Baseline mutational profiles of patients with carcinoma of unknown primary origin enrolled in the CUPISCO study

Abstract

Background: Patients with unfavorable carcinoma of unknown primary origin (CUP) have an extremely poor prognosis of ∼1 year or less, stressing the need for more tailored treatments, which are currently being tested in clinical trials. CUPISCO (NCT03498521) was a phase II randomized study of targeted therapy/cancer immunotherapy versus platinum-based chemotherapy in patients with previously untreated, unfavorable CUP, defined as per the European Society for Medical Oncology guidelines. We present a preliminary, descriptive molecular analysis of 464 patients with stringently diagnosed, unfavorable CUP enrolled in the CUPISCO study.

Materials and methods: Genomic profiling was carried out on formalin-fixed, paraffin-embedded tissue to detect genomic alterations and assess tumor mutational burden and microsatellite instability.

Results: Overall, ∼32% of patients carried a potentially targetable genomic alteration, including PIK3CA, FGFR2, ERBB2, BRAF^V600E, EGFR, MET, NTRK1, ROS1, and ALK. Using hierarchical clustering of co-mutational profiles, 10 clusters were identified with specific genomic alteration co-occurrences, with some mirroring defined tumor entities.

Conclusions: Results reveal the molecular heterogeneity of patients with unfavorable CUP and suggest that genomic profiling may be used as part of informed decision-making to identify the potential primary tumor and targeted treatment options. Whether stringently diagnosed patients with unfavorable CUP benefit from targeted therapies in a similar manner to those with matched known primaries will be a key learning from CUPISCO.

Keywords: genomic profiling; molecular targeted therapy; neoplasms; precision medicine; unknown primary.

Figure 1

Genomic landscape of patients enrolled in CUPISCO. Overall frequency of (A) all genomic alterations and (B) targetable genomic alterations. RE, gene rearrangement; SV, short variant.

Figure 2

Mutational clustering of patients enrolled in CUPISCO. (A) Overview of patient clusters based on mutational profiles and (B) most prevalent genomic alterations by cluster. RE, gene rearrangement; SV, short variant.

Figure 3

Distribution of clinical features by cluster. (A) Age, BMI, and TMB score; (B) Sex, tobacco usage, biopsy location, TMB level, MSI status, alterations in MMR genes,^a and alterations in other DNA repair genes.^b BMI, body mass index; MMR, DNA mismatch repair; MSI, microsatellite instability; MSS, microsatellite stable; TMB, tumor mutational burden. ^aMSH2, MSH3, MSH6, MLH1, and PMS2.^bMUTYH, PARP1, ERCC4, RAD51B, XRCC2, RAD54L, BRCA1, MRE11A, NBN, FANCC, BRCA2, FANCG, BRIP1, FANCL, PALB2, RAD51C, POLE, ATRX, ATM, ATR, and CHEK1.

Figure 4

Mutational signatures by cluster. Mutational signatures were calculated for each sample. Overall, 409 samples were assessable for mutational signatures. APOBEC, apolipoprotein B messenger RNA-editing enzyme, catalytic polypeptide; MMR, DNA mismatch repair.