Understanding the clinical and molecular phenotype of cancer of unknown primary (CUP) with a lung cancer profile.

e20567 Background: Advances in cancer diagnostics including genomic testing has improved our ability to determine the likely tissue of origin (TOO) in CUP. We aimed to describe the clinical and molecular phenotype of CUPs with a lung cancer profile enrolled in SUPER and SUPER-NEXT, a prospective national cohort study with clinical information and molecular data of provisional CUP pts. Methods: Cases were identified with a lung cancer profile based on genomic test results including a dominant tobacco smoking signature, typical lung cancer driver mutations and algorithmic TOO prediction using a Nanostring RNA gene-expression test or whole genome and transcriptome sequencing. Clinical and histopathological characteristics were reviewed to see how often this was consistent with a lung cancer diagnosis. Results: Within the cohort we identified 76/449 (17%) CUP pts with a lung cancer profile who received ≥1 molecular test. Median age was 61 (range:29-82) with 58% male. Key features are in Table 1. 65/76(86%) of pts received systemic therapy, of whom 41 received immune checkpoint inhibitor (ICI) +/- chemotherapy. mOS was 12.9months and was more favourable in pts who received ICI treatment compared to those who didn’t (16.7 vs 9.8 months, p-value 0.02). Conclusions: CUP pts with a lung cancer profile often have typical symptoms and disease sites but most are TTF-1 negative. Detection of a dominant smoking signature and/or lung mutational profile aided in a diagnosis. SMARCA4 (BRG1) mutations occurred in 45% of pts, suggesting BRG1 IHC may be a useful test in the absence of mutation data. Clinicians should be aware of this poor prognostic group with atypical histopathology that may be labelled as CUP but benefit from ICI. Count(%) Smoker – Current/Past 66/76(87) Presentation Pain Lump Dyspnoea Incidental 23/76(30) 11/76(14) 9/76(12) 20/76(26) Site of disease Nodal Lung Bone Liver Adrenal 52/76(68) 44/76(58) 31/76(41) 13/76(17) 6/76(8) Metastatic at diagnosis 71/76(93) Immunohistochemistry (IHC) TTF1+ve CK7+/CK20- PDL>1% 17/69(25) 48/68(71) 22/36(61) TOO assay - Lung 37/53(70) Genomic alterations reported SMARCA4 STK11 KEAP1 KRAS CDKN2A MET EGFR 33/73(45) 24/73(33) 21/73(29) 16/73(22) 7/73(10) 4/73(5) 3/73(4) Dominant smoking signature reported 52/59(88) TMB High (>10 mt/MB) 38/71(54)