Atkins, James N.

3035 Background: Energy balance-associated biomarkers such as insulin-like growth factors (IGFs) and IGF-binding proteins (IGFBPs) have been associated with risk and prognosis of various malignancies. Their relationship to disease progression and mortality in metastatic colorectal cancer (mCRC) requires further study. Methods: In a prospective cohort study, baseline plasma IGFBP-3, IGFBP-7, C-peptide, IGF-I, and adiponectin were measured at trial registration among 1,086 patients participating in a National Cancer Institute-sponsored clinical trial of first-line therapy for mCRC. We used Cox proportional hazards regression to adjust for confounders and examine associations of biomarkers with overall (OS) and progression-free survival (PFS). Results: Higher plasma IGFBP-3 was associated with longer OS (adjusted Ptrend < .001) and PFS (adjusted Ptrend = .003). Compared to patients in the lowest IGFBP-3 quintile, patients in the highest quintile experienced an adjusted HR for all-cause mortality of 0.58 (95% CI 0.42 to 0.78) and for disease progression or mortality of 0.60 (95% CI 0.45 to 0.82). Higher plasma IGFBP-7 was associated with shorter OS (adjusted Ptrend < .001) and PFS (adjusted Ptrend = .02). Compared to patients in the lowest IGFBP-7 quintile, patients in the highest quintile experienced an adjusted HR for all-cause mortality of 1.52 (95% CI 1.24 to 1.88) and for disease progression or mortality of 1.28 (95% CI 1.05 to 1.57). C-peptide and IGF-I were not significantly associated with patient outcomes (adjusted Ptrend = .73 and .30 for OS). Adiponectin was not associated with OS; there was a U shaped association between adiponectin and PFS, wherein low and high values were associated with shorter PFS ( Pnon-linear trend = .03). Conclusions: In patients with mCRC, high plasma IGFBP-3 and low IGFBP-7 were associated with reduced risk of disease progression and mortality. These data suggest that energy-balance associated biomarkers may offer prognostic and biologic insights into mCRC. Support: U10CA180821, U10CA180882, BMS, Genentech, Pfizer, Sanofi; https://acknowledgments.alliancefound.org .

PURPOSE CALGB/SWOG 80405 was a randomized phase III trial that found no statistically significant difference in overall survival (OS) in patients with first-line metastatic colorectal cancer treated with chemotherapy plus either bevacizumab or cetuximab. Primary tumor DNA from 843 patients has been used to discover genetic markers of OS. PATIENTS AND METHODS Gene mutations were determined by polymerase chain reaction. Microsatellite status was determined by genotyping of microsatellites. Tumor mutational burden (TMB) was determined by next-generation sequencing. Cox proportional hazard models were used, with adjusting factors. Interaction of molecular alterations with either the bevacizumab or the cetuximab arms was tested. RESULTS Patients with high TMB in their tumors had longer OS than did patients with low TMB (hazard ratio [HR], 0.73 [95% CI, 0.57 to 0.95]; P = .02). In patients with microsatellite instability–high (MSI-H) tumors, longer OS was observed in the bevacizumab arm than in the cetuximab arm (HR, 0.13 [95% CI, 0.06 to 0.30]; interaction P < .001 for interaction between microsatellite status and the two arms). Patients with BRAF mutant tumors had shorter OS than did patients with wild-type (WT) tumors (HR, 2.01 [95% CI, 1.49 to 2.71]; P < .001). Patients with extended RAS mutant tumors had shorter OS than did patients with WT tumors (HR, 1.52 [95% CI, 1.26 to 1.84]; P < .001). Patients with triple-negative tumors (WT for NRAS/ KRAS/ BRAF) had a median OS of 35.9 months (95% CI, 33.0 to 38.8 months) versus 22.2 months (95% CI, 19.6 to 24.4 months ) in patients with at least one mutated gene in their tumors ( P < .001). CONCLUSION In patients with metastatic colorectal cancer treated in first line, low TMB, and BRAF and RAS mutations are negative prognostic factors. Patients with MSI-H tumors benefited more from bevacizumab than from cetuximab, and studies to confirm this effect of MSI-H are warranted.

638 Background: Colorectal cancer (CRC) is a heterogeneous disease with distinct molecular subtypes in part based on RAS mutational status. It is plausible that RAS mutations are differentially distributed between CC and AA and may contribute to poor outcomes in AAs with CRC. Methods: We did a retrospective analysis of CALGB/SWOG 80405 trial patients. We divided the entire cohort into 2 groups: a) Common RAS: mutation in KRAS exon 2, codon 12 or 13; b) Extended RAS: any NRAS mutations or mutation in KRAS except those listed above. We then analyzed these two subgroups for association between RAS mutations and race (3 categories: Caucasian, AA, Others) using chi-square test for univariate analyses and logistic regression for multivariate analysis. We also analyzed the effect of extended RAS testing on prognosis of metastatic CRC by estimating the overall survival (OS) using Kaplan-Meier method and 95% confidence interval (CI). Cox proportional-hazard model was used for multivariate analyses. Results: There were 1729 CRC patients in common RAS group of which 357 (20.6%) had mutations present. Extended RAS group had 621 patients of which 95 (15.5%) had mutations present. There was no significant difference in the rate of common RAS mutations between CC and AA (20.5% vs. 24%, p=0.22). However, extended RAS mutations were significantly more in AA as compared to CC (25% vs. 14%, p=0.02). Multivariate analysis adjusted for age, gender, prior adjuvant chemotherapy and pelvic radiation confirmed higher odds of extended RAS mutation in AA compared to CC (adjusted OR 1.12; 95% CI 1.01-1.23; p=0.02). The median OS in patients with an extended RAS mutation was shorter as compared to those without extended RAS mutation (25.3 vs. 31.9 months; HR 1.26; 95% CI 0.99-1.62; p=0.05). Multivariate analyses adjusted for age, gender, race, prior adjuvant chemotherapy and pelvic radiation showed a trend towards longer OS in patients without extended RAS mutation as compared those with extended RAS mutation (adjusted HR= 1.24, 95% CI, 0.97-0.1.58, p=0.08). Conclusions: Extended RAS mutations are significantly more common in AA as compared to CC. Additionally, presence of extended RAS mutation may confer a poor prognosis in CRC patients.

11007 Background: Patients (pts) with metastatic sarcoma (SAR) have limited options. Nivolumab(N), a fully human anti-PD-1 mAb and ipilimumab (I), a humanized anti-CTLA-4 mAb, have favorable safety & efficacy in other tumors. Pembrolizumab demonstrated a response rate (RR) of 12% in SAR pts. We evaluated N, independently from N+I, in SAR pts. Methods: This open-label multi-center phase II study enrolled pts failing prior regimens. Randomized (non-comparative) pts received either N3 [N (3 mg/kg q2W)] or N3+I1 [N(3 mg/kg Q3W x4, then Q2W) & [I(1 mg/kg q3W x4)]. Treatment continued beyond progressive disease (PD) in 1st12 weeks. 5 confirmed responses in 38 evaluable pts yielded 90% power (0.05 1-sided alpha) to detect a 20% (vs 5%) confirmed RR. Other endpoints: adverse events (AEs), progression-free, overall survival (PFS, OS), and correlative studies including PD-L1 expression by IHC, mutational burden/neoantigen analysis, TCR clonality and TIL characterization. Results: 85 pts (43 - N3; 42 - N3+I1) were enrolled [mean age 54 yrs (21–81), 52% female). No significant differences in histological subtypes across cohorts: 36% LMS, 4% LPS, 10% UPS/MFH, 6% synovial, 5% bone, 5% Ewing’s, and 34% other. Pts were refractory to 1(20%), 2(22%), and ≥3 (58%) regimens. Grade 3-4 treatment related adverse events (TRAE) occurred in 7% (N3) and 14% (N3+I1) and 0 Gr 5 TRAEs. 8% of pts stopped due to AEs (2% N3, 14% N3+I1). 2/3 confirmed responses on N3, with 2 ongoing (range 1.1-3.2 months). 6/7 confirmed responses (2 complete) on N3+N1, with 5 ongoing (range 6-13 months). Responses occurred in 7 histologies. See Table for pt outcomes. Conclusions: N + I showed acceptable safety and encouraging antitumor activity with most responses ongoing across multiple SAR histologies, passing efficacy criteria. There was minimal activity observed with N alone. Increased TRAEs were observed in N3+I1. Correlative analyses ongoing. NCT02500797. Support: U10CA180821, U10CA180882, Conquer Cancer Foundation, BMS. Clinical trial information: NCT02500797. [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.