Analysis of Soft Tissue Metastases Across Primary Histologies Comparing Radiosensitivity, Immune Infiltration, and Mutational Frequency

Abstract

The soft tissues are a poorly studied subsite for metastases with unclear treatment paradigms. We hypothesize elucidating differences in these metastases by primary histology may allow for optimization of therapies.We isolated soft tissue metastases with microarray data. A subset also had data from a 1,327-gene targeted exome sequencing assay. An existing radiosensitivity index (RSI) was used to estimate intrinsic radiosensitivity, where higher values denote radioresistance (0-1), with a cutpoint of 0.375. An existing 12-gene chemokine signature (12CK) was used to measure the degree of microenvironment inflammation, where higher scores denote greater inflammation. Samples with exome data were enriched for somatic mutations by filtering out artifacts and known germline/silent mutations (MF). Differences by histology were evaluated by the Kruskal-Wallis H test. Correlations between RSI, 12CK, and MB were evaluated by Spearman's rho.Between 1986 and 2010, we found 202 soft tissue metastases from unique patients across 11 primary histologies (breast [B], colorectal [CR], endometrial [E], head and neck [HN], melanoma [M], non-small cell lung [NSC], ovarian [O], renal [R], sarcoma [S], thyroid [T], and urothelial [U]). With a median follow-up of 173.2 months (95% CI 156.7-189.8), median survival was 62.4 months (95% CI 47-77.9). 41 samples across 4 histologies had targeted exome data. Median values for RSI, 12CK, and MB were 0.415 (interquartile range [IQR] 0.306-0.515), 8.20 (IQR 7.16-9.24), and 89.5 (IQR 69.5-122.75), respectively. Significant differences existed among histologies in all metrics (Table 1). After Bonferroni correction, pairwise comparisons were significant for HN-M (P = 0.008) in RSI; T-HN (P = 0.013), U-HN (P = 0.023), O-HN (P = 0.000), B-HN (P = 0.023), CR-HN (P = 0.006) in 12CK; and T-M (P = 0.024) in MB. Correlation between RSI and 12CK was significant (rho = -0.403, P < 0.001), but correlations between MF and RSI/12CK were not.In this novel exploratory analysis of soft tissue metastases, a number of histologies demonstrated sufficient radiosensitivity (RSI < 0.375) to consider radiotherapy as a component of management. Significant differences across primary histologies also suggest an opportunity for dose personalization. Significant differences in microenvironment inflammation and mutational frequency across primary histologies also may inform personalization of immunotherapy and other targeted therapies.