oncology (2017) 28 (suppl_5): v403-v427. 10.1093/annonc/mdx376

Authors

A.B. Schrock1, D. Fabrizio2, Y. He3, J. Chung1, M. Resnick4, P.J. Stephens5, J.S. Ross6, V.A. Miller7, S. Ramkissoon8, J.A. Elvin8, S.M. Ali1, M. Fakih9, S.J. Klempner10

Author affiliations

  • 1 Clinical Development, Foundation Medicine, MA 02141 - Cambridge/US
  • 2 Cancer Immunotherapy, Foundation Medicine Inc., 02141 - Cambridge/US
  • 3 Cancer Genomics, Foundation Medicine, MA 02141 - Cambridge/US
  • 4 Pathology, Brown University, 02903 - Providence/US
  • 5 R & D, Foundation Medicine, 02141 - Cambridge/US
  • 6 Pathology, Albany Medical Center, 12208 - Albany/US
  • 7 Medical Affairs, Foundation Medicine, MA 02141 - Cambridge/US
  • 8 Pathology, Foundation Medicine Inc., 02141 - Cambridge/US
  • 9 Oncology, City of Hope, 91010 - Duarte/US
  • 10 Oncology, The Angeles Clinic, 90025 - Los Angeles/US
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Resources

Abstract 1613

Background

Mutations of the DNA polymerase epsilon (POLE) can lead to a hypermutated tumor phenotype, in the absence of microsatellite instability (MSI). Exceptional responses to ICPIs in POLE-mutated endometrial adenocarcinoma (EA), colorectal (CRC), and glioblastoma (GBM) are described, but detailed pan-tumor POLE analyses are lacking.

Methods

We prospectively analyzed 80,853 primarily advanced solid tumors using hybrid-capture based comprehensive genomic profiling. TMB (mutations/Mb) was calculated from 1.11 Mb of sequenced DNA (PMID: 28420421). Known genomic alterations (kGA) were defined as those reported as somatic in the COSMIC database or with published evidence indicating loss of function.

Results

POLE GA were identified in 5.0% of cases: melanoma (10%), duodenal adeno (DA, 7.8%), uterus carcinosarcoma (CS, 6.9%), EA (6.4%), unknown primary carcinoma (CUP, 6.3%), NSCLC (6.1%), CRC (5.1%), prostate adeno (5.0%), and GBM (4.6%). Most POLE GA were variants of unknown significance (VUS). POLE kGA were found in only 259 (0.3%) total cases, including ovary or uterus CS (2.2%), DA (1.3%), EA (1.2%), CRC (0.7%), GBM (0.6%), and CUP (0.6%). Patients with POLE kGA had a median age of 58 yrs (range 7-95); 53% were male. Median TMB in cases with POLE kGA, VUS and wild-type was 31, 9 and 3.6, respectively (each p 20), while 28% had low TMB (

Conclusions

POLE GA are found across tumor types, but functionally significant GA may be less frequent than previously reported, particularly in advanced tumors. Identification of specific POLE GA associated with a hypermutated phenotype may be important to identify likely responders to ICPIs.

Clinical trial identification

Legal entity responsible for the study

Foundation Medicine

Funding

Foundation Medicine

Disclosure

A.B. Schrock, D. Fabrizio, Y. He, J. Chung, P.J. Stephens, J.S. Ross, V.A. Miller, S. Ramkissoon, J.A. Elvin, S.M. Ali: Employee with stock ownership in Foundation Medicine. M. Resnick: Advisory board for PathAI. S.J. Klempner: Received honoraria from Foundation Medicine. All other authors have declared no conflicts of interest.

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