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    Baseline mutational profiles of patients with carcinoma-of-unknown-primary-origin (CUP) enrolled onto CUPISCO

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    Authors
    Mileshkin, L.
    Karapetyan, A. R.
    Beringer, A.
    Bochtler, T.
    Chalabi, N.
    Cook, Natalie
    Duran-Pacheco, G.
    Golding, S.
    Hoglander, E.
    Losa, F.
    Moch, H.
    Pauli, C.
    Ross, J. S.
    Sokol, E. S.
    Tothill, R. W.
    Westphalen, C. B.
    Kramer, A.
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    Affiliation
    Medical Oncology, Peter MacCallum Cancer Centre, East Melbourne, VIC,Australia
    Issue Date
    2021
    
    Metadata
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    Abstract
    Aims: NCCN guidelines consider next-generation sequencing important in therapeutic decision-making in CUP. CUPISCO (NCT03498521) is an ongoing, phase II, randomized study of targeted therapy/cancer immunotherapy vs platinum-based chemotherapy in ESMO-guideline-defined unfavourable CUP. We present a preliminary, descriptive molecular analysis of ∼50% of patients designated for enrollment. Methods: Upon enrollment, comprehensive genomic profiling, including determination of microsatellite instability and tumour mutational burden (TMB), was performed on formalin-fixed, paraffin-embedded issues using the F1CDx assay. Gene alterations (GAs) found in ≥3% of patients were analyzed using multiple correspondence analyses and hierarchical clustering to identify co-occurrences. Results: Median age was 61.5 years (n = 346 [Apr 2021]; range: 22– 84); median TMB, 2.5 mutations/Mb (0–63.0). In our analysis, 30% of patients carried a potentially targetable GA. Most-frequent GAs were TP53 (44%), CDKN2A (32%), KRAS (21%; 2% G12C alterations), CDKN2B (21%), ARID1A (13%), STK11 (13%), MTAP (12%), PIK3CA (10%), MYC (8%), PBRM1 (8%), BAP1 (8%), and FGFR2 (8%). Beyond PIK3CA and FGFR2, other targetable GAs were identified in EGFR (2%), ERBB2 (6%), ALK (0.3%), ROS1 (1%), MET (2%), NTRK1 (1%), and BRAF (6%). The frequency of microsatellite instability- and TMB-high (> 16 mutations/Mb) samples was 3% and 9%, respectively. Based on hierarchical clustering of co-mutational profiles, multiple clusters were identified in the study cohort, each characterized by specific GA cooccurrences. Conclusions: This descriptive analysis sheds further light on the molecular landscape in patients with poor-prognosis CUP. Our analyses demonstrate that CUP cases can be clustered based on molecular profiling; further studies are needed to determine if these clusters carry clinical relevance. Our early results suggest that comprehensive genomic profiling of CUP samples identifies therapeutically relevant GAs in a significant proportion of patients and could thus guide personalized treatment of these tumors.
    Citation
    Mileshkin L, Karapetyan AR, Beringer A, Bochtler T, Chalabi N, Cook N, et al. Baseline mutational profiles of patients with carcinoma-of-unknown-primary-origin (CUP) enrolled onto CUPISCO. Asia-Pacific Journal of Clinical Oncology. 2021;17:129-30.
    Journal
    Asia-Pacific Journal of Clinical Oncology
    URI
    http://hdl.handle.net/10541/624844
    Type
    Meetings and Proceedings
    Language
    en
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