Abstract 10P
Background
Endometrial cancer (EC) patients harbouring POLE mutations have been shown exceptionally good survival outcomes allowing de-escalation of adjuvant treatment. POLE encodes for the Pol ε catalytic subunit capable of correcting DNA synthesis errors; pathogenic mutations within the exonuclease domain (EDM) result in an ultramutated phenotype. So far, 11 POLE EDM variants have been recognized as hotspot mutations. Given the increasing availability in clinical practice of comprehensive genome profiling (CGP), the interpretation of non-hotspot EDM variants has become challenging.
Methods
EC patients enrolled in a CGP programme at Fondazione Policlinico Universitario Agostino Gemelli IRCCS were profiled using TSO500HT. VCF files containing identified variants were analyzed developing an in-house Python and R language script. The following parameters including the frequency of C > A, C > G, T > G substitutions, tumor mutational burden (TMB), the frequency of indels, and the presence of recurrent mutations were evaluated and a score to interpret POLE mutations was recalibrated from Castillo et al. published score on TCGA data.
Results
From January 2022 to May 2023, CGP was available for 392 EC patients. New thresholds for the frequency of C > A, C > G, T > G substitutions and indels were calculated based on the mean of the median values of each parameter comparing POLE EDM hotspots vs POLE benign variants and wild type (WT) cases. Overall, the score correctly identified the POLE hotspot mutations in 40/42 patients. One of the 2 misclassified cases was a FIGO stage IIIC1 case, displaying a TMB of 36.5; the other displayed a TMB of 87. 5 POLE EDM non-hotspot variants were identified (D287E, N363K, T278M, D262H, R375Q) and none of them reached a score ≥ 4. None of these cases displayed a COSMIC signature 10 as expected for POLE EDM hotspot cases. Among the co-mutations, ATM and APC variants were reported to be differentially expressed among POLE EDM hotspots and POLE EDM non-hotspots vs POLE benign and WT cases (ATM: 60%, 60% vs 10%, 11%; APC: 35%, 20% vs 3.8% and 0% respectively).
Conclusions
We adapted Castillo’s TCGA-based POLE score to a CGP assay. This approach could be helpful to interpret POLE EDM non hotspots variants emerging from wide routine genomic characterization.
Editorial acknowledgement
Clinical trial identification
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
C. Nero: Financial Interests, Personal, Other, Travel grant: Illumina. D. Lorusso: Financial Interests, Institutional, Funding: Clovis, GSK, MSD; Financial Interests, Personal, Funding: AstraZeneca, Clovis Oncology, MSD; Non-Financial Interests, Personal, Advisory Board: GCIG. G. Scambia: Non-Financial Interests, Personal, Advisory Board: Tesaro, Johnson & Johnson; Financial Interests, Institutional, Funding: MSD, Clovis Oncology. All other authors have declared no conflicts of interest.
Resources from the same session
146P - The prognosis value of heat-shock proteins in esophagogastric cancer: A systematic review and meta-analysis
Presenter: Eric Nakamura
Session: Cocktail & Poster Display session
Resources:
Abstract
148P - Identification of potential predictive biomarkers for ovarian cancer chemotherapy response
Presenter: Alsina Nurgalieva
Session: Cocktail & Poster Display session
Resources:
Abstract
149P - Rare RAS mutations are associated with recurrence patterns and recurrence-free survival in colon cancer: First results from Morocco
Presenter: Fatima Agy
Session: Cocktail & Poster Display session
Resources:
Abstract
151P - Development of a predictive model for response to neoadjuvant chemoradiation therapy of rectal cancer using the immunologic profile
Presenter: Eun Shin
Session: Cocktail & Poster Display session
Resources:
Abstract
152P - Biomarkers of neoadjuvant chemoradiotherapy response in locally advanced rectal cancer
Presenter: Cibele Masotti
Session: Cocktail & Poster Display session
Resources:
Abstract
153P - BRAF variants and therapy outcomes in melanoma
Presenter: Eftychia Chatziioannou
Session: Cocktail & Poster Display session
Resources:
Abstract
154P - The impact of proton pump inhibitors in the prognosis of patients with non-metastatic nasopharyngeal carcinoma
Presenter: João Barbosa Martins
Session: Cocktail & Poster Display session
Resources:
Abstract
155P - Use of machine learning for the identification of molecular biomarkers to predict response to neoadjuvant chemotherapy in locally advanced breast cancer patients
Presenter: María Del Río Pisula
Session: Cocktail & Poster Display session
Resources:
Abstract
156P - Molecularly driven therapy recommended by a molecular tumor board: Accessible option or privilege for a minority of patients? A single-center experience from the Czech Republic
Presenter: Michal Eid
Session: Cocktail & Poster Display session
Resources:
Abstract
157P - PCM4EU academy: An educational program for precision oncology
Presenter: Loic Verlingue
Session: Cocktail & Poster Display session
Resources:
Abstract