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Found 1 Presentation For Request "130p"

Poster Display session

130P - PTCH1 Genomic Alterations (GA) in human malignancies: A pangenomic study

Presentation Number
130P
Speakers
  • Jeffrey S. Ross (Albany, NY, United States of America)
Date
17.09.2020

Abstract

Background

Vismodegib and sonidegib are FDA approved for treatment of advanced basal cell carcinoma (BCC), but only 30-40% of patients (pts) respond to these drugs. Inactivating GA in the PTCH1 gene, a member of the sonic Hedgehog pathway, are potential biomarkers for BCC treated with vismodegib/sonidegib, but the pan-tumor landscape of PTCH1 GA is undefined.

Methods

297,209 consecutive clinically advanced cases of malignancy were submitted for comprehensive genomic profiling (CGP) using a hybrid capture based assay. Tumor mutational burden (TMB) and microsatellite instability (MSI) were determined as described (PMID: 28420421, 31445211). PD-L1 expression in tumor cells (Dako 22C3) was measured by IHC.

Results

Overall, 3,047 (1.0%) sequenced cases featured PTCH1 GA, including most frequently skin BCC (71%), medulloblastoma (22%), skin SCC (8%), skin adnexal carcinoma (5%), salivary gland carcinoma (2%) and CRC, NSCLC, GYN, breast carcinomas, and CUP (all 1%). 51% of patients were female and median age was 63 years (range <1 to 89+ years). The median TMB was 14 mutations/Mb with 45% TMB ≥ 20 reflecting the high UV exposure signature in the PTCH1 GA positive cohort. MSI high status was present in 25%, predominantly in the non-skin, non-UV exposed tumors. Low (1-49%) and high (≥50%) PD-L1 expression was present in 22% and high expression in 9% of cases. The most frequent co-altered genes included TP53 (58%), ARID1A (25%), KMT2D (22%), PIK3CA (20%), CDKN2A (20%), TERT (19%), KRAS (16%) and PTEN (15%). PTCH1 GA were 91% short variant mutations, 3% copy number changes and 5% gene rearrangements. SMO GA, which have been attributed to drug resistance in vismodegib treated pts, were exclusively identified in skin BCC samples.

Conclusions

Although highly associated with skin BCC, PTCH1 GA were also identified in other tumor types particularly associated with skin origin and associated with UV light exposure. Non-UV light exposed PTCH1 GA positive cases had significant MSI High enrichment and most cases tend to feature high TMB with associated potential for immunotherapy benefit. Further study of PTCH1 GA as a biomarker of vismodegib and sonidegib efficacy especially in non-skin tumors appears warranted.

Legal entity responsible for the study

Foundation Medicine Inc.

Funding

Foundation Medicine Inc.

Disclosure

J.S. Ross: Leadership role, Research grant/Funding (self), Shareholder/Stockholder/Stock options, Full/Part-time employment: Foundation Medicine Inc.; Advisory/Consultancy: Celsius Therapeutics. E.S. Sokol: Shareholder/Stockholder/Stock options, Full/Part-time employment: Foundation Medicine Inc. D.C. Pavlick: Full/Part-time employment: Foundation Medicine Inc. J-A. Vergilio: Shareholder/Stockholder/Stock options, Full/Part-time employment: Foundation Medicine Inc. J.K. Killian: Shareholder/Stockholder/Stock options, Full/Part-time employment: Foundation Medicine Inc. E. Williams: Shareholder/Stockholder/Stock options, Full/Part-time employment: Foundation Medicine Inc. N.A. Danziger: Full/Part-time employment: Foundation Medicine Inc. J. Tse: Full/Part-time employment: Foundation Medicine Inc. S. Ramkissoon: Shareholder/Stockholder/Stock options, Full/Part-time employment: Foundation Medicine Inc. E. Severson: Shareholder/Stockholder/Stock options, Full/Part-time employment: Foundation Medicine Inc.; Full/Part-time employment: Partners Healthcare. A. Hemmerich: Shareholder/Stockholder/Stock options, Full/Part-time employment: Foundation Medicine Inc. D. Duncan: Shareholder/Stockholder/Stock options, Full/Part-time employment: Foundation Medicine Inc. R. Huang: Shareholder/Stockholder/Stock options, Full/Part-time employment: Foundation Medicine Inc.; Licensing/Royalties, IHC patent: Roche/Ventana. R. Madison: Shareholder/Stockholder/Stock options, Full/Part-time employment: Foundation Medicine Inc. A.B. Schrock: Shareholder/Stockholder/Stock options, Full/Part-time employment: Foundation Medicine Inc. B. Alexander: Leadership role, Full/Part-time employment: Foundation Medicine Inc.; Research grant/Funding (institution): Celgene; Research grant/Funding (institution): Puma; Research grant/Funding (institution): Eli Lilly. J. Venstrom: Shareholder/Stockholder/Stock options, Full/Part-time employment: Foundation Medicine Inc.; Full/Part-time employment: Genentech. P. Reddy: Travel/Accommodation/Expenses, Shareholder/Stockholder/Stock options, Full/Part-time employment: Foundation Medicine Inc. K. McGregor: Shareholder/Stockholder/Stock options, Full/Part-time employment: Foundation Medicine Inc. J. Elvin: Shareholder/Stockholder/Stock options, Full/Part-time employment: Foundation Medicine Inc..

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