Citations

Abstract Background: Plant-based diet is recommended by multiple cancer survivorship guidelines and was reported to be associated with better survival among patients with non-metastatic colorectal cancer. However, the association between plant-based diet and survival in metastatic colorectal cancer is unknown. Methods: Using an NCI-sponsored systemic therapy trial conducted from 2005 to 2015 (CALGB/SWOG 80405), we included 1,279 patients who completed validated food frequency questionnaires at the initiation of treatment for metastatic colorectal cancer. To emphasize different impact of healthful plant foods, less healthful plant foods, and animal foods, we used 18 food groups to calculate three plant-based indexes (ranges: 18-90 points): overall plant-based diet index (PDI), healthful plant-based diet index (hPDI), and unhealthful plant-based diet index (uPDI). The primary outcome was overall survival, and the secondary outcome was progression-free survival. We estimated the associations of three indexes (quintiles) with survival using multivariable Cox proportional hazards regression. Results: Of 1,279 patients (median follow-up: 6.1 years), mean (SD) age at diagnosis was 58.8 (11.7) years, 57.4% were men, 85.6% were White, and 1,096 deaths and 1,201 events of progression occurred. The mean (SD) points of three indexes were 51.2 (6.3) for PDI, 51.1 (6.7) for hPDI, and 51.2 (8.1) for uPDI. Compared to the lowest quintile (Q1), the highest quintile (Q5) of PDI was significantly associated with better overall survival (HR: 0.80 [0.65-0.99]) and progression-free survival (HR: 0.80 [0.65-0.98]). Similar findings were observed for hPDI, but uPDI was not significantly associated with worse survival. Conclusions: Our findings suggest that plant-based diet is associated with better survival among patients with metastatic colorectal cancer, and plant-based dietary interventions should be considered for future trials in metastatic colorectal cancer. Table. Adjusted Associations of Plant-Based Diet with Survival in Metastatic Colorectal Cancer Q1 Q2 Q3 Q4 Q5 P for trend Overall Survival PDI 1.00 0.96 (0.80-1.16) 0.93 (0.77-1.14) 0.82 (0.67-0.99) 0.80 (0.65-0.99) 0.01 hPDI 1.00 0.95 (0.78-1.14) 0.94 (0.77-1.15) 0.86 (0.70-1.04) 0.84 (0.68-1.03) 0.07 uPDI 1.00 1.14 (0.95-1.39) 1.07 (0.87-1.31) 1.18 (0.97-1.45) 1.17 (0.95-1.45) 0.15 Progression-free Survival PDI 1.00 0.84 (0.70-1.01) 0.94 (0.78-1.14) 0.93 (0.77-1.12) 0.80 (0.65-0.98) 0.10 hPDI 1.00 0.86 (0.72-1.03) 0.83 (0.69-1.01) 0.80 (0.67-0.97) 0.80 (0.66-0.97) 0.03 uPDI 1.00 1.12 (0.94-1.34) 1.11 (0.91-1.34) 1.10 (0.91-1.34) 1.15 (0.94-1.41) 0.23 Citation Format: En Cheng, Fang-Shu Ou, Chao Ma, Alan P. Venook, Heinz-Josef Lenz, Eileen M. O’Reilly, Peter T. Campbell, Chaoyuan Kuang, Bette J. Caan, Kimmie Ng, Jeffrey A. Meyerhardt. Plant-based diet and survival among patients with metastatic colorectal cancer: Findings from CALGB/SWOG 80405 (Alliance) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2200.

AbstractBackgroundIdentifying patient‐ and disease‐specific characteristics associated with clinical trial enrollment of adolescents and young adults (AYAs) with cancer may target efforts to improve accrual.MethodsAlliance for Clinical Trials in Oncology (Alliance) trials opened from January 1, 2000, and closed before January 1, 2018, for common AYA cancers were identified. Proportions of AYAs (aged 18–39 years old) versus non‐AYAs (aged ≥40 years old) enrolled by cancer type were summarized by descriptive statistics. Among studies with ≥20 AYAs enrolled, demographic and disease characteristics of AYAs versus non‐AYAs were compared with χ2 and Kruskal–Wallis tests. A qualitative review was also conducted of therapeutic trials included in analysis in PubMed through December 31, 2021, that reported AYA‐specific survival.ResultsAmong 188 trials enrolling 40,396 patients, AYAs represented 11% (4468 of 40,396) of accrual. AYA accrual varied by cancer type (leukemia, 23.6%; breast, 9.9%; lymphoma, 14.8%; colorectal, 6.2%; central nervous system, 8.1%; melanoma, 11.8%; sarcoma, 12%). Across ages, the proportion of Black and Hispanic patients enrolled was 1%–10%. Compared to non‐AYAs, AYAs in breast and colorectal cancer trials were less likely to be White and more likely to be Hispanic. Disease characteristics differed by age for selected trials. Two trials reported AYA‐specific survival, with no significant differences observed by age.ConclusionsAYA accrual to Alliance trials was comparable to or exceeded population‐based, age‐specific prevalence estimates for most cancer types. Greater proportional representation of Hispanic and non‐White patients among AYAs reflects US demographic trends. The small number of minority patients enrolled across ages underscores the persistent challenge of ensuring equitable access to trials, including for AYAs.

3528 Background: Tucatinib (TUC) is a highly selective HER2-directed TKI approved by the FDA in combination w/trastuzumab (Tras) for treatment (tx) of pts w/ RAS wild-type HER2+ unresectable or metastatic colorectal cancer (mCRC) that has progressed following tx w/ fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy. There are currently no established best practices for HER2 testing/interpretation in mCRC. Here we present results of central HER2 testing across multiple platforms and response to tx for MOUNTAINEER pts treated w/ TUC + Tras based on central HER2 status. Methods: MOUNTAINEER (NCT03043313) enrolled pts w/ local HER2+ mCRC using ≥1 method: IHC, ISH, and/or NGS testing; retrospective central assessment of HER2 status was performed on multiple platforms. Pts in cohorts A+B were treated w/ TUC + Tras; pts in cohort C were treated w/ TUC monotherapy. Confirmed objective response rates (cORRs) using RECIST v1.1 per BICR, DOR, and PFS were calculated for pts treated w/ TUC + Tras based on each central testing method. Results: 114 pts were enrolled in cohorts A (n = 45), B (n = 39), and C (n = 30) w/ HER2+ tumors per ≥1 local testing method. Of samples submitted for central testing for Cohorts A and B, 70 per IHC/FISH, 50 per tissue NGS, and 71 per blood NGS had evaluable results. In all cohorts, there was 81.0% (95% CI, 68.6-90.1) agreement between blood and tissue NGS, 92.6% (95% CI, 83.7-97.6) between IHC/FISH and tissue NGS, and 79.5% (95% CI, 69.2-87.6) between IHC/FISH and blood NGS. In cohorts A and B, pts w/ HER2+ tumors by central IHC/ISH had a mDOR of 16.4 months (95% CI: 10.6-25.5) and mPFS of 10.1 months (95% CI: 4.2-15.2). cORR was 41.1% to 47.7% for the 3 assays. Detailed HER2 results are presented in the Table. Conclusions: Percent agreement of HER2 status was highest w/ tissue-based platforms. Detection of HER2 amplification by ctNDA NGS is useful; however, pts w/o HER2 amplification should be confirmed w/ a tissue-based assay. HER2 status by all 3 platforms predicted tx response to TUC + Tras. cORR in IHC2+/ISH+ was numerically lower but remained clinically relevant. These data support use of the above methods to identify HER2+ mCRC patients that may benefit from TUC + Tras. Clinical trial information: NCT03043313 . [Table: see text]

Abstract Purpose: To assess whether higher plasma 25-hydroxyvitamin D [25(OH)D] is associated with improved outcomes in colon cancer and whether circulating inflammatory cytokines mediate such association. Experimental Design: Plasma samples were collected from 1,437 patients with stage III colon cancer enrolled in a phase III randomized clinical trial (CALGB/SWOG 80702) from 2010 to 2015, who were followed until 2020. Cox regressions were used to examine associations between plasma 25(OH)D and disease-free survival (DFS), overall survival (OS), and time to recurrence (TTR). Mediation analysis was performed for circulating inflammatory biomarkers of C-reactive protein (CRP), IL6, and soluble TNF receptor 2 (sTNF-R2). Results: Vitamin D deficiency [25(OH)D <12 ng/mL] was present in 13% of total patients at baseline and in 32% of Black patients. Compared with deficiency, nondeficient vitamin D status (≥12 ng/mL) was significantly associated with improved DFS, OS, and TTR (all Plog-rank<0.05), with multivariable-adjusted HRs of 0.68 (95% confidence interval, 0.51–0.92) for DFS, 0.57 (0.40–0.80) for OS, and 0.71 (0.52–0.98) for TTR. A U-shaped dose–response pattern was observed for DFS and OS (both Pnonlinearity<0.05). The proportion of the association with survival that was mediated by sTNF-R2 was 10.6% (Pmediation = 0.04) for DFS and 11.8% (Pmediation = 0.05) for OS, whereas CRP and IL6 were not shown to be mediators. Plasma 25(OH)D was not associated with the occurrence of ≥ grade 2 adverse events. Conclusions: Nondeficient vitamin D is associated with improved outcomes in patients with stage III colon cancer, largely independent of circulation inflammations. A randomized trial is warranted to elucidate whether adjuvant vitamin D supplementation improves patient outcomes.

ImportanceThe association of chronic inflammation with colorectal cancer recurrence and death is not well understood, and data from large well-designed prospective cohorts are limited.ObjectiveTo assess the associations of inflammatory biomarkers with survival among patients with stage III colon cancer.Design, Setting, and ParticipantsThis cohort study was derived from a National Cancer Institute–sponsored adjuvant chemotherapy trial Cancer and Leukemia Group B/Southwest Oncology Group 80702 (CALGB/SWOG 80702) conducted between June 22, 2010, and November 20, 2015, with follow-up ending on August 10, 2020. A total of 1494 patients with plasma samples available for inflammatory biomarker assays were included. Data were analyzed from July 29, 2021, to February 27, 2022.ExposuresPlasma inflammatory biomarkers (interleukin 6 [IL-6], soluble tumor necrosis factor α receptor 2 [sTNF-αR2], and high-sensitivity C-reactive protein [hsCRP]; quintiles) that were assayed 3 to 8 weeks after surgery but before chemotherapy randomization.Main Outcomes and MeasuresThe primary outcome was disease-free survival, defined as time from randomization to colon cancer recurrence or death from any cause. Secondary outcomes were recurrence-free survival and overall survival. Hazard ratios for the associations of inflammatory biomarkers and survival were estimated via Cox proportional hazards regression.ResultsOf 1494 patients (median follow-up, 5.9 years [IQR, 4.7-6.1 years]), the median age was 61.3 years (IQR, 54.0-68.8 years), 828 (55.4%) were male, and 327 recurrences, 244 deaths, and 387 events for disease-free survival were observed. Plasma samples were collected at a median of 6.9 weeks (IQR, 5.6-8.1 weeks) after surgery. The median plasma concentration was 3.8 pg/mL (IQR, 2.3-6.2 pg/mL) for IL-6, 2.9 × 103pg/mL (IQR, 2.3-3.6 × 103pg/mL) for sTNF-αR2, and 2.6 mg/L (IQR, 1.2-5.6 mg/L) for hsCRP. Compared with patients in the lowest quintile of inflammation, patients in the highest quintile of inflammation had a significantly increased risk of recurrence or death (adjusted hazard ratios for IL-6: 1.52 [95% CI, 1.07-2.14];P = .01 for trend; for sTNF-αR2: 1.77 [95% CI, 1.23-2.55];P < .001 for trend; and for hsCRP: 1.65 [95% CI, 1.17-2.34];P = .006 for trend). Additionally, a significant interaction was not observed between inflammatory biomarkers and celecoxib intervention for disease-free survival. Similar results were observed for recurrence-free survival and overall survival.Conclusions and RelevanceThis cohort study found that higher inflammation after diagnosis was significantly associated with worse survival outcomes among patients with stage III colon cancer. This finding warrants further investigation to evaluate whether anti-inflammatory interventions may improve colon cancer outcomes.Trial RegistrationClinicalTrials.gov Identifier:NCT01150045

198 Background: HER2 overexpression/amplification (HER2+) occurs in 3%-5% of patients (pts) w/ metastatic colorectal cancer (mCRC). Rates of HER2+ can increase to ~10% in pts w/ RAS/BRAF wild-type mCRC tumors. The MOUNTAINEER trial (NCT03043313) evaluated the efficacy and safety of the investigational combination of tucatinib with trastuzumab in pts with HER2+ and RAS wild-type mCRC. Established regional guidelines for mCRC recommend HER2 testing and HER2-directed treatment options; however, there is currently no established best practice for HER2 testing and interpretation in mCRC. Here, we present data from a concordance analysis comparing breast and gastric HER2 testing algorithms in the mCRC setting. Methods: The MOUNTAINEER trial enrolled pts w/ HER2+ mCRC identified using ≥1 method: tissue-based local immunohistochemistry (IHC), in situ hybridization (ISH), and/or next-generation sequencing (NGS) testing. Archival or fresh tumor tissue was submitted to a sponsor-designated central laboratory for confirmatory HER2 testing w/ IHC/FISH per the package insert of the FDA approved assay and scored by both the breast and gastric algorithms for HER2 IHC. A positive result per the breast scoring criteria for IHC requires circumferential membrane staining for HER2, while the gastric criteria allows for circumferential, basolateral, or lateral staining patterns. Results: A total of 114 pts were enrolled with HER2+ tumors per ≥1 local testing methods; 69 pts were HER2+ by NGS, 46 by IHC 3+, and 36 by ISH. Of 105 pts who had tissue available for central HER2 testing w/IHC/FISH, 98 had valid HER2 results; 82/98 (83.7%) of pts had tumors centrally confirmed as HER2+ using both the breast and gastric algorithms. Tissue samples from pts in the MOUNTAINEER trial had 100% concordance between breast and gastric algorithms in HER2 status and 99% concordance in HER2 IHC score. Conclusions: Central pathology testing using both the breast and gastric criteria showed high concordance between these two commonly used algorithms. A high central confirmation rate of local HER2+ results was also observed. These data support the use of either the breast or gastric algorithms to identify HER2+ mCRC tumors until an FDA-approved HER2 assay is available for mCRC. Clinical trial information: NCT03043313 . [Table: see text]

AbstractData on diet and survival among people with metastatic colorectal cancer are limited. We examined dietary fat in relation to all‐cause mortality and cancer progression or death among 1149 people in the Cancer and Leukemia Group B (Alliance)/Southwest Oncology Group (SWOG) 80405 trial who completed a food frequency questionnaire at initiation of treatment for advanced or metastatic colorectal cancer. We examined saturated, monounsaturated, total and specific types (n‐3, long‐chain n‐3 and n‐6) of polyunsaturated fat, animal and vegetable fats. We hypothesized higher vegetable fat intake would be associated with lower risk of all‐cause mortality and cancer progression. We used Cox proportional hazards regression to estimate adjusted hazard ratios (HR) and 95% confidence intervals (CI). Over median follow‐up of 6.1 years (interquartile range [IQR]: 5.3, 7.2 y), we observed 974 deaths and 1077 events of progression or death. Participants had a median age of 59 y; 41% were female and 86% identified as White. Moderate or higher vegetable fat was associated with lower risk of mortality and cancer progression or death (HRs comparing second, third and fourth to first quartile for all‐cause mortality: 0.74 [0.62, 0.90]; 0.75 [0.61, 0.91]; 0.79 [0.63, 1.00];Ptrend: .12; for cancer progression or death: 0.74 [0.62, 0.89]; 0.78 [0.64, 0.95]; 0.71 [0.57, 0.88];Ptrend: .01). No other fat type was associated with all‐cause mortality and cancer progression or death. Moderate or higher vegetable fat intake may be associated with lower risk of cancer progression or death among people with metastatic colorectal cancer.

Abstract Importance: Pancreatic cancer presents as advanced disease in >80% of patients; yet, appropriate ages to consider prevention and early detection strategies are poorly defined. Objective: To investigate age-specific associations and attributable risks of pancreatic cancer for established modifiable and non-modifiable risk factors. Design, Setting, and Participants: We included 167,483 participants from 2 prospective U.S. cohort studies with 1190 incident cases of pancreatic cancer identified during >30 years of follow-up; 5107 pancreatic cancer cases and 8845 control participants of European ancestry from a completed multicenter genome-wide association study (GWAS); and 248,893 pancreatic cancer cases documented in the U.S. Surveillance, Epidemiology, and End Results (SEER) Program. Exposures: Across different age categories, we investigated cigarette smoking, obesity, diabetes, height, and non-O blood group in the prospective cohorts; weighted polygenic risk score of 22 previously identified single nucleotide polymorphisms in the GWAS; and male sex and Black race in the SEER program. Main outcomes and measures: Risk of developing pancreatic cancer by age evaluated by Cox, logistic, or Poisson regression, as determined by the study design. Results: In the prospective cohorts, all 5 risk factors were more strongly associated with pancreatic cancer risk among younger participants, with associations greatly attenuated among those over 70 years. The HRs comparing participants with 3-5 risk factors to those with no risk factors were 9.24 (95% CI, 4.11-20.77) among those aged ≤60 years, 3.00 (95% CI, 1.85-4.86) among those aged 61-70 years, and 1.46 (95% CI, 1.10-1.94) among those over 70 years (Pheterogeneity = 3×10-5). These factors together were related to 65.6%, 49.7%, and 17.2% of incident pancreatic cancers in these age groups, respectively. In the GWAS, the polygenic risk score was most strongly associated with pancreatic cancer risk among those aged ≤60 years, with lesser associations identified in older participants (Pheterogeneity = .01). In the SEER Program, male sex and Black race were also more strongly associated with pancreatic cancer risk among younger individuals (Pheterogeneity < 1×10-8). Conclusions and relevance: Inherited and lifestyle factors are more strongly associated with earlier-onset pancreatic cancer, emphasizing the importance of age at initiation for cancer prevention and control programs targeting this highly lethal malignancy. Citation Format: Chen Yuan, Jihye Kim, Qiao-Li Wang, Alice A. Lee, Ana Babic, PanScan/PanC4 I-III Consortium, Laufey T. Amundadottir, Alison P. Klein, Donghui Li, Marjorie L. McCullough, Gloria M. Petersen, Harvey A. Risch, Rachael Z. Stolzenberg-Solomon, Kimberly Perez, Kimmie Ng, Edward L. Giovannucci, Meir J. Stampfer, Peter Kraft, Brian M. Wolpin. The age-dependent association of risk factors with pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5891.

3553 Background: Higher levels of plasma 25-hydroxyvitamin D [25(OH)D)] are associated with better outcomes in mCRC, but underlying biologic mechanisms are unknown. Key components of the VitD metabolic pathway include CYP27B1 (encodes 1-α-hydroxylase, converts 25(OH)D to active calcitriol), VitD receptor (VDR), and CYP24A1 (encodes 24-hydroxylase, degrades calcitriol and 25(OH)D into excreted metabolites). Since these factors may affect 25(OH)D levels and potentially mediate VitD activity in mCRC, we examined the relationship between tumoral gene expression (GEx) of CYP27B1, VDR, and CYP24A and pt outcome in a study nested in a randomized phase III trial of first-line chemotherapy plus biologics in mCRC pts, CALGB/SWOG 80405. Methods: We determined GEx of CYP27B1, VDR, and CYP24A1 by RNA sequencing (RNA-Seq) of archival tumor samples using the Illumina TruSeq platform. Primary endpoints were overall (OS) and progression-free survival (PFS). Cox proportional hazard models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs), adjusting for prognostic and molecular characteristics. Results: 562 pts with RNA-Seq data were included. Pts with higher CYP27B1 expression (>median) were less likely to have BRAF wild type (WT) (79% vs 90%) compared to pts with lower expression (p=0.0007). Pts with higher VDR expression (>quartile 1 [Q1]) were younger (median age 59 vs 62 years; p=0.03), more likely to have left-sided (63% vs 46%; p=0.0005) and BRAF WT tumors (89% vs 70%; p<0.0001), and less likely to have RAS WT tumors (70% vs 80%; p=0.02) compared to pts with lower VDR. Pts with higher CYP24A1 expression (>median) were more likely to have left-sided tumors compared to pts with lower expression (63% vs 54%; p=0.03). On multivariable analysis, pts with higher CYP27B1 expression had significantly improved OS (HR 0.84; 95% CI, 0.75-0.93; p=0.002) and PFS (HR 0.89; 95% CI, 0.80-0.99; p=0.04). Higher VDR expression (up to Q1) was associated with significantly improved PFS (HR 0.69; 95% CI, 0.53-0.91; p=0.007) but not OS (HR 0.85; 95% CI, 0.66-1.09; p=0.20). Above Q1, this improvement attenuated. Higher CYP24A1 GEx was not associated with improved OS (HR 0.98; 95% CI, 0.88-1.08; p=0.66) or PFS (HR 0.98; 95% CI, 0.89-1.08; p=0.68). We found no significant interactions between GEx of CYP27B1, VDR, or CYP24A with baseline plasma 25(OH)D levels (p for interaction ≥0.10 for all). Conclusions: Our findings suggest an association between GEx of VitD pathway markers, particularly CYP27B1 and VDR, and survival in pts with mCRC, lending biologic plausibility to a role of VitD in CRC pathogenesis. Future studies are needed to confirm these findings and elucidate underlying mechanisms of action. Clinical trial information: NCT00265850 .