Circadian robustness as an independent predictor of prolonged progression-free survival (PFS) and overall survival (OS) in 436 patients with metastatic colorectal cancer (mCRC).

Abstract

464 Background: The rest-activity rhythm is a biomarker of the circadian timing system (CTS), whose disruption accelerates cancer progression in experimental models. Prior studies in cancer pts identified a reliable measure of CTS function in cancer pts based on non invasive wrist actigraphy monitoring. Methods: The prognostic value of I<O, the ratio between activity counts in-bed vs out-of-bed, was explored for PFS and OS in mCRC. The rest-activity rhythm was recorded for >48 h in 436 mCRC pts from 3 international cohorts. Data were stratified per cohort, and analyzed with Kruskall-Wallis ANOVA, log rank tests, and multivariate Cox analyses. Results: Median age was 59.2 y. Pts were mainly men (62.6%); had good performance status (PS = 0, 58.2%; 1, 33%); > 2 metastatic sites (51.6%); metastases in liver (79%) or lung (38.8%); were chemotherapy-naïve (54.6%). After baseline actigraphy recording, pts received a median of 8 courses of oxaliplatin- or irinotecan-based chemotherapy, including chronomodulated schedules (chrono; 81.4%). Despite a strong correlation with PS (p< 0.0001), I<O independently influenced both PFS and OS. Thus, both median PFS and OS nearly doubled in the pts with I<O above 97.5% (upper two quartiles) as compared to those with I<O below 93.2% (lowest quartile). Median PFS ranged from 4.8 to 10.6 months (log rank, p<0.001) and median OS from 10.1 to 20.6 months (p<0.001). In multivariate analyses, I<O ranked as the second best independent predictor of PFS, after metastases surgery, with a hazard ratio (HR) of 0.967 [95% C.L., 0.95-0.98] (p<0.001). I<O ranked as first independent predictor of OS, with a HR of 0.95 [0.94-0.97] (p<0.001). Forrest plots revealed consistent HR of I<O for PFS and OS in each cohort. Conclusions: The circadian biomarker indicator I<O is a robust, consistent and independent quantitative predictor of both PFS and OS in mCRC pts. Rest-activity rhythm monitoring deserves further testing for helping accurate determination of mCRC prognosis. The biological significance of I<O implies that specific treatments of circadian disruption could enhance survival in cancer pts.