Fuchs, Charles S.

3582 Background: The prognostic importance of the incidence, severity, type and duration of AEs pts experience during chemotherapy varies between tumor types, and the available evidence across the board is often conflicting. Here we investigated the impact of the overall severity of AEs among pts with mCRC receiving first-line oxaliplatin (Oxa)- and/or irinotecan(Iri)-based regimens. Methods: The overall severity of AE data (i.e., max grade (G) of all AEs) were available on 3,971 pts (median age 61; 60% male, 47% ECOG PS 1+; 57% 2+ metastatic sites) enrolled onto 6 1st-line randomized trials. Around 46%, 45%, and 9% of pts had received Oxa-, Iri-, and Oxa+Iri-based regimens, respectively. Pts receiving biologic agents were excluded. Stratified multivariate Cox models were used to assess the associations with overall survival (OS) and progression-free survival (PFS); adjusted hazard ratios (HRadj) and 95% confidence intervals (CIs) are reported. Results: Pts who only received Oxa-based treatment reported the lowest rate of G3+ AEs (p < .0001) compared to pts treated with Iri- or Oxa+Iri-based regimens. Older age, female gender, and PS 1 or 2+ were associated with higher grade AEs (all p < .0001). Considering AEs experienced within 6w after randomization, 10% and 61% of pts experienced G4+ and G2-3 AEs, respectively. G3+ AEs were associated with a shorter OS for both pts receiving Oxa- (HRadj= 1.2, 95% CI, 1.1-1.3, padj < .0001) and Iri-based regimens (HRadj= 1.4, 95% CI, 1.2-1.5, padj < .0001). For the entire treatment course, 19% and 72% of pts experienced G4+ and G2-3 AEs, respectively. For Oxa-based regimens, pts with G3+ AEs had a longer OS (HRadj= 0.86, 95% CI, 0.78-0.94, padj = .0016), whereas G3+ AEs were associated with a shorter OS (HRadj= 1.2, 95% CI, 1.1-1.4, padj = .0004) for pts treated with Iri-based regimens. Similar patterns were seen for PFS. Conclusions: Pts who reported higher grade AEs during initial treatment (≤6w) have significantly worse outcome than those who do not. Further analyses with treatment exposure/detailed dose-AE profile and its impact on survival are warranted.

3535 Background: CRC is known to be a heterogeneous disease. This study quantifies within pt heterogeneity in early lesion change rate (LCR) in the era of targeted agents compared to chemo alone and its potential impact on survival. Methods: Pts with 2-10 lesions measured at baseline were included. For each lesion, the early LCR was defined as the change in size (shrinking or growing) from baseline to 12 weeks on treatment. Within pt heterogeneity in early LCR among lesions was estimated by standard deviation (STD). A larger value of STD indicates larger variation of LCR per pt. Stratified multivariate Cox models were used to assess the associations between LCR STD with overall survival (OS). Adjusted hazard ratios (HRadj) and 95% confidence intervals (CIs) are reported. Results: Data were available on 9,092 mCRC pts (median age 61; 60% male, 55% ECOG PS 0; 61% 2+ metastatic sites) enrolled in 16 1st-line randomized trials, with 44%, 42%, and 10% of pts received chemo alone, + a VEGF inhibitor (VEGFi) or an EGFR inhibitor (EGFRi), respectively. LCR heterogeneity is the highest among pts received EGFRi but lowest among pts received VEGFi (Table). Overall, higher heterogeneity is associated with worst OS (HRadj1.22, 95% CI (1.16, 1.27)). The effect is most pronounced in pts received VEGFi (interaction p=0.0012). Conclusions: There was heterogeneity observed in lesion size changes within pts. Its magnitude varies across treatment approaches, and was associated with poor survival. This preliminary result reveals the great potentials to define novel response endpoint and refine treatment decision-making by incorporating heterogeneities in lesion changes. [Table: see text]

Abstract Background: Higher intake of long-chain ω-3 polyunsaturated fatty acids and nuts, rich plant sources of unsaturated fats, after colon cancer diagnosis are associated with improved survival. It is not known whether the amount or the distribution of other types of fat is associated with survival after colon cancer. Methods: We prospectively examined postdiagnostic total, animal, and vegetable fats, as well as the saturated, monounsaturated, polyunsaturated, and trans fat in relation to disease-free survival among 1,011 patients with stage III colon cancer. Patients were enrolled between 1999 and 2001 at the onset of adjuvant chemotherapy and followed for recurrence or death through 2009. Results: During median follow-up of 7 years, we observed 305 deaths and 81 recurrences (total events: 386). Neither total nor any specific type of dietary fat examined was statistically significantly associated with risk of cancer recurrence or death from any cause (disease-free survival) after stage III colon cancer. Conclusions: The amount and type (animal, vegetable, saturated, monounsaturated, polyunsaturated, and trans) of dietary fat consumed after colon cancer does not appear to be substantially associated with risk of recurrence or survival. Impact: Neither total nor major types (animal, vegetable, saturated, monounsaturated, polyunsaturated, and trans) of dietary fat consumed after colon cancer was associated with cancer recurrence or survival. Cancer Epidemiol Biomarkers Prev; 27(10); 1227–30. ©2018 AACR.

Abstract Background Previous genome-wide association studies (GWAS) have identified 42 loci (P < 5 × 10−8) associated with risk of colorectal cancer (CRC). Expanded consortium efforts facilitating the discovery of additional susceptibility loci may capture unexplained familial risk. Methods We conducted a GWAS in European descent CRC cases and control subjects using a discovery–replication design, followed by examination of novel findings in a multiethnic sample (cumulative n = 163 315). In the discovery stage (36 948 case subjects/30 864 control subjects), we identified genetic variants with a minor allele frequency of 1% or greater associated with risk of CRC using logistic regression followed by a fixed-effects inverse variance weighted meta-analysis. All novel independent variants reaching genome-wide statistical significance (two-sided P < 5 × 10−8) were tested for replication in separate European ancestry samples (12 952 case subjects/48 383 control subjects). Next, we examined the generalizability of discovered variants in East Asians, African Americans, and Hispanics (12 085 case subjects/22 083 control subjects). Finally, we examined the contributions of novel risk variants to familial relative risk and examined the prediction capabilities of a polygenic risk score. All statistical tests were two-sided. Results The discovery GWAS identified 11 variants associated with CRC at P < 5 × 10−8, of which nine (at 4q22.2/5p15.33/5p13.1/6p21.31/6p12.1/10q11.23/12q24.21/16q24.1/20q13.13) independently replicated at a P value of less than .05. Multiethnic follow-up supported the generalizability of discovery findings. These results demonstrated a 14.7% increase in familial relative risk explained by common risk alleles from 10.3% (95% confidence interval [CI] = 7.9% to 13.7%; known variants) to 11.9% (95% CI = 9.2% to 15.5%; known and novel variants). A polygenic risk score identified 4.3% of the population at an odds ratio for developing CRC of at least 2.0. Conclusions This study provides insight into the architecture of common genetic variation contributing to CRC etiology and improves risk prediction for individualized screening.

Purpose Factors contributing to early mortality after initiation of treatment of metastatic colorectal cancer are poorly understood. Materials and Methods Data from 22,654 patients enrolled in 28 randomized phase III trials contained in the ARCAD (Aide et Recherche en Cancérologie Digestive) database were pooled. Multivariable logistic regression models for 30-, 60-, and 90-day mortality were constructed, including clinically and statistically significant patient and disease factors and interaction terms. A calculator (nomogram) for 90-day mortality was developed and validated internally using bootstrapping methods and externally using a 10% random holdout sample from each trial. The impact of early progression on the likelihood of survival to 90 days was examined with time-dependent Cox proportional hazards models. Results Mortality rates were 1.4% at 30 days, 3.4% at 60 days, and 5.5% at 90 days. Among baseline factors, advanced age, lower body mass index, poorer performance status, increased number of metastatic sites, BRAF mutant status, and several laboratory parameters were associated with increased likelihood of early mortality. A multivariable model for 90-day mortality showed strong internal discrimination (C-index, 0.77) and good calibration across risk groups as well as accurate predictions in the external validation set, both overall and within patient subgroups. Conclusion A validated clinical nomogram has been developed to quantify the risk of early death for individual patients during initial treatment of metastatic colorectal cancer. This tool may be used for patient eligibility assessment or risk stratification in future clinical trials and to identify patients requiring more or less aggressive therapy and additional supportive measures during and after treatment.

659 Background: Regular physical activity (PA) is associated with reduced risk of recurrence and mortality in non-metastatic colorectal cancer. Its influence on patients with metastatic colorectal cancer (mCRC) is largely unexplored. Methods: 1231 patients participating in CALGB 80405 (first-line phase III chemotherapy trial for mCRC) completed questionnaires that included self-report on PA at time of chemotherapy initiation and total metabolic equivalent task (MET)-hours/week were determined based on responses. The primary endpoint of the clinical trial and this companion study was overall survival (OS), with progression-free survival (PFS) as a secondary endpoint. To minimize confounding by poor and rapidly declining health, we excluded patients who experienced progression or died within 60 days of activity assessment and adjusted for known prognostic factors, comorbid illness, and weight loss over the previous six months. Results: Compared with patients engaged in less than three MET-hours/week of PA, patients engaged in 18 or more MET-hours/week experienced an adjusted hazard ratio for OS of 0.81 (95% CI 0.67 to 0.98, P for trend 0.03) and for PFS of 0.84 (95% CI 0.71 to 1.00, P for trend 0.03). Greater nonvigorous PA and walking duration were both associated with improved OS ( P for trend 0.01 and 0.04, respectively). Conclusions: In mCRC patients from CALGB 80405, greater total PA was associated with improved PFS and OS, while greater walking duration and non-vigorous PA were associated with reduced risk of all-cause mortality. Support: U10CA180821, U10CA180882. ClinicalTrials.gov ID: NCT00265850 [Table: see text]