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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.

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.

PURPOSE Colorectal cancer (CRC) is a malignancy that usually occurs in older age individuals. However, CRC cases in young adults are on the rise, and this increase is expected to continue. Young adult CRC requires the healthcare team to familiarize themselves with the unique needs of this population, including concerns about treatment-related infertility. We performed a retrospective review to determine how often our patients, 18-39 years old (yo), had discussions regarding fertility preservation prior to starting stage III CRC treatment. METHODS Our electronic health record was utilized to identify adult patients

Background The clinical utility of a blood-based biomarker in squamous cell carcinoma of the anus (SCCA) is unknown. We analyzed carcinoembryonic antigen (CEA), a commonly employed assay for patients with colorectal adenocarcinoma, as a serum biomarker for patients with biopsy-proven SCCA. Materials and methods Medical records from 219 patients with biopsy-proven SCCA at the University of Texas MD Anderson Cancer Center were reviewed under an IRB-approved protocol from 2013 to 2020 to assess for correlations between CEA levels and corresponding clinical and pathologic characteristics. Results The mean CEA among subgroups by clinical status at the time of presentation to our institution was highest among those patients with metastatic SCCA to visceral organs (M-V, 20.7 ng/mL), however this finding was not statistically significant by ANOVA (p = .74). By clinical subgroup, the percentage of patients with an abnormally elevated CEA was highest in those patients with metastatic disease to lymph nodes (M-L, 41.2%) followed by recurrent/unresectable SCCA (36.8%), and metastatic SCCA to visceral organs (M-V, 35.2%), and was statistically significant between groups (Fisher's exact test p = .02). Using RECIST criteria for tumor progression and disease response, the mean change in CEA for patients with progression was an increase in 19 ng/mL, compared to a change of -7.3 ng/mL in those with disease response (p = .004). We likewise assessed whether CEA levels were associated with survival outcomes for all patients with metastatic SCCA, and found no correlation between CEA and likelihood for survival in a ROC analysis (multivariate, age-adjusted analysis for CEA cutoff of 8, HR = 1.01, 95% CI 0.52-1.96). Conclusions Despite interesting patterns of abnormally high CEA in SCCA patients with advanced disease, and correlation of increased CEA with disease progression (and conversely decreased CEA with disease response), CEA is not associated with survival outcomes in SCCA, and is not a clinically relevant biomarker in this disease.

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.

Introduction Squamous cell carcinoma of the anal canal (SCCA) presents rising incidence in the US. Standard of care for locally advanced disease is comprised of infusional 5FU plus mitomycin C or cisplatin concurrent with radiation therapy (RT). We designed this trial to evaluate the efficacy and safety of a more convenient regimen composed of capecitabine and oxaliplatin. Methods Single-arm, phase II trial, with treatment-naive stage II-IIIB (T X,1-4 N x M 0 ) SCCA patients. The regimen was composed of capecitabine (825 mg/m 2 BID, 5d) and oxaliplatin (50 mg/m 2 weekly) during weeks 1-6, concurrent with RT (XELOX-XRT) (Group 1). After the first 11 patients, the study was amended to omit chemotherapy during the 3 rd and 6 th weeks (Group 2). The primary objective was 3-year time-to-treatment-failure (TTF) and safety. Secondary objectives were complete response (CR) rate, locoregional control (LRC), colostomy-free survival (CFS), and overall survival (OS). Results Twenty patients were enrolled. Seven patients of group 1 (63%) developed grade 3 toxicity, which reduced to 22% in group 2. No grade 4 toxicities were noted. The median RT dose was 55 Gy. CR occurred in 100% of the 19 patients evaluable for response at 12-14 weeks. After median follow-up of 47.6 months, two patients had local recurrence and one had distant. 3-year TTF was 90.0%, with similar rates between group 1 and 2, respectively (90.9% versus 88.8%, p: 0.984). 3-year CFS was 90.0%. The median OS has not been reached. Conclusions The XELOX-XRT regimen is safe, with promising efficacy, and should be explored in larger trials in for the treatment of locally advanced SCCA.

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.

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.

The prevalence of Lynch syndrome (LS) varies significantly in different populations, suggesting that ethnic features might play an important role. We enrolled 3330 consecutive Chinese patients who had surgical resection for newly diagnosed colorectal cancer. Universal screening for LS was implemented, including immunohistochemistry for mismatch repair (MMR) proteins, BRAFV600E mutation test and germline sequencing. Among the 3250 eligible patients, MMR protein deficiency (dMMR) was detected in 330 (10.2%) patients. Ninety-three patients (2.9%) were diagnosed with LS. Nine (9.7%) patients with LS fulfilled Amsterdam criteria II and 76 (81.7%) met the revised Bethesda guidelines. Only 15 (9.7%) patients with absence of MLH1 on IHC had BRAFV600E mutation. One third (33/99) of the MMR gene mutations have not been reported previously. The age of onset indicates risk of LS in patients with dMMR tumors. For patients older than 65 years, only 2 patients (5.7%) fulfilling revised Bethesda guidelines were diagnosed with LS. Selective sequencing of all cases with dMMR diagnosed at or below age 65 years and only of those dMMR cases older than 65 years who fulfill revised Bethesda guidelines results in 8.2% fewer cases requiring germline testing without missing any LS diagnoses. While the prevalence of LS in Chinese patients is similar to that of Western populations, the spectrum of constitutional mutations and frequency of BRAFV600E mutation is different. Patients older than 65 years who do not meet the revised Bethesda guidelines have a low risk of LS, suggesting germline sequencing might not be necessary in this population.

Colorectal cancer (CRC) is a malignancy that usually occurs in older age individuals. However, CRC cases in young adults are on the rise, and this increase is expected to continue. Young adult CRC requires the healthcare team to familiarize themselves with the unique needs of this population, including concerns about treatment-related infertility. We performed a retrospective review to determine how often our patients, 18-39 years old (yo), had discussions regarding fertility preservation prior to starting stage III CRC treatment.Our electronic health record was utilized to identify adult patients 40 yo with a stage III CRC diagnosis during 1/1/2015-9/1/2019. Fertility preservation discussions were determined by searching the patient's EHR chart. Progress notes from the medical oncology, surgery, and/or radiation oncology teams were reviewed. Additionally, notes from our fertility specialist's team were reviewed when consulted.One hundred and three patients met criteria. Patients were 21-39 yo at diagnosis (median age of 34 yo). Fifty-two percent were male while the remaining 48% were female. Forty-six percent had stage III colon cancer while 54% had stage III rectal cancer. Search terms and progress notes were utilized to determine if discussions were documented. Fertility discussions were documented in 73% of cases while 27% of patients lacked documentation regarding fertility.Our results show that most of our young adult stage III CRC population participate in fertility preservation discussions. However, in order to capture all patients, we recognize that a more formal approach is warranted. We additionally recommend these discussions occur with all patients of child-bearing age.

Introduction Women with pathogenic germline gene variants in BRCA1 and/or BRCA2 are at increased risk of developing ovarian and breast cancer. While surgical and pharmacological approaches are effective for risk-reduction, it is unknown whether lifestyle approaches such as healthful dietary habits, weight management, and physical activity may also contribute to risk-reduction. We conducted a systematic review of evidence related to dietary habits, weight status/change, and physical activity on ovarian and breast cancer risk among women with BRCA1/2 pathogenic variants. Methods We searched Medline, EMBASE, CENTRAL, PubMed, and clinicaltrials.gov up to October 3, 2019. We identified 2775 records and included 21. Results There is limited evidence related to these factors and ovarian cancer risk. For breast cancer risk, evidence suggests higher diet quality, adulthood weight-loss of ≥10 pounds, and activity during adolescence and young-adulthood may be linked with decreased risk. Higher meat intake and higher daily energy intake may be linked with increased risk. Conclusions There is not enough evidence to suggest tailored recommendations for dietary habits or weight management among women with BRCA1/2 pathogenic variants compared to the general population for ovarian and breast cancer risk-reduction, and physical activity recommendations should remain the same.

Purpose Previous studies have reported that hyperfractionated accelerated reirradiation can be used as part of multimodality treatment of locally recurrent rectal cancer with acceptable toxicity and promising outcomes. The purpose of this study was to evaluate the outcomes and toxicity of hyperfractionated accelerated reirradiation for patients with primary rectal adenocarcinoma and a history of prior pelvic radiation for other primary malignancies. Methods and materials We identified 10 patients with a prior history of pelvic radiation for other primary malignancies who were treated with hyperfractionated accelerated reirradiation for primary rectal adenocarcinoma. Radiation therapy was administered with 1.5 Gy twice daily fractions to a total dose of 39 Gy to 45Gy. Results The median follow-up time was 3.2 years (range, 0.6-9.0 years). Seven of 10 patients received surgery after reirradiation. The 3-year freedom-from-local-progression rate was 62% for all patients and 80% for patients who underwent surgery. The 3-year overall survival rate was 100%, with 3 deaths occurring at 4.7, 6.5, and 9.0 years after reirradiation. One patient had an acute Grade 3 toxicity of diarrhea, and 1 patient experienced a late Grade 3 toxicity of sacral insufficiency fracture. Conclusions Hyperfractionated accelerated reirradiation was well tolerated with promising rates of freedom from local progression and overall survival in patients with primary rectal cancer with a history of prior pelvic radiation therapy. This approach, along with concurrent chemotherapy and surgery, appears to be a viable treatment strategy for this patient population.

Purpose To compare health-related quality of life (HRQoL) in colorectal cancer (CRC) survivors with sporadic CRC to those with hereditary cancer, specifically Lynch syndrome (LS). Methods Participants completed a mailed self-administered questionnaire that assessed, among other things, demographics, clinical characteristics, and health-related quality of life. Using a case-case design, CRC survivors with LS or sporadic cancer were matched on age, sex, race/ethnicity, cancer stage, geography, and time since diagnosis. Participants were recruited from patient registries at The University of Texas MD Anderson Cancer Center (MD Anderson) (n = 33 LS; n = 75 sporadic) and through social media (n = 42 LS). The final sample included 71 LS and 74 sporadic CRC survivors. Results For LS patients, the mean FACT-C HRQoL score was 84.8 (11.9) [Median = 86.0; Interquartile Range-17] compared to sporadic patients mean score of 85.8 (16.7) [Median = 92.0; Interquartile Range-21], which indicates high quality of life for both groups. LS patients and sporadic CRC patients had similar HRQoL mean scores across 7 different HRQoL metrics, with no significant differences between groups. Exploratory regression analyses indicate some differences in known predictors of HRQoL by group despite no bivariate differences. Conclusions HRQoL is an important component of survivorship in CRC patients. Given the clinical distinctions between LS and sporadic patients, we expected to find significant differences between these patients. However, the patients’ experiences/quality of life does not appear to illustrate such a clear dissimilarity within CRC survivors. Given the limited data in this area, larger studies, ideally with data obtained from multiple sites, is needed to better investigate the alignment between clinical determination and patient experience as well as to explore the relationship between HRQOL, treatment regimens, and health outcomes.

Preoperative radiotherapy continues to be widely used in patients with operable rectal cancer. However, the indications and goals for such treatment are evolving. Professor Marijnen reviews the historic and current evidence base for the use of preoperative neoadjuvant radiotherapy and the future challenges in tailoring the therapy according to the patients' needs and tumour stage.

PURPOSE: Patients with Lynch syndrome (LS) have a significantly elevated lifetime risk of developing biliary tract cancers (BTCs) compared to the general population. However, few studies have characterized the clinical characteristics, genetic features, or long-term outcomes of mismatch-repair deficient (dMMR) cholangiocarcinomas associated with LS. METHODS: A retrospective review of a prospectively maintained Familial High-Risk GI Cancer Clinic database identified all patients with BTCs evaluated from 2006 to 2016 who carried germline mutations in MLH1, MSH2, MSH6, or PMS2. RESULTS: Eleven patients with BTCs were identified: four perihilar, four intrahepatic, one extrahepatic, one gallbladder, and one ampulla of Vater. All patients had underlying germline mutations and a personal history of a LS-associated malignancy, most commonly (63.3%) colorectal cancer. Ten (90.9%) patients were surgically explored, and margin negative resection was possible in seven (63.3%). Chemotherapy (90.9%) and/or chemoradiation (45.5%) was administered to most patients. Among the seven patients presenting with non-metastatic disease who underwent surgical resection with curative intent, the 5-year overall survival rate was 53.3%. The median overall survival for the four patients not treated with curative intent was 17.2 months. CONCLUSIONS: dMMR biliary tract cancers associated with LS are rare but long-term outcomes may be more favorable than contemporaneous cohorts of non-Lynch-associated cholangiocarcinomas. Given the emerging promise of immunotherapy for patients with dMMR malignancies, tumor testing for dMMR followed by confirmatory germline testing should be considered in patients with BTC and a personal history of other LS cancers.

Background: Select patients with rectal adenocarcinoma with metastatic disease at presentation can be cured with multimodality management. However, the optimal components and sequencing of therapy is unknown. The aim of this study is to evaluate outcomes for patients treated with chemotherapy, short course radiation therapy (SCRT) and surgical resection. Methods: Patients with newly diagnosed metastatic rectal adenocarcinoma who received SCRT from 2010–2016 were identified. All patients were evaluated by a multidisciplinary team and deemed candidates for treatment with curative intent. Overall survival (OS) and progression-free survival (PFS) were calculated using the Kaplan-Meier method. Patient, tumor and treatment characteristics were evaluated as prognostic factors using a Cox proportional hazards model. Results: Thirty-four patients were included with a median [interquartile range (IQR)] follow-up of 25 (14.75–42.25) months; 26 patients (76.5%) received definitive surgery for their rectal tumor, and 24 patients (70.6%) received definitive local management of metastatic disease. One-, 2- and 3-year OS were 97%, 86.2% and 76.0%, respectively, and 1-, 2-, and 3-year PFS were 52.1%, 22.7% and 17%, respectively. On multivariate analysis, definitive management of metastases was associated with improved OS [hazard ratio (HR) 0.03, 95% confidence interval (CI): 0.01–0.33]; P=0.003, and ≤2 months of neoadjuvant chemotherapy was associated with decreased OS (HR 11.7, 95% CI: 2.11–106; P=0.004). Conclusions: These findings suggest that SCRT can be successfully integrated into a definitive, multidisciplinary approach to metastatic rectal adenocarcinoma. Benefits to this approach include decreased time off systemic therapy as compared to standard course RT. Further study is needed to determine the optimum interval between SCRT and surgery.

Lynch syndrome (LS) is a genetic condition secondary to germline alterations in the DNA mismatch repair (MMR) genes with 30% of changes being variants of uncertain significance (VUS). Our aim was to perform an in silico reclassification of VUS from a large single institutional cohort that will help prioritizing functional validation. A total of 54 VUS were detected with 33 (61%) novel variants. We integrated family history, pathology, and genetic information along with supporting evidence from eight different in silico tools at the RNA and protein level. Our assessment allowed us to reclassify 54% (29/54) of the VUS as probably damaging, 13% (7/54) as possibly damaging, and 28% (15/54) as probably neutral. There are more than 1,000 VUS reported in MMR genes and our approach facilitates the prioritization of further functional efforts to assess the pathogenicity to those classified as probably damaging. Cancer Prev Res; 10(10); 580–7. ©2017 AACR.

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.

Purpose: Pathologic complete response to neoadjuvant chemoradiation therapy (CRT) is associated with improved outcomes for patients with locally advanced rectal cancer (LARC). Increased response rates have been reported with higher radiation doses, but these studies often lack long-term outcome and/or toxicity data. We conducted a case-control analysis of patients with LARC who underwent definitive CRT to determine the efficacy and safety of intensified treatment with a concomitant boost (CB) approach. Methods and materials: From 1995 to 2003, a phase 2 protocol examined CRT with 5-fluorouracil and CB radiation therapy (52.5 Gy in 5 weeks) for patients with LARC. Seventy-six protocol patients were matched (case-control approach) for surgery type, tumor (T) stage, and clinical nodal (N) stage with patients who received standard dose (SD) CRT (5-fluorouracil, 45 Gy). A chart review was performed. McNemar's test and Kaplan-Meier analyses were used for statistical analysis. Results: The SD and CB groups did not differ in tumor circumferential involvement and length, but the tumors of CB patients were closer to the anal verge (4.7 vs 5.7 cm; P = .02). Although tumor downstaging was higher in the CB cohort (76% vs 51%; P < .01), pathologic complete response rates did not differ (CB, 17.1% vs SD, 15.8%, P = 1.00). The incidence of grade ≥3 radiation-related toxicities was low and similar in both groups (CB, 10% vs SD, 3%, P = .22). Postoperative (anastomotic leak, wound complications/abscess, bleeding) and late (small bowel obstruction, stricture) complication rates did not differ between the groups (P > .05). The median follow-up was 11.9 years. The 5-year local control rates were higher for CB (100.0%) compared with SD (90.0%) patients (P = .01). CB patients had higher rates of 10-year progression-free survival (71.9% vs 57.6%, P < .01) and overall survival (71.6% vs 62.4%, P = .01) compared with SD patients. Conclusions: CRT dose escalation for patients with LARC is safe and effective. The improved T-downstaging and local control observed in CB patients should encourage further dose escalation studies.

Squamous cell carcinoma (SCC) of the rectum is a rare disease with

Optimal surgical strategy for resectable synchronous colorectal cancer with liver metastasis (SCRLM) remains a therapeutic dilemma. Multiple retrospective studies including several meta-analyses have been published since 2001 to help facilitate the decision making process and identify the optimal surgical approach. Controversy limits the generalization of available data to draw conclusions. A review of available literature on appropriate surgical timing may alleviate confusion among physicians and promote a more evidence based approach. Current evidence supports the feasibility, safety, and equivalent oncological outcomes of simultaneous curative resection of stage IV colorectal cancer with liver metastasis in appropriately selected patients.

Surgery for anal cancer is usually reserved for patients with persistent disease or local recurrence after definitive chemoradiation therapy. Patients with local recurrence should be re-evaluated for evidence of metastatic disease using positron emission tomography-computed tomography, and the local anatomy should be delineated with MRI. Eligible patients should undergo tailored surgery with the aim of achieving an R0 resection. Management is best undertaken within a specialized multidisciplinary setting. Careful patient selection and shared decision making are paramount for achieving acceptable patient-centered outcomes.

Introduction Women with pathogenic germline gene variants in BRCA1 and/or BRCA2 are at increased risk of developing ovarian and breast cancer. While surgical and pharmacological approaches are effective for risk-reduction, it is unknown whether lifestyle approaches such as healthful dietary habits, weight management, and physical activity may also contribute to risk-reduction. We conducted a systematic review of evidence related to dietary habits, weight status/change, and physical activity on ovarian and breast cancer risk among women with BRCA1/2 pathogenic variants. Methods We searched Medline, EMBASE, CENTRAL, PubMed, and clinicaltrials.gov up to October 3, 2019. We identified 2775 records and included 21. Results There is limited evidence related to these factors and ovarian cancer risk. For breast cancer risk, evidence suggests higher diet quality, adulthood weight-loss of ≥10 pounds, and activity during adolescence and young-adulthood may be linked with decreased risk. Higher meat intake and higher daily energy intake may be linked with increased risk. Conclusions There is not enough evidence to suggest tailored recommendations for dietary habits or weight management among women with BRCA1/2 pathogenic variants compared to the general population for ovarian and breast cancer risk-reduction, and physical activity recommendations should remain the same.

Despite the use of neoadjuvant chemoradiation and total mesorectal excision for rectal cancer, lateral pelvic lymph node recurrence is still an important problem.This study aimed to determine the indication for lateral pelvic lymph node dissection in post neoadjuvant chemoradiation rectal cancer.This is a retrospective analysis of a prospectively collected institutional database.This study was conducted at a tertiary care cancer center from January 2006 through December 2017.Patients who had rectal cancer with suspected lateral pelvic lymph node metastasis, who underwent total mesorectal excision with lateral pelvic lymph node dissection, were included.The primary outcome measured was pathologic lateral pelvic lymph node positivity.The associations between lateral pelvic lymph node size on post-neoadjuvant chemoradiation imaging and pathologic lateral pelvic lymph node positivity and recurrence outcomes were evaluated.A total of 64 patients were analyzed. The mean lateral pelvic lymph node size before and after neoadjuvant chemoradiation was 12.6 ± 9.5 mm and 8.5 ± 5.4 mm. The minimum size of positive lateral pelvic lymph node was 5 mm on post neoadjuvant chemoradiation imaging. Among 13 (20.3%) patients who had a5 mm lateral pelvic lymph node after neoadjuvant chemoradiation, none were pathologically positive. Among 51 (79.7%) patients who had a ≥5 mm lateral pelvic lymph node after neoadjuvant chemoradiation, 33 patients (64.7%) were pathologically positive. Five-year overall survival and disease-specific survival were higher in the histologic lateral pelvic lymph node negative group than in the lateral pelvic lymph node positive group (overall survival 79.6% vs 61.8%, p = 0.122; disease-specific survival 84.5% vs 66.2%, p= 0.088). After a median 39 months of follow-up, there were no patients in the5 mm group who died of cancer. There were no lateral compartment recurrences in the entire cohort.Being a single-center retrospective study may limit generalizability.Post-neoadjuvant chemoradiation lateral pelvic lymph node size ≥5 mm was strongly associated with pathologic positivity. No patients with size5 mm had pathologically positive lymph nodes. Following lateral pelvic lymph node dissection, no patients with a positive lateral pelvic lymph node developed lateral compartment recurrence. Therefore, patients who have rectal cancer with clinical evidence of lateral pelvic lymph node metastasis and post-neoadjuvant chemoradiation lateral pelvic lymph node size ≥5 mm should be considered for lateral pelvic lymph node dissection at the time of total mesorectal excision. See Video Abstract at http://links.lww.com/DCR/B3. ¿QUIéN DEBE RECIBIR LINFADENECTOMíA PéLVICA LATERAL DESPUéS DE LA QUIMIORRADIACIóN NEOADYUVANTE?: A pesar del uso de quimiorradiación neoadyuvante y la escisión total de mesorectao para el cáncer de recto, la recurrencia en los ganglios linfáticos pélvicos laterales sigue siendo un problema importante.Determinar la indicación para la disección de los ganglios linfáticos pélvicos laterales en el cáncer rectal post quimiorradiación neoadyuvante. DISEÑO:: Análisis retrospectivo de la base de datos institucional prospectivamente recopilada.Centro de cáncer de atención terciaria, de enero de 2006 hasta diciembre de 2017.Pacientes con cáncer de recto con sospecha de metástasis en los ganglios linfáticos pélvicos laterales, que se sometieron a escisión total mesorectal con disección de los ganglios linfáticos pélvicos laterales.Positividad de ganglios linfáticos pélvicos laterales en histopatología.Se evaluaron las asociaciones entre el tamaño de los ganglios linfáticos pélvicos laterales en imagenología postquimiorradiación neoadyuvante y la positividad y recurrencia en los ganglios linfáticos pélvicos laterales en histopatología.Se analizaron un total de 64 pacientes. La media del tamaño de los ganglios linfáticos pélvicos laterales antes y después de la quimiorradiación neoadyuvante fue de 12.6 ± 9.5 mm y 8.5 ± 5.4 mm, respectivamente. El tamaño mínimo de los ganglios linfáticos pélvicos laterales positivos fue de 5 mm en las imágenes postquimiorradiación neoadyuvante. Entre 13 (20.3%) pacientes que tenían5 mm de ganglio linfático lateral pélvico después de la quimiorradiación neoadyuvante; ninguno fue positivo en histopatología. Entre 51 (79.7%) pacientes con ganglio linfático pélvico lateral ≥ 5 mm después de la quimiorradiación neoadyuvante; 33 pacientes (64.7%) fueron positivos en histopatología. La supervivencia general a 5 años y la supervivencia específica de la enfermedad fueron mayores en el grupo histológico de ganglio linfático pélvico lateral negativo que en el grupo de ganglio linfático pélvico lateral positivo (Supervivencia general 79.6% vs 61.8%, p = 0.122; Supervivencia específica de la enfermedad 84.5% vs 66.2%, p = 0.088). Después de una mediana de seguimiento de 39 meses, no hubo pacientes en el grupo de5 mm que hayan fallecido por cáncer. No hubo recurrencias en el compartimento lateral en toda la cohorte.Al ser un estudio retrospectivo en un solo centro puede limitar la generalización.El tamaño de los ganglios linfáticos pélvicos laterales postquimiorradiación neoadyuvante ≥ 5 mm se asoció fuertemente con la positividad histopatológica. Ningún paciente con tamaño5 mm tuvo ganglios linfáticos histopatológicamente positivos. Después de la disección de los ganglios linfáticos pélvicos laterales, ningún paciente con ganglios linfáticos pélvicos laterales positivos desarrolló recurrencia del compartimiento lateral. Por lo tanto, los pacientes con cáncer rectal con evidencia clínica de metástasis en los ganglios linfáticos pélvicos laterales y tamaño de ganglios linfáticos pélvicos laterales postquimiorradiación neoadyuvante ≥ 5 mm deben considerarse para disección de los ganglios linfáticos pélvicos laterales en el momento de la escisión total de mesorrecto. Vea el Abstract en video en http://links.lww.com/DCR/B3.

e15601 Background: We evaluated demographic, treatment, and survival outcomes of adults age 18 to 49 years treated at our institution with long course chemoradiotherapy (CRT) followed by total mesorectal excision (TME) for locally advanced rectal cancer. Additionally, we compared outcomes between those age < 45 vs. > 45 years. Methods: The records of 219 patients diagnosed with non-metastatic, clinical T3, T4, or node positive rectal adenocarcinoma and treated between April 2000 and November 2017 were reviewed for age, sex, and presenting symptoms; clinical stage and microsatellite stable (MSS)/DNA mismatch repair (MMR) proficiency status; treatments delivered and sequence; pathologic response to pre-operative therapies; and the development of locoregional recurrence (LRR), distant metastasis (DM), and secondary pelvic malignancy. The Kaplan-Meier method and Log-Rank test were used to calculate and compare disease-free survival (DFS) and overall survival (OS) rates from the date of TME. Results: The median age at diagnosis was 44 years (range 19-49) and there was no sex predominance. Rectal bleeding was the most common presenting symptom (91%), with a median time to diagnosis of 5 months. Clinical tumor/nodal categories were T1-2 in 4%, T3 in 87%, T4 in 7%, N0 in 17%, and N1–2 in 80% of patients. MSS/MMR proficient disease was identified in 95% of tumors with status reported (n = 170). CRT followed by TME and post-operative chemotherapy was the most frequent treatment sequence (n = 196), with capecitabine (n = 176) and FOLFOX (n = 115) as the predominant concurrent and post-operative chemotherapies, respectively. Pathologic complete response at both primary and nodal sites occurred in 15% of all cases and 16% of MSS/MMR proficient cases. There was no difference in sex, tumor category, nodal category, MSS/MMR proficiency status, or pathologic complete response, by age ( < 45 years [n = 111] vs. > 45 years [n = 108]). At a median DFS follow-up time of 5.0 years, there were 11 LRR, 40 DM (including 11 DM detected prior to/at time of TME), and 1 synchronous presentation of LRR and DM. The 5-year rate of DFS was 70.4% for age < 45 years and 85.3% for age > 45 years ( P = 0.02). At an OS median follow-up time of 7.5 years, there were 38 deaths. The 5-year rate of OS was 87.7% for age < 45 years and 94.4% for age > 45 years ( P = 0.126). Two patients developed non-rectal pelvic malignancies. Conclusions: The outcomes reported here from one of the largest single-institution series for young-onset, locally advanced rectal cancer could serve as a benchmark to evaluate newer treatment approaches. Rectal bleeding was the leading presenting symptom, with approximately half-year delay from development of symptoms to diagnosis. Most tumors were MSS/MMR proficient. At 5 years’ follow-up time, the DFS rate was lower for patients age < 45 years when compared to those > 45 years. Secondary pelvic malignancies were a rare occurrence.

3549 Background: Strategies to detect and prevent young-onset colorectal cancer (YOCRC, diagnosed under age 50) are critical. Established high-risk screening guidelines (SGs) aim to detect/prevent YOCRCs arising from hereditary syndromes. For non-hereditary YOCRCs, average-risk screening is being considered at an earlier age, but family history (FH)-based increased-risk screening has been poorly studied. We aimed to define the proportion of non-hereditary YOCRC with a FH, and to determine whether existing SGs could have detected/prevented these cases. Methods: 394 consecutive YOCRC patients presenting for surgical resection were reviewed for tumor MMR status, pedigree and genetic testing. Those with known/suspected hereditary syndrome (by phenotype, MMR status, and/or germline mutation) were excluded (N = 65). Pedigrees (N = 329) were analyzed for first- or second-degree relatives (FDR, SDR) with CRC and the ages of diagnosis. The gap between the recommended age for FH-based CRC screening and the age of YOCRC diagnosis was calculated. Results: 89 (27%) non-hereditary YOCRC patients had a FH of CRC. The median age of diagnosis was 45; the tumors were mostly from the distal colon (22%) and rectum (60%), and stage III (48%) and IV (27%). Twenty-one (24%) patients had 22 FDRs with CRCs diagnosed at age 64 (median); and 71 (80%) patients had 92 SDRs with CRCs diagnosed at age 65 (median). Thirteen (15%) had a FH of YOCRC. The existing SGs consider 39 patients (44%) at increased-risk, and the remaining, average-risk (Table). Screening would have begun prior to the YOCRC diagnoses in 28 (31% [or 46, 52%]) patients. But YOCRC diagnosis preceded the recommended screening age in the remaining 61(69% [or 43, 48%]) patients by a median of 5.3 [or 3.9] years (Table). Conclusions: FH is found in 27% of the non-hereditary YOCRC patients; 15% has a FH of YOCRC. In nearly half of the patients, YOCRC was diagnosed several years earlier than the recommended age for FH-based screening, even assuming perfect SG adoption and starting average risk screening at age 45. Refining existing FH-based SGs can potentially be impactful.[Table: see text]

Traditional germline sequencing and deletion/duplication analysis does not detect Lynch syndrome-causing mutations in all individuals whose colorectal or endometrial tumors demonstrate mismatch repair (MMR) deficiency. Unique inversions and other rearrangements of the MMR genes have been reported in families with Lynch syndrome. In 2014, a recurrent inversion of MSH2 exons 1-7 was identified in five families suspected to have Lynch syndrome. We aimed to describe our clinical experience in identifying families with this specific inversion. Four probands whose Lynch syndrome-associated tumors demonstrated absence of MSH2/MSH6 staining and who had negative MMR germline testing were evaluated for the MSH2 inversion of exons 1-7, offered during initial genetic workup or upon routine clinical follow-up. All four probands tested positive for the MSH2 inversion. Proband cancer diagnoses included colon and endometrial adenocarcinoma and sebaceous adenoma. A variety of Lynch syndrome-associated cancers were reported in the family histories, although only one family met Amsterdam II criteria. Thirteen at-risk relatives underwent predictive testing. MSH2 inversion of exons 1-7 was found in four probands previously suspected to have Lynch syndrome based on family history and tumor testing. This testing should be offered routinely to patients with tumors demonstrating loss of MSH2/MSH6 staining.

// Chang Liu 1, 4 , Cathy Eng 1 , Jianjun Shen 3 , Yue Lu 3 , Yoko Takata 3 , Amir Mehdizadeh 1 , George J. Chang 2 , Miguel A. Rodriguez-Bigas 2 , Yanan Li 1 , Ping Chang 1 , Yixiang Mao 1 , Manal M. Hassan 1 , Fangyu Wang 4 , Donghui Li 1 1 Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA 2 Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA 3 Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, Texas, USA 4 Department of Gastroenterology and Hepatology, Jinling Hospital, Southern Medical University, Nanjing, China Correspondence to: Donghui Li, email: dli@mdanderson.org Fangyu Wang, email: wangfy65@nju.edu.cn Keywords: exosome, microRNA, colon cancer, qRT-PCR, Illumina RNA sequencing Received: April 22, 2016 Accepted: October 11, 2016 Published: October 24, 2016 ABSTRACT Purpose: The study was aimed to evaluate the prognostic or predictive value of serum exosomal microRNAs (miRNAs) for tumor recurrence and response to adjuvant therapy in stage II and stage III colon cancer. Results: 145 differentially expressed mature miRNAs were identified ( P

Background Although the safety of combination chemotherapy without primary tumor resection (PTR) in patients with stage IV colon cancer has been established, questions remain regarding a potential survival benefit with PTR. The objective of this study was to compare mortality rates in patients who had colon cancer with unresectable metastases who did and did not undergo PTR. Methods An observational cohort study was conducted among patients with unresectable metastatic colon cancer identified from the National Cancer Data Base (2003-2005). Multivariate Cox regression analyses with and without propensity score weighting (PSW) were performed to compare survival outcomes. Instrumental variable analysis, using the annual hospital-level PTR rate as the instrument, was used to account for treatment selection bias. To account for survivor treatment bias, in situations in which patients might die soon after diagnosis from different reasons, a landmark method was used. Results In the total cohort, 8641 of 15,154 patients (57%) underwent PTR, and 73.8% of those procedures (4972 of 6735) were at landmark. PTR was associated with a significant reduction in mortality using Cox regression (hazard ratio [HR], 0.45; 95% confidence interval [CI], 0.44-0.47) or PSW (HR, 0.46; 95% CI, 0. 44-0.49). However, instrumental variable analysis revealed a much smaller effect (relative mortality rate, 0.91; 95% CI, 0.87-0.96). Although a smaller benefit was observed with the landmark method using Cox regression (HR, 0.6; 95% CI, 0.55-0.64) and PSW (HR, 0.59; 95% CI, 0.54-0.64), instrumental variable analysis revealed no survival benefit (relative mortality rate, 0.97; 95% CI, 0.87-1.06). Conclusions Among patients with unresectable metastatic colon cancer, after adjustment for confounder effects, PTR was not associated with improved survival compared with systemic chemotherapy; therefore, routine noncurative PTR is not recommended. Cancer 2017;123:1124-1133. © 2016 American Cancer Society.

Colorectal cancer is the third most commonly diagnosed cancer in men and the second most common in women. Approximately 20 % of patients with colorectal cancer are found to have metastatic disease (stage IV) at the time of diagnosis. A multidisciplinary approach provides the best chance for a potentially curative option in selected patients with metastases, but in most patients, the metastases are unresectable. The treatment strategy for this entity is not fully established, especially regarding whether and when the primary tumor should be resected. In this manuscript, we review current evidence regarding approaches to the primary tumor in patients with unresectable synchronous metastases from colorectal cancer.

Constitutional mismatch repair deficiency syndrome (CMMRD) is a rare autosomal recessive predisposition to colorectal polyposis and other malignancies, often childhood-onset, that is caused by biallelic inheritance of mutations in the same mismatch repair gene. Here, we describe a patient with a clinical diagnosis of CMMRD based on colorectal polyposis and young-onset endometrial cancer who was identified to have two alterations in trans in PMS2: one known pathogenic mutation (c.1831insA; p.Ile611Asnfs*2) and one novel variant of uncertain significance (c.505C>G; p.Arg169Glu), a missense alteration. We describe the clinical and molecular features in the patient harboring this novel alteration c.505C>G, who meets clinical criteria for CMMRD and exhibits molecular evidence supporting a diagnosis of CMMRD. Although experimental validation is needed to confirm its pathogenicity, PMS2 c.505C>G likely has functional consequences that contributes to our patient's phenotype based on the patient's clinical presentation, tumor studies, and bioinformatics analysis.

Background The practice of salvaging recurrent rectal cancer has evolved. The aim of this study was to define the evolving salvage potential over time among patients with locally recurrent disease, and to identify durable determinants of long-term success. Methods The study included consecutive patients with recurrent rectal cancer undergoing multimodal salvage with curative intent between 1988 and 2012. Predictors of long-term survival were defined by Cox regression analysis and compared over time. Re-recurrence and subsequent treatments were evaluated. Results After multidisciplinary evaluation of 229 patients, salvage therapy with curative intent included preoperative chemotherapy and/or radiotherapy (73·4 per cent; with 41·3 per cent undergoing repeat pelvic irradiation), surgical salvage resection with or without intraoperative irradiation (36·2 per cent), followed by postoperative adjuvant chemotherapy (38·0 per cent). Multivisceral resection was undertaken in 47·2 per cent and bone resection in 29·7 per cent. The R0 resection rate was 80·3 per cent. After a median follow-up of 56·5 months, the 5-year overall survival rate was 50 per cent in 2005–2012, markedly increased from 32 per cent in 1988–1996 (P = 0·044). Long-term success was associated with R0 resection (P = 0·017) and lack of secondary failure (P = 0·003). Some 125 patients (54·6 per cent) developed further recurrence at a median of 19·4 months after salvage surgery. Repeat operative rescue was feasible in 21 of 48 patients with local re-recurrence alone and in 17 of 77 with distant re-recurrence, with a median survival of 19·8 months after further recurrence. Conclusion The long-term salvage potential for recurrent rectal cancer improved significantly over time, with the introduction of an individualized treatment algorithm of multimodal treatments and surgical salvage. Durable predictors of long-term success were R0 resection at salvage operation, avoidance of secondary failure, and feasibility of repeat rescue after re-recurrence.