1950P - Squamous cell carcinoma of unknown primary (SCCUP): A genomic landscape study

Background

SCCUP refers to any SCC for which the primary tumor origin cannot be identified despite guideline-directed evaluation. Although strategies employing comprehensive genomic profiling (CGP) to identify targeted treatments for non-SCC CUP have shown benefit, the genomic landscape in SSCUP remains poorly defined. Here we describe results of CGP testing in patients with SCCUP.

Methods

Cases of advanced SCCUP were identified in the FoundationOne CDx database by review of clinical history, pathology records, and whole slide scan images. Samples suspicious for head and neck SCC (HNSCC) and non-small cell lung cancer were excluded. Samples underwent DNA extraction and sequencing to identify genomic alterations (GA), microsatellite instability (MSI) status, tumor mutation burden (TMB), genomic loss of heterozygosity (gLOH), and genomic mutational signature. PD-L1 expression was determined by IHC.

Results

443 SSCUP cases were identified. Common sites of SSCUP presentation included lymph nodes (LN) (41.1%), liver (15.6%), soft tissue (15.1%), bone (7.2%), and brain (4.7%). The most frequently involved LN sites were inguinal (14.4%), axillary (9.0%), non-HNSCC supraclavicular (4.5%), pelvic (3.8%), and retroperitoneal (3.2%). A mean of 6.5 GAs were observed per case. The most frequent non-targetable GAs involved TP53 (62.5%), CDKN2A (37.0%), CDKN2B (19.6%), KMT2D (18.3%), and TERT (16.0%); the most frequent GAs potentially targetable in biomarker-driven trials included PIK3CA (27.3%), PTEN (15.1%), MTAP (13.1%), NOTCH1 (8.4%), and KRAS (10.4%). Among all SCCUP cases, 2.0% had MSI-High status, 4.7% had high gLOH score (16% threshold), and 33.9% had TMB ≥ 10. Among 204 cases with available PD-L1 testing, 39.2% were low-positive (Tumor Proportion Score [TPS] 1-49%) and 29.9% were high positive (TPS ≥ 50%). HPV infection was identified in 23.3%, while a UV light signature was found in 8.4% of cases, signifying a likely cutaneous origin.

Conclusions

Although this study suggests that putative targeted therapy opportunities in SCCUP are limited, several identified GAs may inform eligibility for biomarker-specific “basket” trials. SCCUPs frequently exhibit biomarkers associated with immunotherapy response.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Research funding support was provided in part from the National Cancer Institute (HHS - NIH) Cancer Center Support Grant P30CA046934 awarded to University of Colorado.

Disclosure

D.C. Pavlick: Financial Interests, Personal, Full or part-time Employment: Foundation Medicine, Inc; Financial Interests, Personal, Stocks/Shares: F. Hoffmann-La Roche AG. S.L. Davis: Financial Interests, Personal, Stocks/Shares: Johnson and Johnson; Financial Interests, Institutional, Local PI, Local PI of Clinical Trials: BMS; Financial Interests, Institutional, Local PI: Merck, Symphogen, I-Mab, Trisalus, Tvardi, EMD Serono, Oric Pharmaceuticals. C. Lieu: Financial Interests, Institutional, Local PI, Research Funding: Genentech. L.S. Graham: Financial Interests, Institutional, Local PI: Johnson and Johnson, Seattle Genetics. P. Spiess: Other, Personal, Leadership Role, President: Global Society of Rare Genitourinary Tumors; Other, Personal, Leadership Role, Vice-Chair: NCCN bladder and penile cancer panel; Other, Personal, Member: ASCO/EAU panel on penile cancer. R. Li: Financial Interests, Research Funding: Predicine, Veracyte, CG Oncology, Valar Labs, Merck; Non-Financial Interests, Advisory Role, Clinical trial protocol committee: CG Oncology, Merck, Janssen; Non-Financial Interests, Advisory Role, Scientific Advisor/Consultant: Bristol Myers Squibb, FerGene, Arquer Diagnostics, UroGen Pharma, Lucence, Thericon, Merck, CG Oncology, Janssen. A. Kamat: Financial Interests, Personal, Advisory Board: Merck, Seagen, Janssen, CG Oncology, Astellas, Ferring, Biological Dynamics, Bristol Myers Squibb, Cystotech, Eisai, EnGene, Imagin Medical, Imvax, Incyte, Medac, Nonagen Bioscience, Pfizer, Photocure, Protara Therapeutics, Roche, Sesen Bio (now Carisma), Theralase, Urogen Pharma, US Biotest, Vivet Therapeutics; Financial Interests, Personal, Member of Board of Directors, President: International Bladder Cancer Group (IBCG); Financial Interests, Personal, Other, Editorial Board: European Urology Oncology, Journal of Urology, UroToday; Financial Interests, Personal, Member of Board of Directors, Co-President: International Bladder Cancer Network (IBCN); Financial Interests, Institutional, Advisory Board: CyPRIT; Financial Interests, Institutional, Research Grant: FKD Therapies (now Ferring), Patient-Centered Outcomes Research Institute (PCORI), Photocure, Seagen, EnGene, Arquer Diagnostics, SWOG; Non-Financial Interests, Member of Board of Directors: AUA; Non-Financial Interests, Advisory Role: EAU. P. Grivas: Financial Interests, Personal, Advisory Role: Merck, Bristol Myers Squibb, AstraZeneca, EMD Serono, Seattle Genetics, Pfizer, Janssen, Roche, Astellas Pharma, Gilead Sciences, BostonGene, Fresenius Kabi, Lucence Health, PureTech, G1 Therapeutics, Aadi Biosciences, CG Oncology, Strata Oncology, ImmunityBio, Asieris Pharmaceuticals, AbbVie; Financial Interests, Institutional, Research Funding: Pfizer, Bristol Myers Squibb, Merck, QED Therapeutics, GSK, Mirati Therapeutics, EMD Serono, G1 Therapeutics, Gilead Sciences, Acrivon Therapeutics, ALX Oncology, Genentech. J.M. Jacob: Financial Interests, Personal, Speaker, Consultant, Advisor: Janssen, Pfizer. G. Bratslavsky: Financial Interests, Personal, Other, Salary, stocks and ownership: Avicella; Financial Interests, Personal, Other, Salary and stocks: Aptametrix; Financial Interests, Personal, Ownership Interest: Ilgen, Taurus; Financial Interests, Institutional, Local PI: Ferring Pharmaceuticals, Curium US LLC, QED Therapeutics, Progenics Pharmaceutical, Janssen Research & Development, Astellas, CoImmune; Non-Financial Interests, Leadership Role, Past President: SUO-CTC; Non-Financial Interests, Officer, President-elect: Northeastern Section of AUA; Non-Financial Interests, Leadership Role, Deputy Director: Upstate Cancer Center. K. Wong: Financial Interests, Institutional, Full or part-time Employment: Foundation Medicine; Financial Interests, Institutional, Stocks/Shares: Roche. K. Murugesan: Financial Interests, Institutional, Full or part-time Employment, Employee of Foundation Medicine Inc., Cambridge, MA, USA: Foundation Medicine Inc.; Financial Interests, Institutional, Stocks/Shares, Own stock of Roche Holding AG, Basel, Switzerland: Roche Holding AG. D.I. Lin: Financial Interests, Personal, Full or part-time Employment: Foundation Medicine, Inc.; Financial Interests, Personal, Stocks/Shares: Roche. A. Necchi: Financial Interests, Institutional, Research Grant: Merck, AstraZeneca, Ipsen, BMS, Gilead; Financial Interests, Personal, Steering Committee Member: Roche, Janssen, Bayer, Astellas, AstraZeneca, Merck, Clovis Oncology; Financial Interests, Coordinating PI: Incyte; Financial Interests, Local PI: Pfizer; Non-Financial Interests, Leadership Role: Global society of Rare Genitourinary Tumors (GSRGT). J.S. Ross: Financial Interests, Personal, Full or part-time Employment, Medical Director: Foundation Medicine; Financial Interests, Personal, Stocks/Shares: Roche Holdings, Tango Therapeutics, Celsius Therapeutics. E.T. Lam: Financial Interests, Personal, Other, Consultant: Calithera Biosciencees; Financial Interests, Institutional, Local PI, Clinical Trial Funding: Advaxis, Amgen, Arrowhead Pharmaceuticals, Astellas, Biosplice Therapeutics, Bristol Myers Squibb, Calithera Biosciences, Decibel Therapeutics, Exelixis, F. Hoffmann-La Roche Ltd., Forma Therapeutics, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Onquality, Peloton Therapeutics, Pfizer, Phosplatin Therapeutics; Financial Interests, Institutional, Research Grant, Funding for Investigator Initiated Study/Clinical Trial: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. All other authors have declared no conflicts of interest.