Germline Cancer Risk Profiles of Patients With Young-Onset Colorectal Cancer: Findings From a Prospective Universal Germline Testing and Telegenetics Program.

BACKGROUND: Colorectal cancer is being increasingly diagnosed in people younger than 50 years. An inheritable cancer predisposition has been reported in 22% of the young-onset cases. Assessment of germline risk is critical for personalized cancer care. OBJECTIVE: The study aimed to implement universal germline cancer risk assessment and testing and to define the germline cancer risk profiles of patients presenting with young-onset disease. DESIGN: This is a prospective cohort study. SETTINGS: This study was conducted at a tertiary-referral academic medical center. PATIENTS: This study included newly diagnosed patients presenting to surgical clinics between September 2019 and February 2021 who were treated on a standardized care pathway including the universal germline risk assessment. INTERVENTIONS: Patients received educational material on young-onset disease, genetic testing, and insurance coverage followed by genetic counseling (either remotely by telegenetics or in person). Consenting patients were assessed on a 47-gene common hereditary cancer panel. MAIN OUTCOME MEASURES: The primary outcome was a proportion of patients with identifiable germline cancer predisposition. RESULTS: Among 500 patients with colorectal cancer, 185 (37%) were 50 years of age or younger (median: 44). A family history was absent for the majority of patients (123; 67%), and in 15 patients, tumors (8.1%) were deficient in DNA mismatch repair. 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 proficient mismatch repair colorectal cancers (versus 71% if deficient; p < 0.001). LIMITATIONS: The study is limited by its implementation at a single tertiary academic institution. CONCLUSIONS: One in 5 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, supports universal germline cancer risk assessment in this patient population. See Video Abstract at http://links.lww.com/DCR/B925 . PERFILES DE RIESGO DE CNCER DE LNEA GERMINAL DE PACIENTES CON CNCER COLORRECTAL DE INICIO JOVEN HALLAZGOS DE UN PROGRAMA UNIVERSAL PROSPECTIVO DE PRUEBAS DE LNEA GERMINAL Y TELEGENTICA: ANTECEDENTES:El cáncer colorrectal se diagnostica cada vez más en personas menores de 50 años. Se ha informado una predisposición hereditaria al cáncer en el 22 % de los casos de aparición temprana. La evaluación del riesgo de la línea germinal es fundamental para la atención personalizada del cáncer.OBJETIVO:Implementar la evaluación y las pruebas universales de riesgo de cáncer de línea germinal, y definir los perfiles de riesgo de cáncer de línea germinal de los pacientes que presentan una enfermedad de aparición temprana.DISEÑO:Un estudio de cohorte prospectivo.AJUSTE:Un centro médico académico de referencia terciaria.PACIENTES:Los pacientes recién diagnosticados que se presentaron en clínicas quirúrgicas entre Septiembre de 2019 y Febrero de 2021 fueron tratados en una vía de atención estandarizada que incluye una evaluación de riesgo de línea germinal universal.INTERVENCIÓN:Los pacientes recibieron material educativo sobre enfermedades de aparición temprana, pruebas genéticas y cobertura de seguro, seguido de asesoramiento genético (ya sea a distancia por telegenética o en persona). Los pacientes que dieron su consentimiento fueron evaluados en un panel de cánceres hereditarios comunes de 47 genes.MEDIDA DE RESULTADO PRINCIPAL:Proporción de pacientes con predisposición identificable al cáncer de línea germinal.RESULTADOS:Entre 500 pacientes con cáncer colorrectal, 185 (37%) tenían 50 años o menos (mediana: 44). No había antecedentes familiares en la mayoría (123, 67%) y 15 tumores (8,1%) eran deficientes en la reparación del desajuste de ácido desoxirribonucleico. La prueba de línea germinal se completó en 130 pacientes (70%); el resto estaban pendientes (7%), fallecidos (1%) o declinados (22%). Se identificaron mutaciones patogénicas de la línea germinal en 25 (de 130, 19%) pacientes: 12 en genes de reparación de errores de emparejamiento y 13 en otros genes. Se encontró una variante de significado incierto en 23 (18%) pacientes. Es importante señalar que se identificó una mutación germinal patogénica en el 12% de los pacientes sin antecedentes familiares (frente al 32% con; p = 0,015) y en el 13% de aquellos con cánceres colorrectales competentes en la reparación de errores de emparejamiento (frente al 71% si eran deficientes; p < 0,001).LIMITACIÓN:Implementado en una sola institución académica terciaria.CONCLUSIÓN:Uno de cada cinco pacientes con enfermedad de inicio joven albergaba predisposición al cáncer de línea germinal. Esta tasa de detección, junto con un alto nivel de interés y aceptación por parte de los pacientes y la viabilidad de la implementación, respaldan la evaluación universal del riesgo de cáncer de línea germinal en esta población de pacientes. Consulte el Video Resumen en http://links.lww.com/DCR/B925 . (Traducción-Dr. Yesenia Rojas-Khalil ).

High Rate of Positive Circumferential Resection Margin in Colon Cancer: A National Appraisal and Call for Action.

OBJECTIVE: To identify rates of positive circumferential resection margin (CRM) for colon cancer surgery in the US. SUMMARY BACKGROUND DATA: CRM is one of the most important determinants of local control in colorectal cancers. The extent to which CRM involvement exists after colon cancer surgery is unknown. METHODS: Colon cancer cases with resection 2010 to 2015 were identified from the National Cancer Data Base. Adjusting for patient and tumor characteristics, comparisons were made between cases with CRM > 1 mm (negative margin) and those with margin involved with tumor or ≤ 1 mm (positive margin, CRM+). Hospital-level analysis was performed, examining observed-to-expected CRM+ rates. RESULTS: In total, 170,022 cases were identified: 150,291 CRM- and 19,731 CRM+ (11.6%). Pathologic T-category was the greatest predictor of CRM+, with higher rates in pT4(25.8%), pT4A(24.7%), and pT4B(31.5%) versus pT1(4.5%), pT2(6.3%) and pT3 (10.9%, P < 0.001). Within pT4 patients, predictors of CRM+ included signet-ring histology (38.1% vs 26.7% nonmucinous, and 26.9% mucinous adenocarcinoma, P < 0.001), removing < 12 lymph nodes (36.5% vs 26.1% >12, P < 0.001), community facilities (32.7%) versus academic/research (23.6%, P < 0.001), year (30.1% 2010 vs 22.6% 2015, P < 0.001), and hospital volume (24.5% highest quartile vs 32.7% lowest, P < 0.001). Across 1288 hospitals, observed-to-expected ratios for CRM+ ranged from 0 to 7.899; 429 facilities had higher than expected rates. CONCLUSIONS: Overall rate of CRM+ in US colon cancer cases is high. Variation exists across hospitals, with higher than expected rates in many facilities. Although biology is a major influencing factor, CRM+ rates represent an area for multidisciplinary improvement in quality of colon cancer care.

Quality and Location of the Surgical Episode Mediate a Large Proportion of Socioeconomic-Based Survival Disparities in Patients with Resected Stage I-III Colon Cancer.

INTRODUCTION: 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. PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Is neoadjuvant therapy an alternative strategy to immediate surgery in locally perforated colon cancer?

BACKGROUND: Perforations are a rare but serious complication of colorectal cancer. The current standard of treatment is emergent surgery followed by adjuvant chemotherapy. The concern with this approach is not only the uncertainty of achieving a R0 resection but also potential injury to adjacent vessels, nerves and ureters due to inflamed tissue planes. A subset of this patient population with a contained perforation who are clinically stable may have superior oncological outcomes with local sepsis control, neoadjuvant therapy followed by radical resection. The aim of this study is to report on the pre-operative safety profile for neoadjuvant therapy in the setting of an abscess from colon cancer perforation and the short-term oncological surgical quality outcomes. METHODS: In this retrospective observational study, all consecutive perforated colon cancer receiving neoadjuvant therapy from Jan 2010 to Dec 2019 were included. RESULTS: There were 21 patients that met the inclusion criteria. The most common symptom at presentation was abdominal pain (71.4%) and most common site of perforation was sigmoid colon (61.9%). Local sepsis control was achieved with a combination of radiological or surgical drainage, diverting ostomy and/or intravenous antibiotics. Thirteen patients had long-course chemoradiation and eight patients had neoadjuvant chemotherapy. Of these, 13 (61.9%) had tumour regression, with one patient having a pathological complete response. All patients achieved a R0 resection. CONCLUSIONS: In a small subset of patients with colon cancer perforation, this study has demonstrated the potential safe usage of neoadjuvant therapy first before radical surgery to achieve a clear resection margin.

Neoadjuvant Pembrolizumab in Localized Microsatellite Instability High/Deficient Mismatch Repair Solid Tumors.

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.

Patients' Perspectives of Surgical Safety: Do They Feel Safe?

BACKGROUND: Increased focus on reducing patient harm has led to surgical safety initiatives, including time-out, surgical safety checklists, and debriefings. The perception of the lay public of the surgical safety process is largely unknown. METHODS: A 20-question survey focused on perceptions of surgical safety practice was distributed to a random sample of patients following elective operations requiring hospitalization. Responses were measured by a 7-point Likert scale. Qualitative feedback was obtained through nonphysician-moderated sessions. Participation was voluntary and anonymous. RESULTS: Surveys were distributed to 345 patients of whom 102 (29.5%) responded. Overall, patients felt safe as evidenced by scores for the questions "I felt safe the day of my surgery" (6.53 ± 0.72) and "Mistakes rarely happen during surgery" (5.39 ± 1.51). Patients undergoing their first surgery and patients with higher income levels were associated with a significant decrease in specific safety perceptions. Qualitative feedback sessions identified the physician-patient relationship as the most important factor positively influencing patient safety perceptions. CONCLUSION: Current surgical safety practice is perceived positively by our patients; however, patients still identify physician-patient interactions, relationships, and trust as the most positive factors influencing their perception of the safety environment.