e-Poster Presentation Clinical Oncology Society of Australia Annual Scientific Meeting 2021

Baseline mutational profiles of patients with carcinoma-of-unknown-primary-origin (CUP) enrolled onto CUPISCO (#240)

Linda Mileshkin 1 , Armen R Karapetyan 2 , Andreas Beringer 3 , Tilmann Bochtler 4 , Nasséra Chalabi 5 , Natalie Cook 6 , Gonzalo Durán-Pacheco 7 , Sophie Golding 8 , Elen Höglander 9 , Ferran Losa 10 , Holger Moch 11 , Chantal Pauli 12 , Jeff S Ross 13 14 , Ethan S Sokol 15 , Richard W Tothill 16 , C. Benedikt Westphalen 17 , Alwin Krämer 18
  1. Medical Oncology, Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia
  2. Product Development Data Sciences, F. Hoffmann-La Roche Ltd, Basel, Switzerland
  3. Product Development Medical Affairs, F. Hoffmann-La Roche Ltd, Basel, Switzerland
  4. Molecular Hematology/Oncology, German Cancer Research Center (DKFZ) and University of Heidelberg, Heidelberg, Germany
  5. Product Development Medical Affairs, F. Hoffmann-La Roche Ltd, Basel, Switzerland
  6. Medical Oncology, The University of Manchester and the Christie NHS Foundation Trust, Manchester, United Kingdom
  7. Statistics, F. Hoffmann-La Roche Ltd, Basel, Switzerland
  8. Statistics, F. Hoffmann-La Roche Ltd, Basel, Switzerland
  9. Oncology Biomarker Development - gRED , F. Hoffmann-La Roche Ltd, Basel, Switzerland
  10. Medical Oncology, Hospital de Sant Joan Despí Moisès Broggi, ICO Hospitalet, Barcelona, Spain
  11. Pathology, University of Zürich and University Hospital Zürich, Zürich, Germany
  12. Pathology, University of Zürich and University Hospital Zürich, Zürich, Germany
  13. Department of Pathology and Urology, Foundation Medicine, Inc., Cambridge, MA, USA
  14. Department of Pathology and Urology, SUNY Upstate Medical University, Syracuse, NY, USA
  15. Cancer Genomics Research, Foundation Medicine, Inc., Cambridge, MA, USA
  16. Clinical Pathology, University of Melbourne, Melbourne, Australia
  17. Department of Internal Medicine III, Comprehensive Cancer Center Munich, Ludwig Maximilian University of Munich, Munich, Germany
  18. Molecular Hematology/Oncology, German Cancer Research Center (DKFZ) and University of Heidelberg, Heidelberg, Germany

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 unfavorable 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 tumor mutational burden (TMB), was performed on formalin-fixed, paraffin-embedded tissues 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 co-occurrences.

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.

Abstract previously presented at ESMO 2021, 1804P, Benedikt Westphalen et al. Reused with permission.