PURPOSE
Assess the clinical impact (CI) of UV-related DNA damage signatures (UVsig) in Veterans with cancer of unknown primary (CUP) and cancer of extracutaneous origin (CEO).
BACKGROUND
UVsig have been reported in CUP and CEO (i.e. head and neck cancer and lung cancer). The presence of UVsig suggests a cutaneous origin and potential misclassification of CEO using conventional histopathologic evaluation. Literature on the association of UVsig in pan-cancer genomics is limited.
METHODS
This is a retrospective study of Veterans who underwent comprehensive genomic profiling with FoundationOne CDx during 2/1/2019 to 9/30/2022 through the VA National Precision Oncology Program. The outcome was the CI of UVsig (high, medium, and low) determined by blinded chart reviews: (1) high: UVsig leading to change in diagnoses (CID) and a different first-line therapy (FLT) would have been offered; (2) medium: UVsig leading to CID, but appropriate FLT offered; (3) low: diagnoses modified by clinicians and treated as cutaneous cancers. NCCN Guidelines were referenced for FLT.
DATA ANALYSIS
Descriptive statistics and chi-square tests were utilized to evaluate the UVsig CI.
RESULTS
Among 5,565 cases with 10 or more assessable alterations for UVsig analysis, 650 (11.7%) were positive for UVsig. CUP and CEO cohorts each had 41 cases analyzed. In the CUP cases, 20 (48.8%), 9 (21.9%), and 12 (29.3%) were categorized as having high, medium, and low CI, respectively; and in the CEO cases, it was 22 (53.7%), 15 (36.6%), and 4 (9.8%). There was no difference statistically between the CUP and CEO groups on the percentage distribution of CI (p=0.06). Among the 42 out of 82 cases having high CI, 37 (88.1%) received cytotoxic chemotherapy without any indication, and 5 (11.9%) were not offered immunotherapy (IO) as FLT. More than half of the 82 cases had high CI; more than 90% of the CEO cases had high and medium CI.
IMPLICATIONS
UVsig serves as a useful biomarker for cancers with cutaneous origin. About 1% of the 5,565 cases analyzed had high UVsig CI. Knowledge of UVsig could lead to omission of chemotherapy (hence avoiding toxicities) or addition of IO (for potential benefits).