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BackgroundThis phase 1 clinical trial was conducted to determine the safety, maximum-tolerated dose (MTD), and pharmacokinetics of imatinib, bevacizumab, and metronomic cyclophosphamide in patients with advanced colorectal cancer (CRC).MethodsPatients with refractory stage IV CRC were treated with bevacizumab 5 mg kg(-1) i.v. every 2 weeks (fixed dose) plus oral cyclophosphamide q.d. and imatinib q.d. or b.i.d. in 28-day cycles with 3+3 dose escalation. Response was assessed every two cycles. Pharmacokinetics of imatinib and cyclophosphamide and circulating tumour, endothelial, and immune cell subsets were measured.ResultsThirty-five patients were enrolled. Maximum-tolerated doses were cyclophosphamide 50 mg q.d., imatinib 400 mg q.d., and bevacizumab 5 mg kg(-1) i.v. every 2 weeks. Dose-limiting toxicities (DLTs) included nausea/vomiting, neutropaenia, hyponatraemia, fistula, and haematuria. The DLT window required expansion to 42 days (1.5 cycles) to capture delayed toxicities. Imatinib exposure increased insignificantly after adding cyclophosphamide. Seven patients (20%) experienced stable disease for >6 months. Circulating tumour, endothelial, or immune cells were not associated with progression-free survival.ConclusionThe combination of metronomic cyclophosphamide, imatinib, and bevacizumab is safe and tolerable without significant drug interactions. A subset of patients experienced prolonged stable disease independent of dose level.

BackgroundBased upon preclinical evidence for improved antitumor activity in combination, this phase I study investigated the maximum-tolerated dose (MTD), safety, activity, pharmacokinetics (PK), and biomarkers of the mammalian target of rapamycin inhibitor, temsirolimus, combined with sorafenib in hepatocellular carcinoma (HCC).Patients and methodsPatients with incurable HCC and Child Pugh score ≤B7 were treated with sorafenib plus temsirolimus by 3 + 3 design. The dose-limiting toxicity (DLT) interval was 28 days. The response was assessed every two cycles. PK of temsirolimus was measured in a cohort at MTD.ResultsTwenty-five patients were enrolled. The MTD was temsirolimus 10 mg weekly plus sorafenib 200 mg twice daily. Among 18 patients at MTD, DLT included grade 3 hand-foot skin reaction (HFSR) and grade 3 thrombocytopenia. Grade 3 or 4 related adverse events at MTD included hypophosphatemia (33%), infection (22%), thrombocytopenia (17%), HFSR (11%), and fatigue (11%). With sorafenib, temsirolimus clearance was more rapid (P < 0.05). Two patients (8%) had a confirmed partial response (PR); 15 (60%) had stable disease (SD). Alpha-fetoprotein (AFP) declined ≥50% in 60% assessable patients.ConclusionThe MTD of sorafenib plus temsirolimus in HCC was lower than in other tumor types. HCC-specific phase I studies are necessary. The observed efficacy warrants further study.

The use of serial serum measurements of the carbohydrate antigen 19-9 (CA19-9) to guide treatment decisions and serve as a surrogate end point in clinical trial design requires further validation. We investigated whether CA19-9 decline represents an accurate surrogate for survival and time to treatment failure (TTF) in a cohort of 76 patients with advanced pancreatic cancer receiving fixed-dose rate gemcitabine in three separate studies. Statistically significant correlations between percentage CA19-9 decline and both overall survival and TTF were found, with median survival ranging from 12.0 months for patients with the greatest degree of biomarker decline (> 75%) compared with 4.3 months in those whose CA19-9 did not decline during therapy (P < 0.001). Using specific thresholds, patients with > or = 25% decline in CA19-9 during treatment had significantly better outcomes than those who did not (median survival and TTF of 9.6 and 4.6 months vs 4.4 and 1.5 months; P < 0.001). Similar results were seen using both 50 and 75% as cutoff points. We conclude that serial CA19-9 measurements correlate well with clinical outcomes in this patient population, and that decline in this biomarker should be entertained for possible use as a surrogate end point in clinical trials for the selection of new treatments in this disease.

Background: Although preclinical and epidemiological data suggest that statins may have antineoplastic properties, the impact of statin use on patient survival after a curative resection of stage III colon cancer is unknown.Methods: We conducted a prospective observational study of 842 patients with stage III colon cancer enrolled in a randomized adjuvant chemotherapy trial from April 1999 to May 2001 to investigate the relationship between statin use and survival. Disease-free survival (DFS), recurrence-free survival (RFS), and overall survival (OS) were investigated by Kaplan-Meier curves and log-rank tests in the overall study population and in a subset of patients stratified by KRAS mutation status (n = 394), and Cox proportional hazards regression was used to assess the simultaneous impact of confounding variables. All statistical tests were two-sided.Results: Among 842 patients, 134 (15.9%) reported statin use after completing adjuvant chemotherapy. DFS among statin users and nonusers was similar (hazard ratio [HR] of cancer recurrence or death = 1.04, 95% confidence interval [CI] = 0.73 to 1.49). RFS and OS were also similar between statin users and nonusers (adjusted HR of cancer recurrence = 1.14, 95% CI = 0.77 to 1.69; adjusted HR of death = 1.15, 95% CI = 0.77 to 1.71). Survival outcomes were similar regardless of increasing duration of statin use before cancer diagnosis (P(trend) = .63, .63, and .59 for DFS, RFS, and OS, respectively). The impact of statin use did not differ by tumor KRAS mutation status, with similar DFS, RFS, and OS for statin use among mutant and wild-type subgroups (P(interaction) = .84, .67, and .98 for DFS, RFS, and OS, respectively).Conclusion: Statin use during and after adjuvant chemotherapy was not associated with improved DFS, RFS, or OS in patients with stage III colon cancer, regardless of KRAS mutation status. [ABSTRACT FROM AUTHOR]

Background: Plant-based diet is associated with better survival among patients with non-metastatic colorectal cancer (CRC), but its association in metastatic CRC is unknown., Methods: Using an NCI-sponsored trial (CALGB/SWOG 80405), we included 1,284 patients who completed validated food frequency questionnaires at the initiation of metastatic CRC treatment. We calculated three indices: overall plant-based diet index (PDI), which emphasized consumption of all plant foods while reducing animal food intake; healthful plant-based diet index (hPDI), which emphasized consumption of healthful plant foods such as whole grains, fruits, and vegetables; and unhealthful plant-based diet index (uPDI), which emphasized consumption of less healthful plant foods such as fruit juices, refined grains, and sugar-sweetened beverages. We estimated the associations of three indices (quintiles) with overall survival (OS) and progression-free survival (PFS) using multivariable Cox proportional hazards regression., Results: We observed 1,100 deaths and 1,204 progression events (median follow-up: 6.1 years). Compared to the lowest quintile, patients in the highest quintile of PDI had significantly better survival (HR for OS: 0.76 [0.62-0.94], P  trend=0.004; PFS: 0.81 [0.66-0.99], P  trend=0.09). Similar findings were observed for hPDI (HR for OS: 0.81 [0.65-1.01], P  trend=0.053; PFS: 0.80 [0.65-0.98], P  trend=0.04), whereas uPDI was not associated with worse survival (HR for OS: 1.16 [0.94-1.43], P  trend=0.21; PFS: 1.12 [0.92-1.36], P  trend=0.42)., Conclusions: Our study suggests that plant-based diet, especially when rich in healthful plant foods, is associated with better survival among patients with metastatic CRC. The cause of survival benefits warrants further investigation., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Purpose: Persistent gastrointestinal (GI) symptoms are frequently experienced by colon cancer survivors and may help identify patients with higher utilization of healthcare services. To assess the relationship between GI symptoms and specialty care utilization among colon cancer survivors., Methods: A prospective longitudinal cohort study at an academic medical center of 126 adults surgically treated for stage I-IV colon cancer between February 2017 and June 2022. Participants reported GI symptoms through the EORTC QLQ-C30 and QLQ-CR29 at enrollment and as frequently as every 6 months for 5 years. Main outcome measures were visits, telephone encounters, and secure messages with a medical provider within specialty oncology clinics within 6 months after each survey completion. Generalized linear mixed regression model for repeated measurements with random trajectory for each participant was performed to estimate the associations between symptoms and healthcare use. Models were adjusted for demographics, clinical and surgical factors, and timing in relation to onset of the COVID-19 pandemic., Results: In the 6 months after each survey time point, patients averaged 1.2 visits, 0.5 telephone encounters, and 3.2 patient-initiated messages. In adjusted models, those with any abdominal pain (RR 1.45; p = 0.002), buttock pain (RR 1.30; p = 0.050), or increased stool frequency (RR 1.26; p = 0.046) had more clinic visits in the following 6 months than those without these symptoms. Including these three symptoms in one model revealed that only abdominal pain was statistically significantly associated with increased clinic visits (RR 1.36; p = 0.016). Patients with any blood or mucus in stool (RR 2.46; p = 0.009) had significantly more telephone encounters, and those with any abdominal pain (RR 1.65; p = 0.002) had significantly more patient-initiated messages than those without these symptoms., Conclusions: Our findings identify GI symptoms associated with increased use of oncologic specialty care among colon cancer survivors, with abdominal pain as an important predictor of utilization., Implications for Cancer Survivors: Early identification and anticipatory management of colon cancer survivors experiencing abdominal pain may decrease healthcare utilization., (© 2024. The Author(s).)

The determination of an optimal treatment plan for an individual patient with rectal cancer is a complex process. In addition to decisions relating to the intent of rectal cancer surgery (ie, curative or palliative), consideration must also be given to the likely functional results of treatment, including the probability of maintaining or restoring normal bowel function/anal continence and preserving genitourinary functions. Particularly for patients with distal rectal cancer, finding a balance between curative-intent therapy while having minimal impact on quality of life can be challenging. Furthermore, the risk of pelvic recurrence is higher in patients with rectal cancer compared with those with colon cancer, and locally recurrent rectal cancer is associated with a poor prognosis. Careful patient selection and the use of sequenced multimodality therapy following a multidisciplinary approach is recommended. These NCCN Guidelines Insights detail recent updates to the NCCN Guidelines for Rectal Cancer, including the addition of endoscopic submucosal dissection as an option for early-stage rectal cancer, updates to the total neoadjuvant therapy approach based on the results of recent clinical trials, and the addition of a "watch-and-wait" nonoperative management approach for clinical complete responders to neoadjuvant therapy.

Background: The liver is the most frequent site of metastases in colorectal cancer (CRC). This study aimed to assess the response rate and survival outcomes in metastatic CRC patients with non-liver metastases (NLM) compared to those with liver metastases (LM) across different lines of treatment., Methods: A total of 17,924 mCRC patients included in 26 trials from the ARCAD CRC database were analyzed. The analysis was conducted based on the presence or absence of LM across different treatment groups: chemotherapy (CT) alone, CT + anti-VEGF, CT + anti-EGFR in KRAS wild-type tumors, within the first-line (1 L) and second-line (2 L), and patients enrolled in third-line (≥3 L) trials treated with trifluridine/tipiracil or regorafenib or placebo. The endpoints were overall survival (OS), progression-free survival (PFS), and overall response rate (ORR)., Results: Out of the 17,924 patients, 14,066 had LM (30.6 % with only liver involvement and 69.4 % with liver and other metastatic sites), while 3858 patients had NLM. In the CT alone and CT + anti-VEGF subgroups, NLM patients showed better OS and PFS in the 1 L and 2 L settings. However, in the CT + anti-EGFR 1 L and 2 L subgroups, there was no significant difference in OS and PFS between NLM and LM patients. In the ≥ 3 L subgroups, better OS and PFS were observed in NLM patients. ORRs were higher in LM patients than in NLM patients across all cohorts treated in the 1 L and only in the anti-EGFR cohort in the 2 L., Conclusion: LM is a poor prognostic factor for mCRC increasing from 1 L to ≥ 3 L except for patients in 1 L and 2 L receiving CT+anti-EGFR. These data justify using LM as a stratification factor in future trials for patients with unresectable mCRC., Competing Interests: Declaration of Competing Interest Benoist Chibaudel reports consulting and advisory role from Amgen, Bayer, Beigine, Biocartis, Lilly, Merck, MSD, Pfizer, Pierre Fabre, Revolution Medicines, Roche, SeqOne, Sanofi, Servier, Takeda. Josep Tabernero reports personal financial interest in form of scientific consultancy role for Array Biopharma, AstraZeneca, Bayer, Boehringer Ingelheim, Cardiff Oncology, Chugai, Daiichi Sankyo, F. Hoffmann-La Roche Ltd, Genentech Inc, HalioDX SAS, Hutchison MediPharma International, Ikena Oncology, Inspirna Inc, IQVIA, Lilly, Menarini, Merck Serono, Merus, MSD, Mirati, Neophore, Novartis, Ona Therapeutics, Orion Biotechnology, Peptomyc, Pfizer, Pierre Fabre, Samsung Bioepis, Sanofi, Scandion Oncology, Scorpion Therapeutics, Seattle Genetics, Servier, Sotio Biotech, Taiho, Tessa Therapeutics, TheraMyc and Tolremo Therapeutics. Stocks: Oniria Therapeutics and also educational collaboration with Imedex/HMP, Medscape Education, MJH Life Sciences, PeerView Institute for Medical Education and Physicians Education Resource (PER). Qian Shi reports consulting/advisory role from Yiviva Inc, Boehringer Ingelheim Pharmaceuticals, Inc, Regeneron Pharmaceuticals, Inc., Hoosier Cancer Research Network, Kronos Bio, and Mirati Therapeutics Inc; Honorarium/speaker role from Chugai Pharmaceutical Co., Ltd (to myself), research funds from Celgene/BMS, Roche/Genentech, Janssen, Novartis (to institution). Thierry Andre reports attending advisory board meetings and receiving consulting fees from Abbvie, Astellas, Aptitude Health, Bristol Myers Squibb, Gritstone Oncology, Gilead, GlaxoSmithKline, Merck & Co. Inc., Nordic Oncology, Seagen, Servier, Takeda and Transgène and honoraria from Bristol Myers Squibb, GlaxoSmithKline, Merck & Co. Inc., Merck Serono, Pierre Fabre, Roche, Sanofi, Seagen and Servier; and support for meetings from Merck & Co. Inc. and Servier. John Zalcberg reports leadership from ICON Group, Lipotek, PRAXIS; Stock from Biomarin, Ophthea, Amarin, Concert Pharmaceuticals, Frequency Therapeutics, Gilead, Madrigal Pharmaceuticals, UniQure, Zogenix, Orphazyme, Moderna Therapeutics, TWST, Novavax, Teladoc; Honoraria from Gilead Sciences, MSD Oncology, Viatris; Consulting & Advisory Role from Merck Sharp & Dohme, Specialized Therapeutics, CEND, Deciphera, REVOLUTION MEDICINE, FivePHusion, Genorbio, 1Global, Novatech, Alloplex Biotherapeutics Inc, Oncology Republic; Research Funding from BMS, AstraZeneca, Pfizer, IQvia, Mylan, Ipsen, Eisai, Medtronic, MSD Oncology, Servier; Travel from MSD Oncology, ICON Group, PRAXIS.Eric Van Cutsem repors participation to advisory boards for Abbvie, ALX, Amgen, Array, Astellas, Astrazeneca, Bayer, Beigene, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi, GSK, Incyte, Ipsen, Lilly, Merck Sharp & Dohme, Merck KGaA, Mirati, Novartis, Nordic, Pierre Fabre, Pfizer, Roche, Seattle Genetics, Servier, Takeda, Terumo, Taiho, Zymeworks; research grants from Amgen, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Ipsen, Lilly, Merck Sharp & Dohme, Merck KGaA, Novartis, Roche, Servier paid to his institution. Takayuki Yoshino reports honoraria from Chugai Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Merck Biopharma Co., Ltd., Bayer Yakuhin, Ltd., Ono Pharmaceutical Co., Ltd., MSD K.K.; consulting fee from Sumitomo Corp.; research grant from Amgen K.K., Bristol-Myers Squibb K.K., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Eisai Co., Ltd, FALCO biosystems Ltd., Genomedia Inc., MEDICAL & BIOLOGICAL LABORATORIES CO., LTD., Merus N.V., Molecular Health GmbH, MSD K.K., Nippon Boehringer Ingelheim Co ., Ltd., Ono Pharmaceutical Co., Ltd., Pfizer Japan Inc.,Roche Diagnostics K.K., Sanofi K.K., Sysmex Corp., Taiho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd. Richard Adams reports receiving consulting fees from Takeda, Bayer, GSK; honoraria from Amgen, Bayer, Seagen; Support for attending meetings and/or travel from Servier, Takeda; Participation on Advisory Board from Takeda, Seagen. Carsten Bokemeyer repors receiving consulting fees as advisory boards from Astra Zeneca, Bayer Healthcare, BioNTech, Heaxal, Lindis Biotech, and Sanofi Aventis; as Invited Speaker from AOK Germany, med update, and Roche Pharma; reports honoraria from DGHO, Hamburg Cancer Society, National Network of German Cancer Centers (DKH), Northern German Society of Internal Medicine, DGHO, German Cancer Society. Cornelis J. A. Punt repors receiving consulting fees as advisory boards from Nordic Pharma. Richard M Goldberg receiving consulting fees as advisory boards from Fight for Colorectal Cancer, US NCI. Volker Heinemann repors receiving consulting fees from Merck, Amgen, Roche, AstraZeneca, Celgene, Servier, Novartis, Pierre-Fabre, Halozyme, MSD, BMS, GSK, Janssen, Terumo, Sirtex, Oncosil, Nordic, Boehringer-Ingelheim; honoraria from Merck, Amgen, Roche, Sanofi, Servier, Pfizer, Pierre-Fabre, AstraZeneca, BMS, MSD, Novartis, Boehringer-Ingelheim, Celgene, Sirtex, Seagen, GSK; support for attending from Merck, Amgen, MSD, Nordic, AstraZeneca, Servier: reports stock from BionTech. Chiara Cremolini repors receiving consulting fees from Nordic Pharma, Merck, Pierre Fabre, Servier, Takeda; reports honoraria from Takeda, MSD, Amgen, Merck, Pierre Fabre, Servier, Bayer; participation to advisory board from Mirat. Miriam Koopman repors receiving consulting fees from Bayer, Bristol Myers Squibb, Merck, Personal Genome Diagnostics (PGDx), Pierre Fabre, Roche, Sirtex, Servier and PI participation from the international cohort study PROMETCO with Servier as sponsor; participation to advisory board from Eisai, Nordic Farma, Merck-Serono, Pierre Fabre, Servier; as leadership or fiduciary role in Chair ESMO RWDD working group, co-chair DCCG, PI PLCRC (national observational cohort study), involved in several clinical trials as PI or co-investigator in CRC. Alan Venook repors receiving consulting fees from Amgen, Genentech/Roche, Deciphera; participation on Advisory Board in Amgen, Agenus. Timothy Maughan repors receiving consulting fees from Merck KGAa, Cancer Research UK, Astrazeneca, Ground Truth Laboratories, Perspectum, Nordin Pharma; participation on Advisory Board and leadership in Cancer Research UK, National Cancer Research Institute-University of Liverpool. All remaining authors have declared no conflicts of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Dose-limiting toxicities remain a major barrier to drug development and therapy, revealing the limited predictive power of human genetics. Herein, we demonstrate the utility of a more comprehensive approach to studying drug toxicity through longitudinal study of the human gut microbiome during colorectal cancer (CRC) treatment (NCT04054908) coupled to cell culture and mouse experiments. 16S rRNA gene and metagenomic sequencing revealed significant shifts in gut microbial community structure during treatment with oral fluoropyrimidines, which was validated in an independent cohort. Gene abundance was also markedly changed by oral fluoropyrimidines, including an enrichment for the preTA operon, which is sufficient for the inactivation of active metabolite 5-fluorouracil (5-FU). Higher levels of preTA led to increased 5-FU depletion by the gut microbiota grown ex vivo . Germ-free and antibiotic-treated mice had increased fluoropyrimidine toxicity, which was rescued by colonization with the mouse gut microbiota, preTA + E. coli , or CRC patient stool with high preTA levels. preTA abundance was negatively associated with patient toxicities. Together, these data support a causal, clinically relevant interaction between a human gut bacterial operon and the dose-limiting side effects of cancer treatment. Our approach is generalizable to other drugs, including cancer immunotherapies, and provides valuable insights into host-microbiome interactions in the context of disease., Competing Interests: W.A.K. has received research funding (institution) from Pfizer; there is no direct overlap with the current study. P.J.T. is on the scientific advisory boards of Pendulum, Seed and SNIPRbiome; there is no direct overlap between the current study and these consulting duties. C.E.A served on the scientific advisory board of Pionyr Immunotherapeutics and has received research funding (institution) from Bristol Meyer Squibb, Erasca, Gossamer Bio, Guardant Health, Kura Oncology, Merck and Novartis; there is no direct overlap with the current study. E.V.B. is on the medical advisory board for Fight CRC; there is no direct overlap with the current study.All other authors declare no competing interests.

Colorectal cancer (CRC) is the fourth most frequently diagnosed cancer and the second leading cause of cancer death in the United States. Management of disseminated metastatic CRC involves various active drugs, either in combination or as single agents. The choice of therapy is based on consideration of the goals of therapy, the type and timing of prior therapy, the mutational profile of the tumor, and the differing toxicity profiles of the constituent drugs. This manuscript summarizes the data supporting the systemic therapy options recommended for metastatic CRC in the NCCN Guidelines for Colon Cancer.

Purpose: The phase III Cancer and Leukemia Group B (CALGB)/SWOG 80405 trial found no difference in overall survival (OS) in patients with metastatic colorectal cancer receiving first-line chemotherapy in combination with either bevacizumab or cetuximab. We investigated the potential prognostic and predictive value of HER2 amplification and gene expression using next-generation sequencing (NGS) and NanoString data., Patients and Methods: Primary tumor DNA from 559 patients was profiled for HER2 amplification by NGS (FoundationOne CDx). Tumor tissue from 925 patients was tested for NanoString gene expression using an 800-gene panel. OS and progression-free survival (PFS) were the time-to-event end points., Results: High HER2 expression (dichotomized at median) was associated with longer PFS (11.6 v 10 months, P = .012) and OS (32 v 25.3 months, P = .033), independent of treatment. An OS benefit for cetuximab versus bevacizumab was observed in the high HER2 expression group ( P = .02), whereas a worse PFS for cetuximab was seen in the low-expression group ( P = .019). When modeled as a continuous variable, increased HER2 expression was associated with longer OS (hazard ratio [HR], 0.83 [95% CI, 0.75 to 0.93]; adjusted P = .0007) and PFS (HR, 0.82 [95% CI, 0.74 to 0.91]; adjusted P = .0002), reaching a plateau effect after the median. In patients with HER2 expression lower than median, treatment with cetuximab was associated with worse PFS (HR, 1.38 [95% CI, 1.12 to 1.71]; adjusted P = .0027) and OS (HR, 1.28 [95% CI, 1.02 to 1.59]; adjusted P = .03) compared with that with bevacizumab. A significant interaction between HER2 expression and the treatment arm was observed for OS ( P intx = .017), PFS ( P intx = .048), and objective response rate ( P intx = .001)., Conclusion: HER2 gene expression was prognostic and predictive in CALGB/SWOG 80405. HER2 tumor expression may inform treatment selection for patients with low HER2 favoring bevacizumab- versus cetuximab-based therapies.

Background: CDC37 is a key determinant of client kinase recruitment to the HSP90 chaperoning system. We hypothesized that kinase-specific dependency on CDC37 alters the efficacy of targeted therapies for metastatic colorectal cancer (mCRC)., Material and Methods: Two independent mCRC cohorts were analyzed to compare the survival outcomes between CDC37-high and CDC37-low patients (stratified by the median cutoff values): the CALGB/SWOG 80405 trial (226 and 207 patients receiving first-line bevacizumab- and cetuximab-containing chemotherapies, respectively) and Japanese retrospective (50 refractory patients receiving regorafenib) cohorts. A dataset of specimens submitted to a commercial CLIA-certified laboratory was utilized to characterize molecular profiles of CDC37-high (top quartile, N = 5055) and CDC37-low (bottom quartile, N = 5055) CRCs., Results: In the bevacizumab-treated group, CDC37-high patients showed significantly better progression-free survival (PFS) (median 13.3 vs 9.6 months, hazard ratio [HR] 0.59, 95% confidence interval [CI] 0.44-0.79, p < 0.01) than CDC37-low patients. In the cetuximab-treated group, CDC37-high and CDC37-low patients had similar outcomes. In the regorafenib-treated group, CDC37-high patients showed significantly better overall survival (median 11.3 vs 6.0 months, HR 0.24, 95% CI 0.11-0.54, p < 0.01) and PFS (median 3.5 vs 1.9 months, HR 0.51, 95% CI 0.28-0.94, p = 0.03). Comprehensive molecular profiling revealed that CDC37-high CRCs were associated with higher VEGFA, FLT1, and KDR expressions and activated hypoxia signature., Conclusions: CDC37-high mCRC patients derived more benefit from anti-VEGF therapies, including bevacizumab and regorafenib, but not from cetuximab. Molecular profiles suggested that such tumors were dependent on angiogenesis-relating pathways., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: H-JL reports receiving honoraria from consultant/advisory board membership for Merck Serono, Bayer, and Genentech. EL reports research grants from the American Cancer Society (RSG-22–022-01-CDP) 2022–2026, and the Minnesota Ovarian Cancer Alliance in 2019, 2021, and 2022; The Randy Shaver Cancer Research and Community Fund; honoraria and travel expenses for lab-based research talks 2018–21, and equipment for laboratory-based research 2018-present, Novocure, Ltd; honorarium for panel discussion organized by Antidote Education for a CME module on diagnostics and treatment of HER2 + gastric and colorectal cancers, funded by Daiichi-Sankyo, 2021 (honorarium donated to lab); compensation for scientific review of proposed printed content, Elsevier Publishing and Johns Hopkins Press; consultant, Nomocan Pharmaceuticals (no financial compensation); Scientific Advisory Board Member, Minnetronix, LLC, 2018–2019 (no financial compensation); consultant and speaker honorarium, Boston Scientific US, 2019. Institutional Principal Investigator for clinical trials sponsored by Celgene, Novocure, Intima Biosciences, and the National Cancer Institute, and University of Minnesota membership in the Caris Life Sciences Precision Oncology Alliance (no financial compensation). YB, JX, and WMK are employees of Caris Life Sciences. All remaining authors have declared no conflicts of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Sorafenib blocks nonstructural protein 5A (NS5A)-recruited c-Raf-mediated hepatitis C virus (HCV) replication and gene expression. Release of Raf-1-Ask-1 dimer and inhibition of Raf-1 via sorafenib putatively differ in the presence or absence of doxorubicin. Cancer and Leukemia Group B (CALGB) 80802 (Alliance) randomized phase III trial of doxorubicin plus sorafenib versus sorafenib in patients with advanced hepatocellular carcinoma (HCC), showed no improvement in median overall survival (OS). Whether HCV viral load impacts therapy and whether any correlation between HCV titers and outcome based on HCV was studied. In patients with HCV, HCV titer levels were evaluated at baseline and at multiple postbaseline timepoints until disease progression or treatment discontinuation. HCV titer levels were evaluated in relation to OS and progression-free survival (PFS). Among 53 patients with baseline HCV data, 12 patients had undetectable HCV (HCV-UN). Postbaseline HCV titer levels did not significantly differ between treatment arms. One patient in each arm went from detectable to HCV-UN with greater than 2 log-fold titer levels reduction. Aside from these 2 HCV-UN patients, HCV titers remained stable on treatment. Patients who had HCV-UN at baseline were 3.5 times more likely to progress and/or die from HCC compared with HCV detectable (HR = 3.51; 95% confidence interval: 1.58-7.78; P = 0.002). HCV titer levels remained unchanged, negating any sorafenib impact onto HCV titer levels. Although an overall negative phase III study, patients treated with doxorubicin plus sorafenib and sorafenib only, on CALGB 80802 had worse PFS if HCV-UN. Higher levels of HCV titers at baseline were associated with significantly improved PFS., Significance: Sorafenib therapy for HCC may impact HCV replication and viral gene expression. In HCV-positive patients accrued to CLAGB 80802 phase III study evaluating the addition of doxorubicin to sorafenib, HCV titer levels were evaluated at baseline and different timepoints. Sorafenib did not impact HCV titer levels. Despite an improved PFS in patients with detectable higher level HCV titers at baseline, no difference in OS was noted., (© 2024 The Authors; Published by the American Association for Cancer Research.)

Introduction: The primary objective of this study was to determine whether workplace culture in academic oncology differed by gender, during the COVID-19 pandemic., Materials and Methods: We used the Culture Conducive to Women's Academic Success (CCWAS), a validated survey tool, to investigate the academic climate at an NCI-designated Cancer Center. We adapted the CCWAS to be applicable to people of all genders. The full membership of the Cancer Center was surveyed (total faculty = 429). The questions in each of 4 CCWAS domains (equal access to opportunities, work-life balance, freedom from gender bias, and leadership support) were scored using a 5-point Likert scale. Median score and interquartile ranges for each domain were calculated., Results: A total of 168 respondents (men = 58, women = 106, n = 4 not disclosed) submitted survey responses. The response rate was 39% overall and 70% among women faculty. We found significant differences in perceptions of workplace culture by gender, both in responses to individual questions and in the overall score in the following domains: equal access to opportunities, work-life balance, and leader support, and in the total score for the CCWAS., Conclusions: Our survey is the first of its kind completed during the COVID-19 pandemic at an NCI-designated Cancer Center, in which myriad factors contributed to burnout and workplace challenges. These results point to specific issues that detract from the success of women pursuing careers in academic oncology. Identifying these issues can be used to design and implement solutions to improve workforce culture, mitigate gender bias, and retain faculty., (© The Author(s) 2023. Published by Oxford University Press.)

Purpose: CALGB (Alliance)/SWOG 80405 was a randomized phase III trial that in first-line patients with metastatic colorectal cancer (mCRC) treated with bevacizumab or cetuximab with chemotherapy. We aimed to discover novel mutated genes associated with prognosis and differential response to therapy with the biologics., Methods: Primary tumor DNA from 548 patients was sequenced using FoundationOne. The effect of mutated genes and mutations on overall survival (OS) was tested adjusting for microsatellite instability status, BRAF V600E, all RAS mutations, arm, sex, and age., Results: The median number (lower-upper quartile) of mutated genes was 5 (3-7), 5 (3-6) in microsatellite stable and 12.5 (4.5-32) in microsatellite instability-high tumors. Mutated KRAS and APC were more frequent in Black (53% and 85%) than White (27% and 65%, respectively) patients while BRAF V600E was less frequent in Black (5%) than White (14%) patients. The median OS in patients with BRAF non-V600E (2.2% of patients) was 31.9 months (95% CI, 15.1 to not applicable [NA]) similar to that of BRAF wild-type (WT) patients (31.2 months [95% CI, 29.0 to 33.9]). Mutated LRP1B (10.7% of patients) was associated with improved OS compared with WT LRP1B (hazard ratio, 0.57 [95% CI, 0.40 to 0.80]). RNF43 (5.6% of patients) interacted with treatment arms as, in the cetuximab arm, patients with mutated RNF43 had a median OS of 11.5 (95% CI, 10.8 to NA) months compared with 30.1 (95% CI, 24.9 to 35.3) months in patients with WT RNF43 , whereas in the bevacizumab arm, patients with mutated RNF43 had a median OS of 25.0 (95% CI, 14.2 to NA) months compared with 31.3 (95% CI, 29.0 to 34.3) months in patients with WT RNF43 ., Conclusion: These results can provide new tools to predict patient outcome and improve therapeutic decisions and trial participation in patient minorities. The molecular alterations identified in this study may direct biomarker-driven studies.

Background: The C-C motif chemokine receptor 5 (CCR5)/C-C motif chemokine ligand 5 (CCL5) axis plays a major role in colorectal cancer (CRC). We aimed to characterize the molecular features associated with CCR5 / CCL5 expression in CRC and to determine whether CCR5 / CCL5 levels could impact treatment outcomes., Methods: 7604 CRCs tested with NextGen Sequencing on DNA and RNA were analyzed. Molecular features were evaluated according to CCR5 and CCL5 tumor gene expression quartiles. The impact on treatment outcomes was assessed in two cohorts, including 6341 real-world patients and 429 patients from the Cancer and Leukemia Group B (CALGB)/SWOG 80405 trial., Results: CCR5 / CCL5 expression was higher in right-sided versus left-sided tumors, and positively associated with consensus molecular subtypes 1 and 4. Higher CCR5 / CCL5 expression was associated with higher tumor mutational burden, deficiency in mismatch repair and programmed cell death ligand 1 (PD-L1) levels. Additionally, high CCR5 / CCL5 were associated with higher immune cell infiltration in the tumor microenvironment (TME) of MMR proficient tumors. Ingenuity pathway analysis revealed upregulation of the programmed cell death protein 1 (PD-1)/PD-L1 cancer immunotherapy pathway, phosphatase and tensin homolog (PTEN) and peroxisome proliferator-activated receptors (PPAR) signaling, and cytotoxic T-lymphocyte antigen 4 (CTLA-4) signaling in cytotoxic T lymphocytes, whereas several inflammation-related pathways were downregulated. Low CCR5 / CCL5 expression was associated with increased benefit from cetuximab-FOLFOX treatment in the CALGB/SWOG 80405 trial, where significant treatment interaction was observed with biologic agents and chemotherapy backbone., Conclusions: Our data show a strong association between CCR5/CCL5 gene expression and distinct molecular features, gene expression profiles, TME cell infiltration, and treatment benefit in CRC. Targeting the CCR5/CCL5 axis may have clinical applications in selected CRC subgroups and may play a key role in developing and deploying strategies to modulate the immune TME for CRC treatment., Competing Interests: Competing interests: H-JL reports receiving honoraria from consultant/advisory board membership for Merck Serono, Bayer, and Genentech. JX, YB, JPA and WMK are employers of Caris Life Sciences. AFS reports funding for research, travel, and the speakers bureau from Caris Life Sciences. BAW reports receiving honoraria from Bayer, Sirtex, Lilly, Taiho, and HalioDx. RMG reports stock and other ownership interests from Advanced Chemotherapy Technologies and Compass Therapeutics, consulting/advisory role for AbbVie, G1 Therapeutics, GSK, Merck, Eisai, Compass Therapeutics, Inspirna, Taiho, Novartis, AstraZeneca, and Bayer, expert testimony from Taiho Pharmaceutical. FI is an AbbVie employee and receives stocks from the company. All remaining authors have declared no conflicts of interest., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: One in three patients with stage III colon cancer will experience tumor recurrence. It is uncertain whether physical activity during and after postoperative chemotherapy for stage III colon cancer improves overall survival after tumor recurrence., Methods: A prospective cohort study nested within a randomized multicenter trial of patients initially diagnosed with stage III colon cancer who experienced tumor recurrence (N = 399) was conducted. Postoperative physical activity before tumor recurrence was measured. Physical activity energy expenditure was quantified via metabolic equivalent task hours per week (MET-h/week). The primary end point was overall survival after tumor recurrence. Multivariable flexible parametric survival models estimated relative and absolute effects with two-sided hypothesis tests., Results: Compared with patients expending <3.0 MET-h/week of physical activity (comparable to <1.0 h/week of brisk walking), patients with ≥18.0 MET-h/week of physical activity (comparable to 6 h/week of brisk walking) had a 33% relative improvement in overall survival time after tumor recurrence (hazard ratio, 0.67; 95% CI, 0.42-0.96). The overall survival rate at 3 years after tumor recurrence was 61.3% (95% CI, 51.8%-69.2%) with <3.0 MET-h/week of physical activity and 72.2% (95% CI, 63.1%-79.6%) with ≥18 MET-h/week of physical activity (risk difference, 10.9 percentage points; 95% CI, 1.2-20.8 percentage points)., Conclusions: Higher postoperative physical activity is associated with improved overall survival after tumor recurrence in patients initially diagnosed with stage III colon cancer. These data may be relevant to patients who, despite optimal postoperative medical therapy, have a high risk of tumor recurrence., (© 2023 American Cancer Society.)

Metastatic colorectal cancer (mCRC) is a heterogeneous disease that can evoke discordant responses to therapy among different lesions in individual patients. The Response Evaluation Criteria in Solid Tumors (RECIST) criteria do not take into consideration response heterogeneity. We explored and developed lesion-based measurement response criteria to evaluate their prognostic effect on overall survival (OS)., Patients and Methods: Patients enrolled in 17 first-line clinical trials, who had mCRC with ≥ 2 lesions at baseline, and a restaging scan by 12 weeks were included. For each patient, lesions were categorized as a progressing lesion (PL: > 20% increase in the longest diameter (LD)), responding lesion (RL: > 30% decrease in LD), or stable lesion (SL: neither PL nor RL) based on the 12-week scan. Lesion-based response criteria were defined for each patient as follows: PL only, SL only, RL only, and varied responses (mixture of RL, SL, and PL). Lesion-based response criteria and OS were correlated using stratified multivariable Cox models. The concordance between OS and classifications was measured using the C statistic., Results: Among 10,551 patients with mCRC from 17 first-line studies, varied responses were noted in 51.6% of patients, among whom, 3.3% had RL/PL at 12 weeks. Among patients with RL/SL, 52% had stable disease (SD) by RECIST 1.1, and they had a longer OS (median OS (mOS) = 19.9 months) than those with SL only (mOS = 16.8 months, HR (95% CI) = 0.81 (0.76, 0.85), p < 0.001), although a shorter OS than those with RL only (mOS = 25.8 months, HR (95% CI) = 1.42 (1.32, 1.53), p < 0.001). Among patients with SL/PL, 74% had SD by RECIST 1.1, and they had a longer OS (mOS = 9.0 months) than those with PL only (mOS = 8.0 months, HR (95% CI) = 0.75 (0.57, 0.98), p = 0.040), yet a shorter OS than those with SL only (mOS = 16.8 months, HR (95% CI) = 1.98 (1.80, 2.18), p < 0.001). These associations were consistent across treatment regimen subgroups. The lesion-based response criteria showed slightly higher concordance than RECIST 1.1, although it was not statistically significant., Conclusion: Varied responses at first restaging are common among patients receiving first-line therapy for mCRC. Our lesion-based measurement criteria allowed for better mortality discrimination, which could potentially be informative for treatment decision-making and influence patient outcomes.

Background: Pelvic radiation plus sensitizing chemotherapy with a fluoropyrimidine (chemoradiotherapy) before surgery is standard care for locally advanced rectal cancer in North America. Whether neoadjuvant chemotherapy with fluorouracil, leucovorin, and oxaliplatin (FOLFOX) can be used in lieu of chemoradiotherapy is uncertain., Methods: We conducted a multicenter, unblinded, noninferiority, randomized trial of neoadjuvant FOLFOX (with chemoradiotherapy given only if the primary tumor decreased in size by <20% or if FOLFOX was discontinued because of side effects) as compared with chemoradiotherapy. Adults with rectal cancer that had been clinically staged as T2 node-positive, T3 node-negative, or T3 node-positive who were candidates for sphincter-sparing surgery were eligible to participate. The primary end point was disease-free survival. Noninferiority would be claimed if the upper limit of the two-sided 90.2% confidence interval of the hazard ratio for disease recurrence or death did not exceed 1.29. Secondary end points included overall survival, local recurrence (in a time-to-event analysis), complete pathological resection, complete response, and toxic effects., Results: From June 2012 through December 2018, a total of 1194 patients underwent randomization and 1128 started treatment; among those who started treatment, 585 were in the FOLFOX group and 543 in the chemoradiotherapy group. At a median follow-up of 58 months, FOLFOX was noninferior to chemoradiotherapy for disease-free survival (hazard ratio for disease recurrence or death, 0.92; 90.2% confidence interval [CI], 0.74 to 1.14; P = 0.005 for noninferiority). Five-year disease-free survival was 80.8% (95% CI, 77.9 to 83.7) in the FOLFOX group and 78.6% (95% CI, 75.4 to 81.8) in the chemoradiotherapy group. The groups were similar with respect to overall survival (hazard ratio for death, 1.04; 95% CI, 0.74 to 1.44) and local recurrence (hazard ratio, 1.18; 95% CI, 0.44 to 3.16). In the FOLFOX group, 53 patients (9.1%) received preoperative chemoradiotherapy and 8 (1.4%) received postoperative chemoradiotherapy., Conclusions: In patients with locally advanced rectal cancer who were eligible for sphincter-sparing surgery, preoperative FOLFOX was noninferior to preoperative chemoradiotherapy with respect to disease-free survival. (Funded by the National Cancer Institute; PROSPECT ClinicalTrials.gov number, NCT01515787.)., (Copyright © 2023 Massachusetts Medical Society.)

In 2023, the NCCN Guidelines for Hepatobiliary Cancers were divided into 2 separate guidelines: Hepatocellular Carcinoma and Biliary Tract Cancers. The NCCN Guidelines for Biliary Tract Cancers provide recommendations for the evaluation and comprehensive care of patients with gallbladder cancer, intrahepatic cholangiocarcinoma, and extrahepatic cholangiocarcinoma. The multidisciplinary panel of experts meets at least on an annual basis to review requests from internal and external entities as well as to evaluate new data on current and emerging therapies. These Guidelines Insights focus on some of the recent updates to the NCCN Guidelines for Biliary Tract Cancers as well as the newly published section on principles of molecular testing.

This discussion summarizes the NCCN Clinical Practice Guidelines for managing squamous cell anal carcinoma, which represents the most common histologic form of the disease. A multidisciplinary approach including physicians from gastroenterology, medical oncology, surgical oncology, radiation oncology, and radiology is necessary. Primary treatment of perianal cancer and anal canal cancer are similar and include chemoradiation in most cases. Follow-up clinical evaluations are recommended for all patients with anal carcinoma because additional curative-intent treatment is possible. Biopsy-proven evidence of locally recurrent or persistent disease after primary treatment may require surgical treatment. Systemic therapy is generally recommended for extrapelvic metastatic disease. Recent updates to the NCCN Guidelines for Anal Carcinoma include staging classification updates based on the 9th edition of the AJCC Staging System and updates to the systemic therapy recommendations based on new data that better define optimal treatment of patients with metastatic anal carcinoma.

Purpose: We sought to determine whether adherence to the American Cancer Society (ACS) Nutrition and Physical Activity Guidelines was associated with better bowel function among colon cancer survivors., Methods: This prospective cohort study included patients surgically treated for stage I-IV colon cancer enrolled in the Lifestyle and Outcomes after Gastrointestinal Cancer (LOGIC) study between February 2017 and May 2021. Participants were assigned an ACS score (0-6 points) at enrollment. Stool frequency (SF) was assessed every 6 months using the EORTC QLQ-CR29. Higher SF is an indication of bowel function impairment. ACS score at enrollment was examined in relation to SF at enrollment and over a 3-year period. Secondarily, we examined associations between the ACS score components (body mass index, dietary factors, and physical activity) and SF. Multivariable models were adjusted for demographic and surgical characteristics., Results: A total of 112 people with colon cancer (59% women, mean age 59.5 years) were included. Cross-sectionally, for every point increase in ACS score at enrollment, the odds of having frequent stools at enrollment decreased by 43% (CI 0.42-0.79; p < 0.01). Findings were similar when we examined SF as an ordinal variable and change in SF over a 3-year period. Lower consumption of red/processed meats and consuming a higher number of unique fruits and vegetables were associated with lower SF (better bowel function) at enrollment., Conclusions: Colon cancer survivors who more closely followed the ACS nutrition and physical activity guidelines had lower SF, an indication of better bowel function., Implications for Cancer Survivors: Our findings highlight the value of interventions that support health behavior modification as part of survivorship care for long-term colon cancer survivors., (© 2022. The Author(s).)

The incidence and biochemical consequences of rare tumor subtypes are often hard to study. Fibrolamellar liver cancer (FLC) is a rare malignancy affecting adolescents and young adults. To better characterize the incidence and biochemical consequences of this disease, we combined a comprehensive analysis of the electronic medical record and national payer data and found that FLC incidence is likely five to eight times higher than previous estimates. By employing unsupervised learning on clinical laboratory data from patients with hyperammonemia, we find that FLC-associated hyperammonemia mirrors metabolic dysregulation in urea cycle disorders. Our findings demonstrate that advanced computational analysis of rich clinical datasets can provide key clinical and biochemical insights into rare cancers., (© 2023. The Author(s).)

Purpose: We aimed to estimate the effect of a 12-week web-based dietary intervention with text messages on quality of life (QoL) among colorectal cancer (CRC) survivors., Methods: Between 2017 and 2018, 50 CRC survivors were randomized (1:1) to receive a 12-week web-based dietary intervention with daily text messages or wait-list control. Health-related QoL was assessed using the European Organization for the Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) and colorectal quality of life module (QLQ-CR29) at baseline, 12, and 24 weeks. Within- and between-group mean changes in health-related QoL with 95% confidence intervals (CI) were calculated for both arms., Results: Compared to the controls, participants receiving the intervention had an improvement in emotional functioning (mean change: 14.3; 95% CI: 3.0, 25.6) at 12 weeks and social functioning (mean change: 13.8; 95% CI: 2.1, 25.5) at 24 weeks. A decrease of fatigue from baseline was also observed in the intervention arm (mean change: - 9.1; 95% CI: - 17.1, - 1.1) at 24 weeks. No other changes in QoL scores were associated with the intervention., Conclusion: CRC survivors randomized to receive a web-based dietary intervention with text messages experienced higher emotional and social functioning. Further study with a larger population may be warranted., Trial Registration: clinicaltrials.gov, NCT02965521. Registered 16 November 2016, https://clinicaltrials.gov/ct2/keydates/NCT02965521., (© 2023. The Author(s).)

Background: Studies suggest that adjuvant chemotherapy should be initiated at the earliest possible time. The Eastern Cooperative Oncology Group (ECOG) and Intergroup evaluated the effect of perioperative fluorouracil (5-FU) on overall survival (OS) for colon cancer., Patients and Methods: This phase III trial randomized patients to receive continuous infusional 5-FU for 7 days starting within 24 h after curative resection (arm A) or no perioperative 5-FU (arm B). Patients with Dukes' B3 and C disease received adjuvant chemotherapy per standard of care. The primary endpoint of the trial was overall survival in patients with Dukes' B3 and C disease. The secondary objective was to determine whether a week of perioperative infusion would affect survival in patients with Dukes' B2 colon cancer with no additional chemotherapy., Results: From August 1993 to May 2000, 859 patients were enrolled and 855 randomized (arm A: 427; arm B: 428). The trial was terminated early due to slow accrual. The median follow-up is 15.4 years (0.03-20.3 years). Among patients with Dukes' B3 and C disease, there was no statistically significant difference in OS [median 10.3 years (95% CI 8.4, 13.2) for perioperative chemotherapy and 9.3 years (95% CI 5.7, 12.3) for no perioperative therapy, one-sided log-rank p = 0.178, HR = 0.88 (95% CI 0.66, 1.16)] or disease-free survival (DFS). For patients with Dukes' B2 disease, there was also no significant difference in OS (median 16.1 versus 12.9 years) or DFS. There was no difference between treatment arms in operative complications. One week of continuous infusion of 5-FU was tolerable; 18% of arm A patients experienced grade 3 or greater toxicity., (© 2022. The Author(s).)

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. Acquired genomic alterations (Acq-GAs), specifically RAS , BRAF , and EGFR -ectodomain mutations and ERBB2 and MET amplifications, are recognized as major mechanisms of resistance to later-line anti-EGFR-antibody therapy in metastatic colorectal cancer (mCRC). However, data regarding emergence of these Acq-GAs under the selective pressure of first-line anti-EGFR-chemotherapy are lacking. We performed next-generation sequencing (Guardant360) on circulating tumor DNA obtained from paired plasma samples (pretreatment and postprogression) from the CALGB/SWOG-80405 trial, which randomly assigned patients with mCRC between first-line chemotherapy with cetuximab (anti-EGFR-chemotherapy) or bevacizumab (anti-VEGF-chemotherapy). The primary objective was to determine the prevalence of Acq-GAs on anti-EGFR-chemotherapy and compare this to the prevalence with anti-VEGF-chemotherapy on trial and pooled estimates (N = 292) seen with later-line anti-EGFR-antibody therapy as reported in the literature. Among the 61 patients on anti-EGFR-chemotherapy, only four (6.6%) developed ≥ 1 Acq-GAs of interest compared with 10.1% (7) on anti-VEGF-chemotherapy (odds ratio, 0.62; 95% CI, 0.20 to 2.11) and 62.0% on anti-EGFR-antibody therapy in later lines (odds ratio, 0.09; 95% CI, 0.03 to 0.23). Acq-GAs, classically associated with anti-EGFR-antibody resistance in later lines ( RAS , BRAF , and EGFR -ectodomain mutations; ERBB2 and MET amplifications), were rare with up-front use of anti-EGFR-chemotherapy indicating divergent resistance mechanisms. These findings have critical translational relevance to timing and value of circulating tumor DNA-guided anti-EGFR rechallenge in patients with mCRC, especially those treated with anti-EGFR therapy upfront.

Data 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]; P trend: .12; for cancer progression or death: 0.74 [0.62, 0.89]; 0.78 [0.64, 0.95]; 0.71 [0.57, 0.88]; P trend: .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., (© 2022 UICC.)

Background: Extrahepatic disease progression limits clinical efficacy of Yttrium-90 ( 90 Y) radioembolization (TARE) for patients with chemotherapy-refractory metastatic colorectal cancer (mCRC). Trifluridine and tipiracil (TAS-102) has overall survival benefit for patients with refractory mCRC and may be a radiosensitizer., Methods: Sequential lobar TARE using 90 Y resin microspheres in combination with TAS-102 in 28-day cycles were used to treat adult patients with bilobar liver-dominant chemo-refractory mCRC according to 3 + 3 dose escalation design with a 12-patient dose expansion cohort. Study objectives were to establish safety and determine maximum tolerated dose (MTD) of TAS-102 in combination with TARE., Results: A total of 21 patients (14 women, 7 men) with median age of 60 years were enrolled. No dose limiting toxicities were observed. Treatment related severe adverse events included cytopenias (10 patients, 48%) and radioembolization-induced liver disease (2 patients, 10%). Disease control rate in the liver lobes treated with TARE was 100%. Best observed radiographic responses were partial response for 4 patients (19%) and stable disease for 12 patients (57%)., Conclusions: The combination of TAS-102 and TARE for patients with liver-dominant mCRC is safe and consistently achieves disease control within the liver., Trial Registration: ClinicalTrials.gov identifier NCT02602327 (first posted 11/11/2015)., (© 2022. The Author(s).)

This selection from the NCCN Guidelines for Rectal Cancer focuses on management of malignant polyps and resectable nonmetastatic rectal cancer because important updates have been made to these guidelines. These recent updates include redrawing the algorithms for stage II and III disease to reflect new data supporting the increasingly prominent role of total neoadjuvant therapy, expanded recommendations for short-course radiation therapy techniques, and new recommendations for a "watch-and-wait" nonoperative management technique for patients with cancer that shows a complete response to neoadjuvant therapy. The complete version of the NCCN Guidelines for Rectal Cancer, available online at NCCN.org, covers additional topics including risk assessment, pathology and staging, management of metastatic disease, posttreatment surveillance, treatment of recurrent disease, and survivorship.

Most colorectal (CRC) tumors are dependent on EGFR/KRAS/BRAF/MAPK signaling activation. ARID1A is an epigenetic regulator mutated in approximately 5% of non-hypermutated CRC tumors. Here we show that anti-EGFR but not anti-VEGF treatment enriches for emerging ARID1A mutations in CRC patients. In addition, we find that patients with ARID1A mutations, at baseline, are associated with worse outcome when treated with cetuximab- but not bevacizumab-containing therapies; thus, this suggests that ARID1A mutations may provide both an acquired and intrinsic mechanism of resistance to anti-EGFR therapies. We find that, ARID1A and EGFR-pathway genetic alterations are mutually exclusive across lung and colorectal cancers, further supporting a functional connection between these pathways. Our results not only suggest that ARID1A could be potentially used as a predictive biomarker for cetuximab treatment decisions but also provide a rationale for exploring therapeutic MAPK inhibition in an unexpected but genetically defined segment of CRC patients., (© 2022. The Author(s).)

Purpose: CALGB 80405 compared the combination of first-line chemotherapy with cetuximab or bevacizumab in the treatment of advanced or metastatic colorectal cancer (mCRC). Although similar clinical outcomes were observed in the cetuximab-chemotherapy group and the bevacizumab-chemotherapy group, biomarkers could identify patients deriving more benefit from either biologic agent., Patients and Methods: In this exploratory analysis, the Angiome, a panel of 24 soluble protein biomarkers were measured in baseline plasma samples in CALGB 80405. Prognostic biomarkers were determined using univariate Cox proportional hazards models. Predictive biomarkers were identified using multivariable Cox regression models including interaction between biomarker level and treatment., Results: In the total population, high plasma levels of Ang-2, CD73, HGF, ICAM-1, IL6, OPN, TIMP-1, TSP-2, VCAM-1, and VEGF-R3 were identified as prognostic of worse progression-free survival (PFS) and overall survival (OS). PlGF was identified as predictive of lack of PFS benefit from bevacizumab [bevacizumab HR, 1.51; 95% confidence interval (CI), 1.10-2.06; cetuximab HR, 0.94; 95% CI, 0.71-1.25; Pinteraction = 0.0298] in the combined FOLFIRI/FOLFOX regimens. High levels of VEGF-D were predictive of lack of PFS benefit from bevacizumab in patients receiving FOLFOX regimen only (FOLFOX/bevacizumab HR, 1.70; 95% CI, 1.19-2.42; FOLFOX/cetuximab HR, 0.92; 95% CI, 0.68-1.24; Pinteraction = 0.0097)., Conclusions: In this exploratory, hypothesis-generating analysis, the Angiome identified multiple prognostic biomarkers and two potential predictive biomarkers for patients with mCRC enrolled in CALGB 80405. PlGF and VEGF-D predicted lack of benefit from bevacizumab in a chemo-dependent manner. See related commentaries by Mishkin and Kohn, p. 2722 and George and Bertagnolli, p. 2725., (©2021 American Association for Cancer Research.)

Purpose: There are over 1.3 million colorectal cancer (CRC) survivors in the USA, many of whom report lower health-related quality of life (HRQoL) years after treatment. This study aimed to explore the effect of digital health tools on HRQoL in CRC survivors., Methods: We conducted a two-arm, randomized controlled trial of 42 subjects who had completed treatment for CRC. Participants in the intervention arm received a Fitbit Flex™ and daily text messages for 12 weeks. HRQoL was assessed as a secondary endpoint in both arms at enrollment and 12 weeks using the Medical Outcomes Study Short Form Survey (SF-36) and the Functional Assessment of Cancer Therapy-Colorectal (FACT-C). Survey score changes from enrollment to 12 weeks were compared between the two arms using independent t tests, and scores at enrollment and 12 weeks were compared using paired t tests., Results: An increase in the FACT-C functional well-being subscale was observed in individuals in the intervention arm pre- to post-intervention (median difference, 2; interquartile range (IQR), 1, 4; P = .02). Although the between-group comparison was not statistically significant, no change in the functional well-being subscale was observed in the control arm (median difference, 0; IQR, 1, 1; P = .71). No other measures of HRQoL appeared to differ within arm across time points or between arms., Conclusion: A 12-week digital physical activity intervention may improve functional well-being among CRC survivors. Larger randomized studies are needed to determine if digital health tools improve functional well-being among CRC survivors and if this improvement can be sustained over time., Trial Registration: NCT02966054; registration date, November 17, 2016., (© 2022. The Author(s).)

Background: Little is known about the interaction of comorbidities and age on survival outcomes in colorectal cancer (mCRC), nor how comorbidities impact treatment tolerance., Methods: We utilized a cohort of 1345 mCRC patients enrolled in CALGB/SWOG 80405, a multicenter phase III trial of fluorouracil/leucovorin + oxaliplatin (FOLFOX) or irinotecan (FOLFIRI) plus bevacizumab, cetuximab or both. Endpoints were overall survival (OS), progression-free survival (PFS), and grade ≥ 3 toxicities assessed using NCI CTCAE v.3.0. Participants completed a questionnaire, including a modified Charlson Comorbidity Index. Adjusted Cox and logistic regression models tested associations of comorbidities and age on the endpoints., Results: In CALGB/SWOG 80405, 1095 (81%) subjects were < 70 years and >70 250 (19%). Presence of ≥1 comorbidity was not significantly associated with either OS (HR 1.10, 95% CI 0.96-1.25) or PFS (HR 1.03, 95% CI 0.91-1.16). Compared to subjects <70 with no comorbidities, OS was non-significantly inferior for ≥70 with no comorbidities (HR 1.21, 95% CI 0.98-1.49) and significantly inferior for ≥70 with at least one comorbidity (HR 1.51, 95% CI 1.22-1.86). There were no significant associations or interactions between age or comorbidity with PFS. Comorbidities were not associated with treatment-related toxicities. Age ≥ 70 was associated with greater risk of grade ≥ 3 toxicities (OR 2.15, 95% CI 1.50-3.09, p < 0.001)., Conclusions: Among participants in a clinical trial of combination chemotherapy for mCRC, presence of older age with comorbidities was associated with worse OS but not PFS. The association of age with toxicity suggests additional factors of care should be measured in clinical trials., Competing Interests: Declaration of Competing Interest BHO is employed by Eli Lilly and Co. JAM has received institutional research funding from Boston Biomedical, has served as an advisor/consultant to Ignyta and COTA Healthcare and served on a grant review panel for the National Comprehensive Cancer Network funded by Taiho Pharmaceutical., (Copyright © 2022. Published by Elsevier Ltd.)

Purpose: CALGB/SWOG 80405 was a randomized phase III trial in first-line patients with metastatic colorectal cancer treated with bevacizumab, cetuximab, or both, plus chemotherapy. We tested the effect of tumor immune features on overall survival (OS)., Experimental Design: Primary tumors (N = 554) were profiled by RNA sequencing. Immune signatures of macrophages, lymphocytes, TGFβ, IFNγ, wound healing, and cytotoxicity were measured. CIBERSORTx scores of naive and memory B cells, plasma cells, CD8+ T cells, resting and activated memory CD4+ T cells, M0 and M2 macrophages, and activated mast cells were measured., Results: Increased M2 macrophage score [HR, 6.30; 95% confidence interval (CI), 3.0-12.15] and TGFβ signature expression (HR, 1.35; 95% CI, 1.05-1.77) were associated with shorter OS. Increased scores of plasma cells (HR, 0.55; 95% CI, 0.38-0.87) and activated memory CD4+ T cells (HR, 0.34; 95% CI, 0.16-0.65) were associated with longer OS. Using optimal cutoffs from these four features, patients were categorized as having either 4, 3, 2, or 0-1 beneficial features associated with longer OS, and the median (95% CI) OS decreased from 42.5 (35.8-47.8) to 31.0 (28.8-34.4), 25.2 (20.6-27.9), and 17.7 (13.5-20.4) months respectively (P = 3.48e-11)., Conclusions: New immune features can be further evaluated to improve patient response. They provide the rationale for more effective immunotherapy strategies., (©2022 American Association for Cancer Research.)

Background: The incidence of young-onset colorectal cancer (yoCRC) is increasing. It is unknown if there are survival differences between young and older patients with metastatic colorectal cancer (mCRC)., Methods: We studied the association of age with survival in 2326 mCRC patients enrolled in the Cancer and Leukemia Group B and SWOG 80405 trial, a multicenter, randomized trial of first-line chemotherapy plus biologics. The primary and secondary outcomes of this study were overall survival (OS) and progression-free survival (PFS), respectively, which were assessed by Kaplan-Meier method and compared among younger vs older patients with the log-rank test. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated based on Cox proportional hazards modeling, adjusting for known prognostic variables. All statistical tests were 2-sided., Results: Of 2326 eligible subjects, 514 (22.1%) were younger than age 50 years at study entry (yoCRC cohort). The median age of yoCRC patients was 44.3 vs 62.5 years in patients aged 50 years and older. There was no statistically significant difference in OS between yoCRC vs older-onset patients (median = 27.07 vs 26.12 months; adjusted HR = 0.98, 95% CI = 0.88 to 1.10; P = .78). The median PFS was also similar in yoCRC vs older patients (10.87 vs 10.55 months) with an adjusted hazard ratio of 1.02 (95% CI = 0.92 to 1.13; P = .67). Patients younger than age 35 years had the shortest OS with median OS of 21.95 vs 26.12 months in older-onset patients with an adjusted hazard ratio of 1.08 (95% CI = 0.81 to 1.44; Ptrend = .93)., Conclusion: In this large study of mCRC patients, there were no statistically significant differences in survival between patients with yoCRC and CRC patients aged 50 years and older., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Purpose: Colorectal cancer (CRC) affects many older adults. We investigated the efficacy and safety of adding anti-epidermal growth factor receptor (EGFR) agents to doublet chemotherapy (DC) in older patients., Methods: Patients with RAS wild-type (WT) metastatic CRC (mCRC) receiving first-line DC + anti-EGFR (n = 1191) or DC alone (n = 729) from seven trials in the Aide de Recherche en Cancerologie Digestive database were included. The prognostic and predictive effects of age were investigated. Progression-free and overall survival (OS) were evaluated between age groups (≥70 vs <70) for DC + anti-EGFR. In addition, outcomes were compared between DC+/-anti-EGFR within age groups in three trials with a DC alone arm. Subsequently, the same analysis was conducted for left-sided tumours. Adverse events grade ≥3 (G3+) were compared between age groups., Results: Older (vs younger) patients receiving DC + anti-EGFR had similar progression-free survival (PFS) (8.7 vs 10.3 months; hazard ratio (HR) = 1.20 [0.96-1.49];p = 0.107) but inferior OS (21.3 vs 26.3; HR = 1.36 [1.08-1.72];p = 0.011). DC + anti-EGFR (vs DC alone) improved OS (23.9 vs 20.3; HR = 0.82 [0.70-0.95];p = 0.008) and PFS (11.2 vs 8.9; HR = 0.70 [0.60-0.82];p < 0.001) in younger but not older patients: OS (24.7 vs 17.6; HR [95% confidence interval {CI}] = 0.77 [0.58-1.04];p = 0.092) and PFS (9.1 vs 8.7; HR [95% CI] = 0.85[0.63-1.15];p = 0.287). In left-sided 'only' tumours, the following outcomes for older (vs younger) patients were observed. For DC + anti-EGFR, PFS 9 versus 11.2 months; HR1.10 (95% CI 0.83-1.46); p = 0.52, OS 25.6 vs 30.3 HR 1.32 (95% CI 0.97-1.79), p = 0.086. For DC + anti-EGFR (vs DC alone), PFS and OS for younger patients were 11.9 vs 9.2 months HR 0.60 (95% CI 0.47-0.78) p < 0.001 and 24.1 versus 23.3 months HR 0.84 (95% CI 0.67-1.04), respectively. For older patients, PFS and OS were 13.1 versus 8.5 months, HR 0.51 (95% CI, 0.28-0.93), P = 0.027 and 26.3 versus 16.5 months HR 0.49 (95% CI, 0.28-0.85), respectively. There was no significant difference in toxicity among different age groups., Conclusions: Older (vs younger) patients with mCRC RAS WT patients had comparable toxicity and efficacy with the addition of anti-EGFR agents to chemotherapy., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: DP: Merck Serono – AdBoards, invited speaker; Amgen – invited speaker. MSD – research grant. GSL reported no Conflict of interest to disclose. CLO reported no conflict of interest to disclose. JD reported no conflict of interest to disclose. RAA: honoraria – Amgen; Merck Serono; SERVIER. consulting or advisory role – Amgen; Bayer; Merck Serono; SERVIER. Speakers' Bureau – Merck Serono. Research funding – AstraZeneca (Inst); Merck Sharp & Dohme (Inst). Travel, accommodations, expenses – Amgen; AstraZeneca; Merck Serono; SERVIER. TSM: consulting or advisory role – vertex; vertex; vertex; vertex. EVC: consulting or advisory role – Array BioPharma; AstraZeneca; Bayer; Bristol-Myers Squibb; Celgene; Halozyme; Lilly; Merck KGaA; Merck Sharp & Dohme; Novartis; Roche; SERVIER. Research funding – Amgen (Inst); Bayer (Inst); Boehringer Ingelheim (Inst); Bristol-Myers Squibb (Inst); Celgene (Inst); Ipsen (Inst); Lilly (Inst); Merck (Inst); Merck KGaA (Inst); Novartis (Inst); Roche (Inst); SERVIER (Inst). APV: consulting or advisory role – Bayer; Bayer; Bayer; Bayer; Eisai; Eisai; Eisai; Eisai; Halozyme; Halozyme; Halozyme; Halozyme; Taiho Pharmaceutical; Taiho Pharmaceutical; Taiho Pharmaceutical; Taiho Pharmaceutical. Research funding – Bristol-Myers Squibb (Inst); Bristol-Myers Squibb (Inst); Bristol-Myers Squibb (Inst); Bristol-Myers Squibb (Inst); Genentech/Roche (Inst); Genentech/Roche (Inst); Genentech/Roche (Inst); Genentech/Roche (Inst). Patents, royalties, other Intellectual property – Royalties from Now-UptoDate for authoring and maintaining two chapters; royalties from Now-UptoDate for authoring and maintaining two chapters; royalties from Now-UptoDate for authoring and maintaining two chapters; royalties from Now-UptoDate for authoring and maintaining two chapters. Travel, accommodations, expenses - Bayer; 275 Bayer; Bayer; Bayer; Genentech; Genentech; Genentech; Genentech; Halozyme; Halozyme; Halozyme; Halozyme; Roche; Roche; Roche; Roche. HL: Ad board/consulting. BMs Roche Merck kg Bayer oncocyte fulgent Jazz therapeutics G1 therapeutics. Astellas. Clinical trial support. SWOG NCI BMs Boehringer Ingelheim. NGM psioyx Genentech Pfizer Merck Bayer. VH: honoraria – Amgen; Amgen; Amgen; Amgen; Baxalta; Baxalta; Baxalta; Baxalta; Boehringer Ingelheim; Boehringer Ingelheim; Boehringer Ingelheim; Boehringer Ingelheim; Celgene; Celgene; Celgene; Celgene; Lilly; Lilly; Lilly; Lilly; Merck; Merck; Merck; Merck; Roche; Roche; Roche; Roche; Sanofi; Sanofi; Sanofi; Sanofi; SERVIER; SERVIER; SERVIER; SERVIER; Sirtex Medical; Sirtex Medical; Sirtex Medical; Sirtex Medical; Taiho Pharmaceutical; Taiho Pharmaceutical; Taiho Pharmaceutical; Taiho Pharmaceutical Consulting or advisory role - Amgen; Amgen; Amgen; Amgen; Baxalta; Baxalta; Baxalta; Baxalta; Boehringer Ingelheim; Boehringer Ingelheim; Boehringer Ingelheim; Boehringer Ingelheim; Bristol-Myers Squibb; Bristol-Myers Squibb; Bristol-Myers Squibb; Bristol-Myers Squibb; Celgene; Celgene; Celgene; Celgene; Halozyme; Halozyme; Halozyme; Halozyme; Merck; Merck; Merck; Merck; MSD; MSD; MSD; MSD; MSD Oncology; MSD Oncology; MSD Oncology; MSD Oncology; Roche; Roche; Roche; Roche; Sanofi; Sanofi; Sanofi; Sanofi; SERVIER; SERVIER; SERVIER; SERVIER; Sirtex Medical; Sirtex Medical; Sirtex Medical; Sirtex Medical. Research funding - Amgen (Inst); Amgen (Inst); Amgen (Inst); Amgen (Inst); Boehringer Ingelheim (Inst); Boehringer Ingelheim (Inst); Boehringer Ingelheim (Inst); Boehringer Ingelheim (Inst); Celgene (Inst); Celgene (Inst); Celgene (Inst); Celgene (Inst); Merck (Inst); Merck (Inst); Merck (Inst); Merck (Inst); Roche (Inst); Roche (Inst); Roche (Inst); Roche (Inst); Servier (Inst); Servier (Inst); Servier 298 (Inst); Servier (Inst); Shire (Inst); Shire (Inst); Shire (Inst); Shire (Inst); Sirtex Medical (Inst); Sirtex Medical (Inst); Sirtex Medical (Inst); Sirtex Medical (Inst). Travel, accommodations, expenses – Amgen; Amgen; Amgen; Amgen; Bristol-Myers Squibb; Bristol-Myers Squibb; Bristol-Myers Squibb; Bristol-Myers Squibb; Merck; Merck; Merck; Merck; MSD; MSD; MSD; MSD; Roche; Roche; Roche; Roche; SERVIER; SERVIER; SERVIER; SERVIER; Shire; Shire; Shire; Shire; Sirtex Medical; Sirtex Medical; Sirtex Medical; Sirtex Medical. RK reported no conflict of interest to disclose. CB: honoraria – AstraZeneca; Bayer; Berlin Chemie; Berlin Chemie; Bristol-Myers Squibb; Merck KGaA; Merck Sharp Dohme; Roche; Sanofi. Consulting or advisory role – AOK Health Insurance; Bayer Schering Pharma; GSO; Lilly/ImClone; Merck Serono; Merck Sharp & Dohme; Novartis; Sanofi. Research funding – AbbVie (Inst); ADC Therapeutics (Inst); Agile Therapeutics (Inst); Alexion Pharmaceuticals (Inst); Amgen (Inst); Apellis Pharmaceuticals (Inst); Astellas Pharma (Inst); AstraZeneca (Inst); Bayer (Inst); BerGenBio (Inst); Blueprint Medicines (Inst); Boehringer Ingelheim (Inst); Bristol-Myers Squibb (Inst); Celgene (Inst); Daiichi Sankyo (Inst); Eisai (Inst); Gilead Sciences (Inst); GlaxoSmithKline (Inst); Glycotope GmbH (Inst); Incyte (Inst); IO Biotech (Inst); Isofol Medical (Inst); Janssen- Cilag (Inst); Karyopharm Therapeutics (Inst); Lilly (Inst); Millennium (Inst); MSD (Inst); Nektar (Inst); Novartis (Inst); Rafael Pharmaceuticals (Inst); Roche (Inst); Springworks Therapeutics (Inst); Taiho Pharmaceutical (Inst). Travel, accommodations, expenses – Bristol-Myers Squibb; Merck Serono; Pfizer; Sanofi. BC: honoraria - Bayer; Pfizer; Roche; Sanofi; SERVIER. Consulting or advisory role – BeiGene; Roche; Sanofi; SERVIER. Travel, accommodations, expenses – Merck; MSD; Roche; Sanofi. AG: honoraria – Aptitude Health; Elsevier; IMEDEX. Consulting or advisory role – Amgen (Inst); Array BioPharma (Inst); Bayer (Inst); Boston Biomedical (Inst); Bristol-Myers Squibb (Inst); Daiichi Sankyo (Inst); Genentech/Roche; Lilly (Inst); OBI Pharma. Research Funding - Array BioPharma (Inst); Bayer (Inst); Boston Biomedical (Inst); Daiichi Sankyo (Inst); Eisai (Inst); Genentech/Roche (Inst); Lilly (Inst); Pfizer (Inst). Travel, accommodations, expenses – Amgen; Array BioPharma; Bayer; Boston Biomedical; Bristol-Myers Squibb; Genentech/Roche. TY: Research funding from Taiho Pharmaceuticals, Sumitomo Dainippon Pharma Co., Ltd, Chugai Pharmaceutical Co., Ltd, Amgen KK, Sanofi KK, Daiichi Sankyo Co., Ltd, Meck Sharp and Dohme KK, Parexel International Inc., and ONO Pharmaceutical Co., Ltd. Honoraria - Bayer Yakuhin; Chugai Pharma; Lilly Japan; Merck; Takeda. Research Funding - Amgen (Inst); Chugai Pharma (Inst); DAIICHI SANKYO COMPANY, LIMITED (Inst); MSD (Inst); Ono Pharmaceutical (Inst); PAREXEL International Inc. (Inst); Sanofi (Inst); Sumitomo Dainippon (Inst); Taiho Pharmaceutical (Inst). JZ: stock and other ownership interests – Acceleron Pharma; Aimmune; Alnylam; Amarin Corporation; BioMarin; Concert Pharmaceuticals; Frequency Therapeutics; Gilead Sciences; Global Blood Therapeutics; GW Pharmaceuticals; Madrigal Pharmaceuticals; Moderna. Therapeutics; Myovant Sciences; Opthea; Orphazyme; Sangamo Bioscience; Twist Bioscience; UniQure; Vertex; Zogenix. Honoraria - Deciphera; Gilead Sciences; Halozyme; Merck Serono; Specialised Therapeutics; Targovax. Consulting or advisory role – Centre for Emerging and Neglected Diseases (CEND); Deciphera; H 342 Halozyme; Lipotec; Merck Serono; Merck Sharp & Dohme; Specialised Therapeutics; Targovax. Research funding - AstraZeneca (Inst); Bristol-Myers Squibb (Inst); Eisai (Inst); Ipsen (Inst); IQvia (Inst); Medtronic (Inst); Merck Serono (Inst); MSD Oncology (Inst); Mylan (Inst); Pfizer (Inst). Travel, accommodations, expenses – AstraZeneca; Deciphera; Merck Serono; Merck Sharp & Dohme; Sanofi. AdG: honoraria – Chugai Pharma; Chugai Pharma; Chugai Pharma; Chugai Pharma; Yakult Pharmaceutical; Yakult Pharmaceutical; Yakult Pharmaceutical; Yakult Pharmaceutical. QS: Dr. Shi reports consulting/advisory role from Yiviva Inc, Boehringer Ingelheim Pharmaceuticals, Inc, Regeneron Pharmaceuticals, Inc., Hoosier Cancer Research Network (to myself), honorarium/speaker role from Chugai Pharmaceutical Co., Ltd, stock from Johnson & Johnson, Amgen, and Merck & CO. (to myself), research funds from Celgene/BMS, Roche/Genentech, Janssen, Novartis (to institution)., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Importance: The American Cancer Society and American Institute for Cancer Research recommend that cancer survivors limit intake of red and processed meats. This recommendation is based on consistent associations between red and processed meat intake and cancer risk, particularly risk of colorectal cancer, but fewer data are available on red and processed meat intake after cancer diagnosis., Objectives: To examine whether intake of unprocessed red meat or processed meat is associated with risk of cancer recurrence or mortality in patients with colon cancer., Design, Setting, and Participants: This prospective cohort study used data from participants with stage III colon cancer enrolled in the Cancer and Leukemia Group B (CALGB 89803/Alliance) trial between 1999 and 2001. The clinical database for this analysis was frozen on November 9, 2009; the current data analyses were finalized in December 2021., Exposures: Quartiles of unprocessed red meat and processed meat intake assessed using a validated food frequency questionnaire during and 6 months after chemotherapy., Main Outcomes and Measures: Hazard ratios (HRs) and 95% CIs for risk of cancer recurrence or death and all-cause mortality., Results: This study was conducted among 1011 patients with stage III colon cancer. The median (IQR) age at enrollment was 60 (51-69) years, 442 patients (44%) were women, and 899 patients (89%) were White. Over a median (IQR) follow-up period of 6.6 (1.9-7.5) years, we observed 305 deaths and 81 recurrences without death during follow-up (386 events combined). Intake of unprocessed red meat or processed meat after colon cancer diagnosis was not associated with risk of recurrence or mortality. The multivariable HRs comparing the highest vs lowest quartiles for cancer recurrence or death were 0.84 (95% CI, 0.58-1.23) for unprocessed red meat and 1.05 (95% CI, 0.75-1.47) for processed meat. For all-cause mortality, the corresponding HRs were 0.71 (95% CI, 0.47-1.07) for unprocessed red meat and 1.04 (95% CI, 0.72-1.51) for processed meat., Conclusions and Relevance: In this cohort study, postdiagnosis intake of unprocessed red meat or processed meat was not associated with risk of recurrence or death among patients with stage III colon cancer.

Background: Individualized estimates of the risk of recurrence in colon cancer patients are needed that reflect current medical practice and available treatment options., Methods: Three validation studies of the 12-gene colon recurrence score assay were used with pre-specified patient-specific meta-analysis (PSMA) methods to integrate the 12-gene Oncotype DX Colon Recurrence Score result (RS) with the clinical and pathology risk factors stage, T-stage, mis-match repair (MMR) status, and number of nodes examined to calculate individualized recurrence risk estimates. Baseline risk estimation used the most recent studies, so the risk estimates reflect current medical practice. The effect of fluorouracil (5FU) was estimated with a meta-analysis of two studies. The effect of oxaliplatin was estimated using one of the RS assay validation studies, in which patients were randomized to 5FU with or without oxaliplatin., Results: The RS result and each of the clinical-pathologic factors provided independent prognostic information for recurrence. Among stage II, T3, MMR-proficient patients with ≥12 nodes examined (the most common scenario), patients with RS ≤30 (approximately 48%) have estimated 5-year recurrence risk ≤10% with surgery alone. Among stage IIIA/B, T3, MMR-deficient patients with ≥12 nodes examined, patients with RS ≤19 (approximately 14%) have an estimated 5-year recurrence risk ≤10% with surgery alone. Among stage IIIA/B, T3, MMR-proficient patients with ≥12 nodes examined, those with RS ≤14 (approximately 6%) have estimated 5-year recurrence risk ≤10% with 5FU alone., Discussion: The PSMA integrates the 12-gene colon RS result with clinical and pathology factors to provide individualized recurrence risk estimates that reflect current medical practice. The risk estimates are in a range that may help inform treatment decisions for a substantial number of stage II and stage III patients., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-21-620/coif). MRC, FLB and CC are or were employees of and received remuneration and stock from Genomic Health, Inc., a wholly owned subsidiary of Exact Sciences Corporation, which provides test results based on the 12-gene assay. EO received lecture fees from Bayer Japan, Chugai Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., Eli Lilly, Ono Pharmaceutical Co., Ltd., and Takeda Pharmaceutical Co., Ltd. NW reports support for the present manuscript via NCI grant #U10CA180868, directly to his institution only. TY reports grants from Taiho Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Ono Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., Amgen K.K., Parexel International Inc., MSD K.K., Daiichi Sankyo Co., Ltd., and Sanofi K.K., outside the submitted work. The other authors have no conflicts of interest to declare., (2022 Journal of Gastrointestinal Oncology. All rights reserved.)