Differences Between Colon Cancer Primaries and Metastases Using a Molecular Assay for Tumor Radiation Sensitivity Suggest Implications for Potential Oligometastatic SBRT Patient Selection

Abstract

Purpose/Objectives We have previously developed a multigene expression model of tumor radiosensitivity (RSI) with clinical validation in multiple independent cohorts (breast, rectal, esophageal, and head and neck). The purpose of this study was to assess differences in RSI scores between primary colon cancer and metastases. Methods and Materials Patients were identified from our institutional IRB approved prospective observational protocol. A total of 704 metastatic and 1,362 primary lesions were obtained from a de-identified meta-data pool. RSI was calculated using the previously published ranked based algorithm. An independent cohort of 29 lung or liver colon metastases treated with 60 Gy in 5 fractions stereotactic body radiotherapy (SBRT) was used for validation. Results The most common sites of metastases included liver (n=374; 53%), lung (n=116; 17%), and lymph nodes (n=40; 6%). Sixty percent of metastatic tumors compared with 54% of primaries were in the RSI-radioresistant (RSI-RR) peak, suggesting that, metastatic tumors may be slightly more radioresistant than primaries (p=0.01). In contrast, when we analyzed metastases based on anatomical site, we uncovered large differences in RSI. The median RSIs for metastases in descending order of radioresistance were ovary (0.48), abdomen (0.47), liver (0.43), brain (0.42), lung (0.32), and lymph nodes (0.31), p<0.0001. These findings were confirmed when the analysis was restricted to lesions from the same patient (n=139). In our independent cohort of treated lung and liver metastases, lung metastases had an improved local control (LC) rate over patients with liver metastases (2 yr LC 100% vs. 73.0%, p=0.026). Conclusions Assessment of radiosensitivity between primary and metastatic tissues of colon cancer histology, reveals significant differences based on anatomical location of metastases. These initial results warrant validation in a larger clinical cohort.

Decision support systems for personalized and participative radiation oncology

“…Large differences in RSI based on anatomical site of metastases (P b .0001) were observed, which persisted when the analysis was restricted to lesions from the same patient (P b .0001). Initial clinical validation in a cohort of 29 liver and lung metastases patients treated with stereotactic body radiation therapy confirmed these results [310]. Appreciation of the strengths and weaknesses of the RSI is essential when evaluating these results and the implications.…”

“…These efforts could be significantly augmented by genetic analysis, providing superior selection of the target population, and therefore increasing the likelihood of success. At the vanguard to personalized therapy within radiation oncology is the development of a radiation sensitivity index (RSI), a multigene expression model proposed to predict radiation responsiveness (a high RSI indicates radioresistance) [310][311][312][313]. The RSI signature has been previously validated [313], and was recently applied to primary and metastatic colon cancer samples [310].…”

“…At the vanguard to personalized therapy within radiation oncology is the development of a radiation sensitivity index (RSI), a multigene expression model proposed to predict radiation responsiveness (a high RSI indicates radioresistance) [310][311][312][313]. The RSI signature has been previously validated [313], and was recently applied to primary and metastatic colon cancer samples [310]. Large differences in RSI based on anatomical site of metastases (P b .0001) were observed, which persisted when the analysis was restricted to lesions from the same patient (P b .0001).…”

Tumour radiosensitivity is associated with immune activation in solid tumours

“…RSI was designed to detect intrinsic tumor radiosensitivity using 10 genes that play a role in DNA damage response, histone deacetylation, cell-cycle regulation, apoptosis, and proliferation. (12,28,29) RSI has been shown to predict outcomes among patients treated with radiation therapy with breast cancer(13,30), head and neck cancer, rectal cancer, esophageal cancer(12) pancreatic cancer,(15), glioblastoma(16), and metastatic colorectal cancer(14). In contrast, 12-CK was designed using 12 immune-related and inflammation-related genes with the purpose of detecting intra-tumoral lymphoid cell aggregates as a marker of immune activation.…”

Radiosensitivity index predicts for survival with adjuvant radiation in resectable pancreatic cancer

“…The RSI score has previously been validated in six independent, prospectively collected data sets, including esophageal, rectal, head and neck, breast, and colon cancer patients [10,11,14]. The RSI score is not specific to pancreatic cancer, but includes genes that affect DNA damage response, histone deacetylation, the cell cycle, apoptosis and cellular proliferation [11].…”