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With the evolution of oligometastatic care, it's prevalent to note not all histologies (or anatomic sites) respond equivalently to systemic therapy or radiation. Dr. Kamran Ahmed, a radiation oncologist at Moffitt Cancer Center, shares his study at 2022 ASTRO evaluating single base substitution mutations across various metastatic sites and within matched primary-metastatic patient samples.


This analysis highlights diversity in mutation type and incidence among metastases.

This study evaluates collected institutional biorepository for metastatic (Met) tumors that underwent targeted exome sequencing for 1,327 cancer-related genes. The collected institutional biorepository was then evaluated for metastatic (Met) tumors which underwent targeted exome sequencing for 1,327 cancer-related genes. The patient cohorts included – 1. Non-matched Mets (N-Met; n=794 [707 tumors]) and 2. A subset of matched primary (Pri)-Met (M-Pri-Met; n=207 [390 tumors]). Subsequently, exome data were enriched for somatic non-silent mutations by filtering out artifacts and known germline and silent mutations. Mutation signatures based on 6 nucleotide base alterations (96 subtypes) were generated, then compared across samples followed by hierarchical clustering analysis to assess mutation signature correlation to the COSMIC mutation database. The mutation signatures were assessed across unique histology groups from Prim (n=17) and Met (n=16) sites and compared by Kruskal-Wallis test. Counts of individual mutations were related to given mutation signatures. A generalized linear mixed model was used to infer the odds ratio (OR) of mutation incidence in Pri vs Met tumors.

The outcomes showed across all Mets C>T and G>A alterations were identified in 23% and 21% of tumors, respectively, whereas T>A was <2%. There were notable differences seen in the proportions of mutation signatures (n=9) across Pri histology (range p < 0.03 to 1.0e−16) and among different Met sites within a given histology. For example, our 6th signature was associated with AID/APOBEC family activity and varied across Pri histology (p = 1.0e−13) and within Met sites (p = 4.3e−09).  In contrast, the 4th signature was related to ERCC2 mutation, but only differed across Pri histology and not Met site. The median number of mutations related with mutation signatures was 27 (range: 1-1404) with the highest counts in melanoma. Within the M-Pri-Met analysis, several genes were identified to be either private or shared among tumors. For example, within the M-Pri-Met breast (n=93) group, EPHB4 mutation was concordant in 58% of samples with a LogOR 1.38 (95% CI 1.2-13.2; p= 0.02) in Pri vs Met. In contrast, BRAF mutation was 40% concordant with higher odds of being in Met vs Pri (p=0.04). No significant differences were identified in the lung M-Pri-Met cohort (n=45). Individual mutations did not appear to be different in lung histology, we did observe differences in the proportions of mutation signatures within individual patient tumors.

In conclusion, the study gifts a deeper knowledge of similarities and differences amongst metastases, aiding in biologically informed metastasis-directed therapy.

Read Dr. Ahmed's 2022 ASTRO Abstract.

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