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PURPOSE Pembrolizumab significantly improves clinical outcomes in advanced/metastatic microsatellite instability high (MSI-H)/deficient mismatch repair (dMMR) solid tumors but is not well studied in the neoadjuvant space. METHODS This is a phase II open-label, single-center trial of localized unresectable or high-risk resectable MSI-H/dMMR tumors. Treatment is pembrolizumab 200 mg once every 3 weeks for 6 months followed by surgical resection with an option to continue therapy for 1 year followed by observation. To continue on study, patients are required to have radiographic or clinical benefit. The coprimary end points are safety and pathologic complete response. Key secondary end points are response rate and organ-sparing at one year for patients who declined surgery. Exploratory analyses include interrogation of the tumor immune microenvironment using imaging mass cytometry. RESULTS A total of 35 patients were enrolled, including 27 patients with colorectal cancer and eight patients with noncolorectal cancer. Among 33 evaluable patients, best overall response rate was 82%. Among 17 (49%) patients who underwent surgery, the pathologic complete response rate was 65%. Ten patients elected to receive one year of pembrolizumab followed by surveillance without surgical resection (median follow-up of 23 weeks [range, 0-54 weeks]). An additional eight did not undergo surgical resection and received less than 1 year of pembrolizumab. During the study course of the trial and subsequent follow-up, progression events were seen in six patients (four of whom underwent salvage surgery). There were no new safety signals. Spatial immune profiling with imaging mass cytometry noted a significantly closer proximity between granulocytic cells and cytotoxic T cells in patients with progressive events compared with those without progression. CONCLUSION Neoadjuvant pembrolizumab in dMMR/MSI-H cancers is safe and resulted in high rates of pathologic, radiographic, and endoscopic response, which has implications for organ-sparing strategies.

Definitive radiation therapy with concurrent chemotherapy is curative for nonmetastatic squamous cell carcinoma of the anus (SCCA). However, the true effect of chemoradiation on long-term functional outcomes is poorly understood owing to limited follow-up and patient-reported outcomes (PROs).We conducted a cross-sectional survey of 248 patients with SCCA treated with definitive intensity modulated radiation and concurrent chemotherapy from 2010 to 2018 who were alive and without recurrence. PRO measures were collected, including Functional Assessment of Cancer Therapy-General (FACT-G7), Fecal Incontinence Quality of Life (FIQoL), Low Anterior Resection Syndrome (LARS), and International Consultation on Incontinence Questionnaires (ICIQ). Models were used to determine the association between demographic, tumor, treatment, and dosimetric data with PROs.One hundred twelve (45%) patients completed PROs. Median [interquartile range (IQR)] time from radiation completion to survey was 51 [37-85] months. The median scores [IQR] for FACT-G7, FIQoL, and LARS were 21 [15-24], 14 [11-16], and 32 [25-37], respectively. For men, median subscores [IQR] for ICIQ voiding and incontinence subscores were 5 [2-6] and 1 [1-3], respectively. For women, median subscores [IQR] for ICIQ voiding, incontinence, and filling were 1 [1-3], 5 [3-8], and 4 [2-5], respectively. Higher (better) FIQoL scores were associated with higher (better) FACT-G7 scores (β = 0.83; 95% confidence interval, 0.58-1.09; P.001), and higher (worse) LARS scores were associated with lower (worse) FACT-G7 scores (β = -0.22; 95% confidence interval, -0.31 to -0.13; P.001). A separate multivariable analysis revealed higher bowel bag D1% was associated with lower (worse) FIQoL (P = .001) and higher (worse) LARS (P = .003) scores. Higher bladder V40 Gy was associated with increased (worse) ICIQ voiding subscore (P = .001).Patients treated with modern chemoradiation for SCCA experience significant long-term bowel toxic effects with considerable effect on quality of life. Minimizing bowel hotspots and bladder V40 Gy may improve bowel and urinary function. Other interventions to reduce long-term toxic effects and improve quality of life are needed.

Lateral pelvic lymph node (LPLN) metastases are an important cause of preventable local failure in rectal cancer. The aim of this study was to evaluate clinical and oncological outcomes following magnetic resonance imaging (MRI)-directed surgical selection for lateral pelvic lymph node dissection (LPLND) after total neoadjuvant therapy (TNT).A retrospective consecutive cohort analysis was performed of rectal cancer patients with enlarged LPLN on pretreatment MRI. Patients were categorized as LPLND or non-LPLND. The main outcomes were lateral local recurrence rate, perioperative and oncological outcomes and factors associated with decision making for LPLND.A total of 158 patients with enlarged pretreatment LPLN and treated with TNT were identified. Median follow-up was 20 months (interquartile range 10-32). After multidisciplinary review, 88 patients (56.0%) underwent LPLND. Mean age was 53 (SD±12) years, and 54 (34.2%) were female. Total operative time (509 vs 429 minutes; P =0.003) was greater in the LPLND group, but median blood loss ( P =0.70) or rates of major morbidity (19.3% vs 17.0%) did not differ. LPLNs were pathologically positive in 34.1%. The 3-year lateral local recurrence rates (3.4% vs 4.6%; P =0.85) did not differ between groups. Patients with LPLNs demonstrating pretreatment heterogeneity and irregular margin (odds ratio, 3.82; 95% confidence interval: 1.65-8.82) or with short-axis ≥5 mm post-TNT (odds ratio 2.69; 95% confidence interval: 1.19-6.08) were more likely to undergo LPLND.For rectal cancer patients with evidence of LPLN metastasis, the appropriate selection of patients for LPLND can be facilitated by a multidisciplinary MRI-directed approach with no significant difference in perioperative or oncologic outcomes.

In the past decades the incidence of colorectal cancer (CRC) in people under the age of 50 years has increased, which is referred to as early-onset CRC or young-onset CRC (YO-CRC). YO-CRC is expected to account for 11% of colon cancers and 23% of rectal cancers by 2030. This trend is observed in different parts of the world and in both men and women. In 20% of patients with YO-CRC, a hereditary cancer syndrome is found as the underlying cause; however, in the majority of patients no genetic predisposition is present. Beginning in the 1950s, major changes in lifestyle such as antibiotic use, low physical activity and obesity have affected the gut microbiome and may be an important factor in YO-CRC development. Owing to a lack of screening, patients with YO-CRC are often diagnosed with advanced-stage disease. Long-term treatment-related complications should be taken into account in these younger patients, making the more traditional sequential approaches of drug therapy not always the most appropriate option. To better understand the underlying mechanism and define relationships between environmental factors and YO-CRC development, long-term prospective studies are needed with lifestyle data collected from childhood.

Supplementary Figure S2. A. Proportion of VUS with different pathogenic probabilities estimated from a calibrated algorithm based on customized MAPP and Polyphen2 scores; B. Proportion of VUS per gene with different pathogenic probabilities; C. Distribution of probabilities of pathogenicity for all four MMR genes; D. MLH1; E. MSH2; F. MSH6; G. PMS2 genes.

S1. Variants of unknown significance detected in the MD Anderson cohort. S2. Clinical characteristics of the VUS carriers reported in Supplementary Table 1. Pathogenic mutations detected in the same patient carrying a VUS are presented in bold. S3. Clinical characteristics of carriers of variants reclassified as InSIGHT Class 1 and 5. These variants have been used for validation purposes. S4. Validation set of splicing variants obtained from the InSiGHT database that have been already reclassified as Class 1 and 5. S5. Classification at the RNA level using three bioinformatic in silico programs of all reported VUS. Results in gray indicate major alterations which are those that are predicted to destroy or create splicing sites or produce a SS score modification {greater than or equal to}20%; Predictions are interpreted as inconclusive when the same results are not obtained by all the programs used. S6. Detailed results of in silico RNA bioinformatic prediction tools for those variants classified as affecting Splicing Sites or Inconclusive by In silico prediction tools. Results in gray indicate major alterations. For splice site predictions, major alterations are those that are predicted to destroy or create splicing sites or produce a SS score modification {greater than or equal to}20%; Predictions are interpreted as inconclusive when the same results are not obtained by all the programs used. S7. Splicing validation set using three bioinformatic in silico programs of a set of splicing variants obtained from the InSIGHT database and that have been already re-classified as Class 1 and 5. Results in gray indicate major alterations, which are destroyed or created SS or score modifications {greater than or equal to}20%; Predictions are interpreted as inconclusive when only one program predict pathogenicity. S8. Detailed in silico RNA bioinformatic prediction results for splicing variants already reclassified as class 5 used for validation of in silico tools. Variants presented here were predicted to be Aberrant or Inconclusive based on our RNA in silico approach. Results in gray indicate major alterations. For splice site prediction, major alternations are destroyed or created SS or score modifications {greater than or equal to}20%; Predictions are interpreted as inconclusive when the same results are not obtained by all the programs used. S9. Classification at protein level of reported VUS using five bioinformatic in silico programs. Results in gray indicate major alterations. Predictions are interpreted as inconclusive when the same results are not obtained by all the programs used. S10. Detailed results of in silico analysis at protein level. S11. Summary of the clinical characteristics and mRNA and protein in silico predictions of the identified MMR VUS. Raw data concerning these analyses is detailed in Supplementary Tables 1-6. S12. Classification at the RNA level using three bioinformatic in silico programs of Identified Variants reclasified as InSIGHT Class 1 and 5 from the MD Anderson database. These variants have been used for validation purposes. Results in gray indicate major alterations, which are destroyed or created SS or score modifications {greater than or equal to}20%; Predictions are interpreted as inconclusive when only one program predict pathogenicity. S13. Detailed in silico RNA bioinformatic prediction results for variants reclassified as InSIGHT class 1 and 5 that obtained results of affecting splicing sites or Inconclusive. Results in gray indicate major alterations. For splice site prediction, major alternations are destroyed or created SS or score modifications {greater than or equal to}20%; Predictions are interpreted as inconclusive when the same results are not obtained by all the programs used. S14. Classification at protein level using five bioinformatic in silico programs of variants reclassified as InSIGHT Class 1 and 5. These variants were used for validation purposes. Results in gray indicate major alterations. Predictions are interpreted as inconclusive when the same results are not obtained by all the programs used. S15. Summary of the clinical characteristics and mRNA and protein in silico analyses of variants reclassified as InSIGHT Class 1 and 5. These variants were used for valiadation purposes. Information concerning these variants is detailed in supplementary Tables 8-11.

BackgroundYoung adults and other working-age adults with cancer are at risk for cancer-related financial toxicity (FT), including material hardships, depletion of coping resources, and psychological burden. This study compares FT domains in young adults (18-39years old) (YAs), other working-age adults (40-64years old), and older adults (≥65years old) receiving cancer care.MethodsA total of 311 adults were surveyed using the multi-domain Economic Strain and Resilience in Cancer instrument measuring FT (0-10 score indicating least to greatest FT; score ≥5 severe FT). Participants were receiving ambulatory care from March-September 2019. Associations of age with overall FT and material hardship, coping resource depletion, and psychological burden FT domains were tested using Kruskal-Wallis and χ2 tests and multivariable generalized linear models with gamma distribution.ResultsYAs (median age, 31.5years) comprised 9.6% of the sample; other working-age adults comprised 56.9%. Overall, material, coping, and psychological FT scores were worse in younger age adults versus older adults (P&nbsp

PURPOSE To develop recommendations for adjuvant therapy for patients with resected stage II colon cancer. METHODS ASCO convened an Expert Panel to conduct a systematic review of relevant studies and develop recommendations for clinical practice. RESULTS Twenty-one observational studies and six randomized controlled trials met the systematic review inclusion criteria. RECOMMENDATIONS Adjuvant chemotherapy (ACT) is not routinely recommended for patients with stage II colon cancer who are not in a high-risk subgroup. Patients with T4 tumors are at higher risk of recurrence and should be offered ACT, whereas patients with other high-risk factors, including sampling of fewer than 12 lymph nodes in the surgical specimen, perineural or lymphovascular invasion, poorly or undifferentiated tumor grade, intestinal obstruction, tumor perforation, or grade BD3 tumor budding, may be offered ACT. The addition of oxaliplatin to fluoropyrimidine-based ACT is not routinely recommended, but may be offered as a result of shared decision making. Patients with mismatch repair deficiency/microsatellite instability tumors should not be routinely offered ACT; if the combination of mismatch repair deficiency/microsatellite instability and high-risk factors results in a decision to offer ACT, oxaliplatin-containing chemotherapy is recommended. Duration of oxaliplatin-containing chemotherapy is also addressed, with recommendations for 3 or 6 months of treatment with capecitabine and oxaliplatin or fluorouracil, leucovorin, and oxaliplatin, with decision making informed by key evidence of 5-year disease-free survival in each treatment subgroup and the rate of adverse events, including peripheral neuropathy. Additional information is available at www.asco.org/gastrointestinal-cancer-guidelines .

Background Although intensity-modulated radiation therapy (IMRT) is considered the standard of care for the treatment of squamous cell carcinoma of the anus (SCCA), few large series have reported oncologic outcomes and toxicities. In this retrospective report, we aim to describe outcomes and toxicities after IMRT-based chemoradiation (CRT) for the treatment of SCCA, evaluate the impact of dose escalation (>54 Gy), and compare concurrent fluoropyrimidine in combination with either mitomycin or with cisplatin as chemosensitizers. Methods Patients treated at The University of Texas MD Anderson Cancer Center between January 1, 2003 and December 31, 2018 with IMRT-based CRT were included. Median time to locoregional recurrence, time to colostomy, and overall survival were estimated using the Kaplan–Meier method. Results A total of 428 patients were included; median follow-up was 4.4 years. Three hundred and thirty-four patients (78.0%) were treated with concurrent cisplatin and fluoropyrimidine, and 160 (37.4%) with >54 Gy. Two- and 5-year freedom from locoregional failure, freedom from colostomy failure, and overall survival were 86.5% and 81.2%, respectively, 90.0% and 88.3%, respectively, and 93.6% and 85.8%, respectively. Neither dose escalation nor mitomycin-based concurrent chemotherapy resulted in improved outcomes. Mitomycin-based concurrent chemotherapy was associated with in approximately 2.5 times increased grade 3 or greater acute toxicity. Radiation dose >54 Gy was associated with approximately 2.6 times increased Grade 3 or greater chronic toxicity. Conclusions Our results suggest IMRT-based CRT with concurrent fluoropyrimidine and cisplatin is a safe and feasible option for patient with SCCA and may cause less acute toxicity. The role for radiation dose escalation is unclear and requires further study.

Figures S1, S2, S3 and S4. APC and KRAS genotyping of crypts and bulk biopsies in adenomas from MAP, UPF, LS and cMMRD cases. Figures S5, S6 and S7. APC and KRAS genotyping of crypts and bulk biopsies in adenomas from SPO cases. Figure S8, S9 and S10. Hyerarchical clustering analysis of crypts based on KRAS genotyping results. Figure S11. Comparative analysis of mutant allele discrimination by (A) Light Cycler 480 (Roche) and (B) nanofluidic PCR using Dynamic array (Fluidigm). Figure S12. A. Comparative analysis of KRAS genotyping using whole genome amplified (WGA) DNA or pre-amplified DNA using 15 cycles of a nested PCR. Figure S13. Genotyping results including water controls of random KRAS hotspot mutation analysis after performing a pre-amplification step using a nested PCR apporach. Figure S14. Independent validation of KRAS hotspot mutation that have been detected by Nanofluidic Dynamic array using the Nanofluidic Digital PCR genotyping as an alternative approach. Figure S15. Independent validation of KRAS hotspot mutation that have been detected by Nanofluidic Dynamic array using the Nanofluidic Digital PCR genotyping as an alternative approach.

Purpose: Determination of microsatellite instability (MSI) by PCR is the gold standard; however, IHC of mismatch repair (MMR) proteins is frequently performed instead. The reliability of these methods on postneoadjuvant therapy specimens is unknown. We examined the effect of neoadjuvant therapy on MSI results by PCR and IHC.Experimental design: A total of 239 colorectal cancers resected after neoadjuvant therapy were assessed for MSI with PCR and IHC. PCR and IHC results for matched paired pre- and posttreatment specimens were compared. In parallel, 2 isogenic cell lines conditioned for MMR functioning and 2 different patient-derived xenografts (PDXs) were exposed to chemotherapy, radiation, or both. We also examined whether establishment of PDXs induced MSI changes in 5 tumors. IHC and MSI were tested after treatment to assess for changes.Results: We identified paired pre- and posttreatment specimens for 37 patients: 2 with PCR only, 34 with IHC only, and 1 with both. All 3 patients with PCR had microsatellite stable pre- and posttreatment specimens. Of the 35 patients with IHC, 30 had intact MMR proteins in pre- and posttreatment specimens, 1 had equivocal MLH1 staining in the pretreatment and loss in the posttreatment specimen, and 4 had intact pretreatment MSH6 but variable posttreatment staining. In the experimental setting, no changes in MSI status were detected after treatment or tumor implantation in animals.Conclusions: Our findings show that the expression of MMR proteins, commonly MSH6, can change after neoadjuvant therapy and confirm PCR as the gold-standard test for MSI after neoadjuvant therapy. Clin Cancer Res; 23(17); 5246–54. ©2017 AACR.

Supplementary Figure Legend

Purpose: The majority of genomic alterations causing intratumoral heterogeneity (ITH) in colorectal cancer are thought to arise during early stages of carcinogenesis as a burst but only after truncal mutations in APC have expanded a single founder clone. We have investigated if the initial source of ITH is consequent to multiple independent lineages derived from different crypts harboring distinct truncal APC and driver KRAS mutations, thus challenging the prevailing monoclonal monocryptal model.Experimental Design: High-depth next-generation sequencing and SNP arrays were performed in whole-lesion extracts of 37 familial adenomatous polyposis colorectal adenomas. Also, ultrasensitive genotyping of hotspot mutations of APC and KRAS was performed using nanofluidic PCRs in matched bulk biopsies (n = 59) and crypts (n = 591) from 18 adenomas and seven carcinomas and adjacent normal tissues.Results: Multiple co-occurring truncal APC and driver KRAS alterations were uncovered in whole-lesion extracts from adenomas and subsequently confirmed to belong to multiple clones. Ultrasensitive genotyping of bulk biopsies and crypts revealed novel undetected APC mutations that were prominent among carcinomas, whereas abundant wild-type APC crypts were detected in adenomas. KRAS mutational heterogeneity within crypts was evident in both adenomas and carcinomas with a higher degree of concordance between biopsy and crypt genotyping in carcinomas. Nonrandom heterogeneity among crypts was also observed.Conclusions: The striking degree of nonrandom intercrypt heterogeneity in truncal and driver gene mutations observed in adenomas and carcinomas is consistent with a polycryptal model derived from multiple independent initiation linages as the source of early ITH in colorectal carcinogenesis. Clin Cancer Res; 23(19); 5936–47. ©2017 AACR.

Table S1. Summary of adenomas with multiple APC and KRAS somatic hits identified by next-generation sequencing. Table S2. Clinical and pathologic characteristics of patients analyzed in this manuscript. Table S3. Analysis of APC, KRAS and 5q loss using AmpliSeq and SNP array TableS4. Number of normal mucosa, adenomas, tumors and crypts analyzed per case. NM; normal mucosa. Table S5. Analytical sensibility of Light Cycler® 480 (Roche) and dynamic array (Fluidigm) to detect KRAS mutations. Table S6. In silico of the APC somatic hits observed by next-generaiton sequencing that were labelled as VUS. B, benign; N, neutral; D, damaging; P, Probably damaging. Table S7. APC analysis of adenomas and carcinomas in bulk biopsies and isolated crypts. The analysis of adjancent normal mucosa was not performed. Table S8. KRAS genotyping results of adenomas and carcinomas by digital and dynamic array (Fluidigm) in bulk biopsies and isolated crypts Table S9. Primers and probes used in this manuscript.

Supplementary Materials and Methods (Includes reference to Table S9 and Figures S11-15)

Supplementary Table 1. Patient Demographic Characteristics. *2 patients with metachronous tumors, 1 poor and 1 moderate; **One patient with both pre- and posttreatment IHC and MSI testing. Supplementary Table 2. Tumor characteristics and results of the IHC and MSI analysis of those cases exhibiting loss of MSH6 after neoadjuvant treatment. Abbreviations: yp, pathologic stage after neoadjuvant treatment; NT, not tested; pre-tx, pre-treatment; post-tx, post-treatment; MSS, microsatellite stable; MSI-L, microsatellite low. Supplementary Table 3. MSI and IHC Analysis of in vivo pre- and post-treatment data. Abbreviations: yp, pathologic stage after neoadjuvant treatment; pre-tx, pre-treatment; post-tx, post-treatment; MSS, microsatellite stable; MSI-L, microsatellite low. Supplementary Table 4. PDX Patient Demographic Characteristics (n = 5) Supplementary Figure 1. Confirmation of MLH1 loss in the cell line HCT116 was performed via Sanger sequencing (A) and Western Blot (B) Supplementary Figure 2. In vitro treatment method. MMR deficient (HCT116) and proficient (HCT116+Ch3) isogenic cell lines were exposed to treatment every 48 hours for 3 cycles. On Day 1, 500,000 cells/10 mm plate were seeded and allowed to grow exponentially for 24-48 hours. Cells were then treated with radiation or drug. After 48hrs, the cells were allowed to grow in drug-free medium until confluency. Cells were split and allowed to grow again in drug-free medium for 48 hours before being treated with the next round of treatment. This process was repeated for 3 cycles. After 48 hours of the 3rd treatment, the slides were fixed with 4% paraformaldehyde.

Lower socioeconomic status (SES) is associated with shorter overall survival (OS) in patients with locoregional colon cancer. We aimed to estimate: (1) the proportion of SES-based OS disparities mediated by disparities in the quality and location of surgical treatment in patients with resected stage I–III colon cancer and (2) the relative importance of components of surgical quality. We examined patients ages 18–80 years with resected stage I–III colon adenocarcinoma using the 2010–2016 National Cancer Database. SES was defined at the zip code level. Inverse odds weighting mediation analysis was used to estimate the proportion mediated (PM) for nine treatment quality-related and facility-related factors and composite PMs in models including all nine mediators. Models compared high SES patients with each lower SES stratum. Among 171,009 patients, 5-year OS increased from 70.4% in low SES patients to 78.1% in high SES. When high SES patients were compared with low, lower-middle, and upper-middle SES patients, PM ranges among lower SES strata were: minimally invasive surgery 16.0–16.6%, lymph nodes examined 7.7–9.6%, positive margins 3.8–6.5%, length of stay 16.7–28.1%, readmissions insignificant to 3.7%, treatment at > 1 CoC facility 2.7–3.1%, facility type insignificant to 7.3%, facility volume 2.9–8.2%, and adjusted facility 90-day mortality rates 33.2–42.8%. Composite PMs were 76.9% (95% CI 61.3%, 92.4%) for low SES, 68.7% (95% CI 56.4%, 81.1%) for lower-middle SES, and 60.9% (95% CI 43.1%, 78.6%) for upper-middle SES. These data suggest that improving the quality of the surgical episode for disadvantaged patients undergoing resection for locoregional colon cancer could decrease SES-based survival disparities by over half.

Background The impact of molecular aberrations on survival after resection of colorectal liver metastases (CLM) in patients with early-age-onset (EOCRC) versus late-age-onset colorectal cancer (LOCRC) is unknown. Methods Patients who underwent liver resection for CLM with known RAS, BRAF and MSI status were retrospectively studied. The prognostic impact of RAS mutations by age was analysed with age as a categorical variable and a continuous variable. Results The study included 573 patients, 192 with EOCRC and 381 with LOCRC. The younger the age of onset of CRC, the greater the negative impact on overall survival of RAS mutations in the LOCRC, EOCRC, and ≤40 years (hazard ratio (HR), 1.64 (95% confidence interval (CI), 1.23–2.20), 2.03 (95% CI, 1.30–3.17), and 2.97 (95% CI, 1.44–6.14), respectively. Age-specific mortality risk and linear regression analysis also demonstrated that RAS mutations had a greater impact on survival in EOCRC than in LOCRC (slope: −4.07, 95% CI −8.10 to 0.04, P = 0.047, R2 = 0.08). Conclusion Among patients undergoing CLM resection, RAS mutations have a greater negative influence on survival in patients with EOCRC, more so in patients ≤40 years, than in patients with LOCRC and should be considered as a prognostic factor in multidisciplinary treatment planning.

The objectives of this expert review are: (1) to prepare clinicians to recognize the presentation and evidence-based risk factors for young adult-onset colorectal cancer (CRC), defined as CRC diagnosed in individuals 18 -50 years of age; (2) to improve management for patients with young onset CRC. This review will focus on the following topics relevant to young adult-onset CRC: epidemiology and risk factors; clinical presentation; diagnostic and therapeutic management including options for colorectal and extra-colonic surgical intervention, chemotherapy and immune-oncology therapies; genetic testing and its potential impact on preimplantation genetics; fertility preservation; and cancer surveillance recommendations for these individuals and their family members.The evidence reviewed in this manuscript is a summation of relevant scientific publications, expert opinion statements, and current practice guidelines. BEST PRACTICE ADVICE 1: With the rising incidence of people developing CRC before 50 years of age, diagnostic evaluation of the colon and rectum is encouraged for all patients, irrespective of age, who present with symptoms that may be consistent with CRC, including but not limited to: rectal bleeding, weight loss, change in bowel habit, abdominal pain, iron deficiency anemia. BEST PRACTICE ADVICE 2: Clinicians should obtain family history of colorectal and other cancers in first and second degree relatives of patients with young adult-onset CRC and discuss genetic evaluation with germline genetic testing either in targeted genes based on phenotypic presentation or in multiplex gene panels regardless of family history. BEST PRACTICE ADVICE 3: Clinicians should present the role of fertility preservation prior to cancer-directed therapy including surgery, pelvic radiation, or chemotherapy BEST PRACTICE ADVICE 4: Clinicians should counsel patients on the benefit of germline genetic testing and familial cancer panel testing in the pre-surgical period to inform which surgical options may be available to the patient with young adult-onset CRC BEST PRACTICE ADVICE 5: Clinicians should consider utilizing germline and somatic genetic testing results to inform chemotherapeutic strategies BEST PRACTICE ADVICE 6: Clinicians should offer hereditary CRC syndrome specific screening for CRC and extra-colonic cancers only to young adult-onset CRC patients who have a genetically or clinically diagnosed hereditary CRC syndrome. For patients with sporadic young adult-onset CRC, extra-colonic screening and CRC surveillance intervals are the same as for patients with older adult-onset CRC.

Several factors can affect the risk of recurrence after curative resection of colorectal cancer (CRC). We aimed to develop a risk model for recurrence after definitive treatment of Stage I–III CRC using data from a nationally representative database and to develop an individualized web-based risk calculator. A random sample of patients who underwent resection for Stage I–III CRC between 2006 and 2007 at Commission on Cancer (CoC) accredited centers were included. Primary data regarding first recurrence was abstracted from medical records and merged with the National Cancer Database. Multivariable cox regression analysis was used to test for factors associated with cancer recurrence, stratified by stage. Model performance was tested by c statistic and calibration plots. Hazard Ratios were utilized to develop an individualized web-based recurrence prediction tool. A total of 8249 patients from 1175 CoC centers were included. Of these, 1656 (20.1%) patients had a recurrence during 5 years of follow-up. Median time to recurrence was 16 months. The final predictive models displayed excellent discrimination and calibration with concordance indexes of 0.7. The online calculator included 12 variables, including tumor site, stage, time since surgery, and surveillance intensity. Output is displayed numerically and graphically with an icon array. Using primarily abstracted recurrence data from a random sample of patients treated for CRC at CoC accredited centers across the United States, we successfully created an individualized CRC recurrence risk assessment tool. This web-based calculator can be used by physicians and patients in shared decision making to guide management discussions. ClinicalTrials.gov Registration Number: NCT02217865.

Colorectal cancer in the young adult population is of increasing incidence and concern. Genetic predisposition and heritable syndromes contribute to this trend, but perhaps more concerning is the majority of new diagnoses that involve no traceable genetic risk factors. Prevention and early recognition, with a high suspicion in the symptomatic young adult, are critical in attenuating recent trends. Clinical management requires coordinated multidisciplinary care from diagnosis to surveillance in order to ensure appropriate management. This review provides a summary of key aspects related to colorectal cancer in adolescents and young adults, including epidemiology, biology, genetics, clinical management, and prevention.

Curative-intent surgical resection of colon cancer involves optimal approaches to the peri-tumoral tissue, the mesocolon, and the draining lymph nodes. The key corresponding concepts that will be discussed are complete mesocolic excision (CME), central vascular ligation (CVL) or D3 dissection, and circumferential resection margin (CRM). We aim to describe these techniques and delineate evidence surrounding their technical feasibility, pathologic detail, as well as long-term oncologic impact. CME with CVL and D3 dissection are overlapping concepts both emphasizing anatomy-based resection of tumor and regional lymph nodes that does not breach the embryonic visceral fascia and ensures complete lymph node dissection up to the mesenteric root. Completeness of the mesocolic plane, number of harvested nodes, and CRM are surgical pathologic parameters that impact oncologic outcome. Attention to these details has been associated with improved outcomes in retrospective observational trials and the choice of open or minimally invasive approaches must be determined by surgeon's technical experiences.

Colorectal cancer is being increasingly diagnosed under age 50. An inheritable cancer predisposition has been reported in 22% of the young-onset cases. Assessment of germline risk is critical for personalized cancer care.To implement universal germline cancer risk assessment and testing, and to define the germline cancer risk profiles of patients presenting with young-onset disease.A prospective cohort study.A tertiary-referral academic medical center.Newly diagnosed patients presenting to surgical clinics between September 2019 and February 2021 were treated on a standardized care pathway including universal germline risk assessment.Patients received education material on young-onset disease, genetic testing, and insurance coverage, followed by genetic counseling (either remotely by tele-genetics or in-person). Consenting patients were assessed on a 47-gene common hereditary cancers panel.Proportion of patients with identifiable germline cancer predisposition.Among 500 colorectal cancer patients, 185(37%) were aged 50 or younger (median: 44). A family history was absent in the majority (123, 67%), and 15 tumors (8.1%) were deoxyribonucleic acid mismatch-repair-deficient. Germline testing was completed in 130 patients (70%); the remainder were pending (7%), deceased (1%), or declined (22%). Pathogenic germline mutations were identified in 25 (of 130, 19%) patients: 12 in mismatch repair genes and 13 in other genes. A variant of uncertain significance was found in 23 (18%) patients. Importantly, a pathogenic germline mutation was identified in 12% of the patients without a family history (versus 32% with; p = 0.015) and in 13% of those with mismatch-repair-proficient colorectal cancers (versus 71% if deficient; p0.001).Implemented at single tertiary academic institution.One in five patients with young-onset disease harbored germline cancer predisposition. This detection rate, coupled with a high level of interest and acceptance from patients and feasibility of implementation, support universal germline cancer risk assessment in this patient population. See Video Abstract at http://links.lww.com/DCR/B925.

The identification of transcriptomic and protein biomarkers prognosticating recurrence risk after chemoradiation of localized squamous cell carcinoma of the anus (SCCA) has been limited by a lack of available fresh tissue at initial presentation. We analyzed archival FFPE SCCA specimens from pretreatment biopsies prior to chemoradiation for protein and RNA biomarkers from patients with localized SCCA who recurred (N = 23) and who did not recur (N = 25). Tumor cells and the tumor microenvironment (TME) were analyzed separately to identify biomarkers with significantly different expression between the recurrent and non-recurrent groups. Recurrent patients had higher mean protein expression of FoxP3, MAPK-activation markers (BRAF, p38-MAPK) and PI3K/Akt activation (phospho-Akt) within the tumor regions. The TME was characterized by the higher protein expression of immune checkpoint biomarkers such as PD-1, OX40L and LAG3. For patients with recurrent SCCA, the higher mean protein expression of fibronectin was observed in the tumor and TME compartments. No significant differences in RNA expression were observed. The higher baseline expression of immune checkpoint biomarkers, together with markers of MAPK and PI3K/Akt signaling, are associated with recurrence following chemoradiation for patients with localized SCCA. These data provide a rationale towards the application of immune-based therapeutic strategies to improve curative-intent outcomes beyond conventional therapies for patients with SCCA.

72 Background: Online prediction tools for cancer risk can inform individuals about their risk and potentially encourage adoption of risk-modifying health behavior. The Colorectal Cancer Risk Assessment Tool (CCRAT) is an interactive tool developed by the National Cancer Institute for estimating colorectal cancer (CRC) risk for individuals between the ages of 45 and 85 without high risk predisposing conditions. Given the rising incidence of CRC among young adults under age 50, we aimed to investigate the performance of CCRAT in estimating their CRC risk. Methods: An institutional protocol prospectively enrolled 563 patients newly diagnosed with non-hereditary CRC and administered a health behavior questionnaire at baseline. Self-reported demographics, diet and physical activity, medication use, and family history were extracted and entered into the CCRAT ( https://ccrisktool.cancer.gov/calculator.html ) to calculate their predicted 5-year and lifetime CRC risks. Health behaviors and the predicted CRC risks in reference to the population average were compared among three groups: youngest- (aged 18-44, N = 276, 49%), young- (aged 45-50, N = 178, 32%), and older-onset (aged > 50, N = 109; 19%). Results: The patient groups did not significantly differ in gender or in family history of CRC, but the youngest group had significantly more non-White patients (27, 22, vs. 19%; p = 0.008) and distal tumors (80, 76 and 65%; p = 0.05). The youngest and young groups had a higher prevalence of morbid obesity (18 and 15% vs. 12%; p = 0.002) and active smokers (6 and 8% vs. 3%; p = 0.005). There were no significant differences in vegetable intake, moderate exercise, NSAID use, or female hormone use. The 5-year CRC risk was correctly predicted as “higher than average population” for a significantly smaller proportion of the youngest (42%) and young (45%) patients, when compared to their older counterpart (71%; p < 0.001). Similarly, the tool communicated “higher than average” lifetime risk for CRC in only 56 and 60% of the youngest and young patients, but 72% of the older ones (p = 0.021). Conclusions: The existing risk prediction tool inadequately communicated CRC risk for adults younger than 50 years of age. Risk factors underlying young-onset CRC likely differ from and extend beyond those as currently assessed. New tools capturing age-specific risk factors are needed to accurately communicate individualized risk and potentially motivate risk-modifying lifestyles.

7 Background: This NCTN multi-arm randomized phase II modular clinical trial platform utilizes TNT with parallel experimental arms (EAs) in LARC. EAs are not intended for direct comparison, but rather to concurrently randomized control arm (CA) patients. Primary endpoint (EP) and available secondary EPs (from EA1 using veliparib [V], PARPi; and EA2 using pembrolizumab [P], anti-PD-1) have been previously reported. We present long-term outcomes of all pts enrolled (NCT02921256). Methods: Stage II/III pts with MSS LARC (with any ONE of the following: distal location [cT3-4 ≤5cm from anal verge, any N]; bulky [any cT4 or tumor within 3mm of mesorectal fascia]; high risk for metastatic disease [cN2]; or not a sphincter-sparing surgery [SSS] candidate) were randomized to CA (neoadjuvant FOLFOX [x 4mo] → chemoRT [capecitabine with 50.4Gy] → surgery 8-12 wks later). EA1 added V (400mg PO BID) and EA2 added P (200mg IV Q3 wks x 6 doses) each concurrent with chemoRT. Primary EP: 4-point reduction in Neoadjuvant Rectal Cancer (NAR) score with a one-sided α=0.10, 80% power. NAR compared by linear model controlling for clinical T4 at entry (Y/N). Secondary EPs: OS, DFS. p-values are two-sided. Results: From 10/2016-2/2018, 178 pts were randomized (88 CA, 90 EA1). From 8/2018-5/2019, 185 pts were randomized (95 CA, 90 EA2). Baseline characteristics were previously reported. Median follow-up is 3.50 yrs for the 1st comparison. Median follow-up is 3.15 yrs for the 2nd comparison. Updated primary and long-term secondary outcomes are in the table. Conclusions: With longer follow-up, addition of V to TNT provided no significant differences in the NAR score or 3yr outcomes. The addition of P to TNT was associated with a statistically significant improvement in 3yr OS, but not DFS. Correlative molecular analyses are ongoing. Support: U10CA180868, -180822; UG1-189867; U24-196067; AbbVie; Merck. Clinical trial information: NCT02921256 . [Table: see text]

196 Background: The association between tumor mutations beyond KRAS and BRAF for patients with peritoneal metastases (PM) from colorectal cancer (CRC) are poorly understood. Here we describe these associations with survival after diagnosis of PM. Methods: CRC patients with PM with or without synchronous liver or lung metastases treated at a single institution from 2016 to 2020 were retrospectively studied. Standard of care next-generation sequencing was performed on tissue specimens with a targeted panel of genes frequently mutated in cancer. Clinical data, including survival and last contact, were obtained from medical records. Multivariate Cox regression was used to identify associations between overall survival after diagnosis of PM (OS) with clinical, histopathologic and somatic mutation data. Results: Of 526 PM patients, 179 (34.2%) also had synchronous liver metastases, and these patients had worse OS compared to PM alone (HR 1.67, [1.26-2.22], p=0.0003). Lung metastases were identified in 57 (10.8%) and were not associated with worse OS (HR 1.34, [0.90-1.97], p=0.15). Poorly differentiated grade (HR 2.08, [1.42-3.04], p=0.0002), mucinous histology (HR 1.44, [1.07-1.94], p=0.016), male gender (HR 1.37, [1.05-1.78), p=0.019), and age (HR 1.02, [1.01-1.04], p=0.004) were independently associated with OS. Tumor sequencing data was available for 442 (87%) patients. TP53 was the most common mutation (61.5% of patients) and was associated with decreased OS (HR=1.51 [1.12-2.02], p=0.005). BRAF mutation (85% of which were V600E) was identified in 9.7% of patients and was also associated with decreased OS (HR=1.88 [1.23-2.86], p=0.003). In contrast, PTEN mutation (4.3%) was associated with improved OS (0.41 (0.17-0.99), p=0.049), while both KRAS (51.4%) and SMAD4 mutations (16%) were not (KRAS: HR 0.94, [0.72-1.24], p=0.68; SMAD4: HR 0.78, [0.53-1.16], p=0.21). Conclusions: Mutational data for PM patients has a distinct profile and unique associations with OS when compared to other sites of metastatic disease. TP53 and BRAF mutations were associated with worse survival, while PTEN mutation was associated with improved OS. KRAS mutation was more prevalent than expected in an unselected cohort, and not associated with OS. A better understanding of PM-specific associations with survival may influence treatment strategies for this difficult disease site.

Patients with inflammatory bowel disease (IBD) have a higher risk of developing colorectal cancer (CRC) and mortality from colitis-associated CRC (CA-CRC) is currently rising. Clinical and molecular differences between CA-CRC and sporadic-CRC (S-CRC) have been previously identified, however there are conflicting reports on outcomes of CA-CRC, especially for those with metastatic CRC (mCRC). Due to the earlier onset of CA-CRC, undiagnosed IBD has been speculated to be a contributing factor to the rising prevalence of early-onset CRC (EOCRC), but confirmatory studies are lacking. In this retrospective study, three independent CRC patient datasets from MDACC were used – the mATTACC discover cohort (n=32 CA-mCRC; n=425 S-mCRC), a tumor registry (n=1696, excluding MSI-High samples), and a real-world evidence (RWE) validation dataset (n=269 CA-mCRC; n=29,596 S-mCRC). These cohorts were analyzed in order to explore characteristics of patients with CA-mCRC, evaluate the amount of EOCRC attributable to CA-mCRC, and compare outcomes of patient populations with CA-mCRC. Median age at diagnosis for patients with CA-mCRC (48yo) was significantly lower compared to S-mCRC (58yo; p Citation Format: Oscar E. Villarreal, Fadl Zeineddine, Ray Chacko, Christine Parseghian, Benny Johnson, Jason Willis, Michael Lee, Van Karlyle Morris, Arvind Dasari, Kanwal Raghav, Michael Overman, Y. Nancy You, Yinghong Wang, Dipen Maru, John Paul Shen, Scott Kopetz. Outcomes in colitis-associated metastatic colorectal cancer and intersection with early-onset and signet ring cell carcinoma [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr PR005.

Background Colorectal cancer in young adults is on the rise. This rise combined with delayed childbearing increases the likelihood of colorectal cancer diagnosed during pregnancy or in the postpartum period. Methods Electronic health records were used to identify individuals with colorectal cancer in pregnancy or the postpartum period from 1 August 2007 to 1 August 2019. Results Forty-two cases were identified. Median age at diagnosis was 33 years. Most (93%) were diagnosed in an advanced stage (III or IV) and had left-sided colorectal cancer tumors (81%). Molecular analysis was completed in 18 (43%) women with microsatellite status available in 40 (95%). The findings were similar to historical controls. Sixty percent were diagnosed in the postpartum period. Common presenting symptoms were rectal bleeding and abdominal pain. Conclusion Currently there is no consensus recommendation regarding how to manage colorectal cancer during pregnancy. Given the overlapping symptoms with pregnancy, patients often present with advanced disease. We encourage all health care professionals caring for pregnant women to fully evaluate women with persistent gastrointestinal symptoms to rule out colorectal cancer.

Background While the prognostic implications of positive circumferential resection margins (CRM) have been established for rectal cancer, its significance in colon cancer has not been well defined. The aim of the current study was to determine national rates for positive CRM in locally advanced colon cancer, associated factors, and survival impact. Methods The National Cancer Database was queried to identify patients with stage II-III adenocarcinoma of the colon (2004-2015). Results Positive CRM was identified in 9% of stage II and 12% of stage III patients. Factors associated with negative CRM included surgery in a high-volume facility, adequate lymph-node harvest, and negative distal/proximal margins. No difference in CRM rates was observed between surgical approaches, although having a positive CRM was significantly associated with higher conversion rates. Positive CRM was associated with significantly lower overall survival on both univariate and multivariable analysis. Conclusions Positive CRM rates exceeded 10% nationally and have an adverse impact on survival. While several tumor characteristics were identified as independent risk factors, oncologic resections and surgery at high-volume centers were associated with lower rates of positive CRM. These findings emphasize the need for process improvement initiatives targeting modifiable factors, including adoption of appropriate oncologic techniques, standardized pathology reporting, and potential neoadjuvant strategies.

Lifestyle factors related to energy balance, such as excess body weight, poor diet, and physical inactivity, are associated with risk of sporadic endometrial cancer (EC) and colorectal cancer (CRC). There are limited data on energy balance-related lifestyle factors and EC or CRC risk among individuals with Lynch syndrome, who are at extraordinarily higher risk of developing EC or CRC. We conducted a systematic review of evidence related to weight status, weight change, dietary habits, and physical activity on EC and CRC risk among individuals with Lynch syndrome. Findings are reported narratively. We searched Medline, EMBASE, CENTRAL, PubMed, and clinicaltrials.gov up to June 14(th), 2018. In total, 1,060 studies were identified and 16 were included. Three studies were related to EC and 13 to CRC. Overall, evidence suggests that weight status/weight change may not be associated with EC risk and multivitamin and folic-acid supplementation may be associated with decreased EC risk. Early-adulthood overweight/obese weight-status and adulthood weight-gain may be associated with increased CRC risk, whereas multivitamin supplementation, tea and high fruit intake, and physical activity may be associated with decreased CRC risk. Current evidence proposes that recommendations related to weight, some dietary habits, and physical activity recommended for the general public are also relevant to individuals with Lynch syndrome. More research is needed, specifically prospective cohorts and randomized controlled trials, to determine if tailored recommendations are needed among individuals with Lynch syndrome.

PURPOSE To develop recommendations for duration of adjuvant chemotherapy with a fluoropyrimidine and oxaliplatin for patients with completely resected stage III colon cancer based on the results of trials of 3 months compared with 6 months of treatment. METHODS ASCO convened an Expert Panel and conducted a systematic review of relevant studies. The guideline recommendations were based on the review of evidence by the Expert Panel. RESULTS Pooled data from the six International Duration Evaluation of Adjuvant Chemotherapy (IDEA) Collaboration randomized controlled trials comprise the evidence base for these guideline recommendations. RECOMMENDATIONS The recommendations for therapy duration apply to patients with completely resected stage III colon cancer who are being offered adjuvant chemotherapy with oxaliplatin and a fluoropyrimidine. Recommendations are informed by the findings of a recent pooled analysis of clinical trials that compared 6 months versus 3 months of oxaliplatin-based chemotherapy. For patients at a high risk of recurrence (T4 and/or N2), adjuvant chemotherapy should be offered for a duration of 6 months. For patients at a low risk of recurrence (T1, T2, or T3 and N1), either 6 months of adjuvant chemotherapy or a shorter duration of 3 months may be offered on the basis of a potential reduction in adverse events and no significant difference in disease-free survival with the 3-month regimen. In determining duration of therapy, the Expert Panel recommends a shared decision-making approach, taking into account patient characteristics, values and preferences, and other factors and including a discussion of the potential for benefit and risks of harm associated with treatment duration. Additional information is available at www.asco.org/gastrointestinal-cancer-guidelines .

Genomic profiling of colorectal cancer aims to identify actionable somatic mutations but can also discover incidental germline findings.The purpose of this study was to report the detection of pathogenic germline variants that confer heritable cancer predisposition.This was a retrospective study.The study was conducted at a tertiary-referral institution.Between 2012 and 2015, 1000 patients with advanced cancer underwent targeted exome sequencing of a 202-gene panel. The subgroup of 151 patients with advanced colorectal cancer who underwent matched tumor-normal (blood) sequencing formed our study cohort.Germline variants in 46 genes associated with hereditary cancer predisposition were classified according to a defined algorithm based on in silico predictions of pathogenicity. Patients with presumed pathogenic variants were examined for type of mutation, as well as clinical, pedigree, and clinical genetic testing data.We measured detection of pathogenic germline variants.A total of 1910 distinct germline variants were observed in 151 patients. After filtering, 15 pathogenic germline variants (9.9%) were found in 15 patients, arising from 9 genes of varying penetrance for colorectal cancer (APC (n = 2; 13%), ATM (n = 1; 6%), BRCA1 (n = 2; 13%), CDH1 (n = 2; 13%), CHEK2 (n = 4; 27%), MSH2 (n = 1; 7%), MSH6 (n = 1; 7%), NF2 (n = 1; 7%), and TP53 (n = 1; 7%)). Patients with pathogenic variants were diagnosed at a younger age than those without (median, 45 vs 52 y; p = 0.03). Of the 15 patients, 7 patients (46.7%) with variants in low/moderate- penetrant genes for colorectal cancer would likely have not been tested based on clinical and pedigree criteria, where 2 harbored clinically actionable variants (CDH1 and NF2, 28.5% of 7).This study was limited by its small sample size and advanced-stage patients.Tumor-normal sequencing can incidentally discover clinically unsuspected germline variants that confer cancer predisposition in 9.9% of patients with advanced colorectal cancer. Precision medicine should integrate clinical cancer genetics to inform and interpret the actionability of germline variants and to provide follow-up care to mutation carriers. See Video Abstract at http://links.lww.com/DCR/A906.