Predicting Risk of Recurrence After Colorectal Cancer Surgery in the United States: An Analysis of a Special Commission on Cancer National Study.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. TRIAL REGISTRATION: ClinicalTrials.gov Registration Number: NCT02217865.

Association Between Intensity of Posttreatment Surveillance Testing and Detection of Recurrence in Patients With Colorectal Cancer.

Importance: Surveillance testing is performed after primary treatment for colorectal cancer (CRC), but it is unclear if the intensity of testing decreases time to detection of recurrence or affects patient survival. Objective: To determine if intensity of posttreatment surveillance is associated with time to detection of CRC recurrence, rate of recurrence, resection for recurrence, or overall survival. Design, Setting, and Participants: A retrospective cohort study of patient data abstracted from the medical record as part of a Commission on Cancer Special Study merged with records from the National Cancer Database. A random sample of patients (n=8529) diagnosed with stage I, II, or III CRC treated at a Commission on Cancer-accredited facilities (2006-2007) with follow-up through December 31, 2014. Exposures: Intensity of imaging and carcinoembryonic antigen (CEA) surveillance testing derived empirically at the facility level using the observed to expected ratio for surveillance testing during a 3-year observation period. Main Outcomes and Measures: The primary outcome was time to detection of CRC recurrence; secondary outcomes included rates of resection for recurrent disease and overall survival. Results: A total of 8529 patients (49% men; median age, 67 years) at 1175 facilities underwent surveillance imaging and CEA testing within 3 years after their initial CRC treatment. The cohort was distributed by stage as follows: stage I, 25.0%; stage II, 35.2%; and stage III, 39.8%. Patients treated at high-intensity facilities-4188 patients (49.1%) for imaging and 4136 (48.5%) for CEA testing-underwent a mean of 2.9 (95% CI, 2.8-2.9) imaging scans and a mean of 4.3 (95% CI, 4.2-4.4) CEA tests. Patients treated at low-intensity facilities-4341 patients (50.8%) for imaging and 4393 (51.5%) for CEA testing-underwent a mean of 1.6 (95% CI, 1.6-1.7) imaging scans and a mean of 1.6 (95% CI, 1.6-1.7) CEA tests. Imaging and CEA surveillance intensity were not associated with a significant difference in time to detection of cancer recurrence. The median time to detection of recurrence was 15.1 months (IQR, 8.2-26.3) for patients treated at facilities with high-intensity imaging surveillance and 16.0 months (IQR, 7.9-27.2) with low-intensity imaging surveillance (difference, -0.95 months; 95% CI, -2.59 to 0.68; HR, 0.99; 95% CI, 0.90-1.09) and was 15.9 months (IQR, 8.5-27.5) for patients treated at facilities with high-intensity CEA testing and 15.3 months (IQR, 7.9-25.7) with low-intensity CEA testing (difference, 0.59 months; 95% CI, -1.33 to 2.51; HR, 1.00; 95% CI, 0.90-1.11). No significant difference existed in rates of resection for cancer recurrence (HR for imaging, 1.22; 95% CI, 0.99-1.51 and HR for CEA testing, 1.12; 95% CI, 0.91-1.39) or overall survival (HR for imaging, 1.01; 95% CI, 0.94-1.08 and HR for CEA testing, 0.96; 95% CI, 0.89-1.03) among patients treated at facilities with high- vs low-intensity imaging or CEA testing surveillance. Conclusions and Relevance: Among patients treated for stage I, II, or III CRC, there was no significant association between surveillance intensity and detection of recurrence. Trial Registration: clinicaltrials.gov Identifier: NCT02217865.

Patients' information needs and attitudes about post-treatment surveillance for colorectal cancer in the United States: a multi-perspective, mixed methods study.

OBJECTIVE: We sought to determine patients' informational needs for post-treatment surveillance and elicit clinicians' and patient advocates' (ie, stakeholders) opinions regarding what patients should know about post-treatment surveillance in the USA. DESIGN: A mixed-methods study, using semi-structured interviews followed by a survey study. SETTING: Participants for the interviews were from two large academic medical centres and a safety-net hospital. The stakeholders were recruited from attendees at the Alliance for Clinical Trials in Oncology Network Spring 2016 meeting. PARTICIPANTS: Participants for the in-depth interviews were purposively sampled. Eligible patients were 6 months to 5 years post curative resection for colorectal cancer and were fluent in English. Participants for the anonymous survey were stakeholders. MAIN OUTCOMES AND MEASURES: The main outcome was patients' with colorectal cancer informational needs for post-treatment surveillance, using an interview guide. The second outcome was the importance of the identified informational needs using an anonymous survey. RESULTS: Of the 67 patients approached, 31 were interviewed (response rate=46%), the majority were between 1 and 3 years post-treatment (81%) and diagnosed at stage III (74%). Despite a desire to monitor for cancer recurrence, patients had little understanding of the concept of post-treatment surveillance, equating surveillance with screening and a belief that if a recurrence was found early there would be a higher likelihood of cure. The survey suggested that clinicians (n=38) and patient advocates (n=11) had some differing opinions regarding what patients should know about surveillance to be active in decisions. For example, compared with clinicians, patient advocates felt that patients should know recurrence treatment options (100% vs 58%) and likelihood for cure following recurrence treatment (100% vs 38%). CONCLUSIONS: The results of this exploratory mixed-methods study suggest that novel educational interventions targeting both patients and clinicians are needed to address the informational needs for post-treatment surveillance of colorectal cancer.

Clinical and Genetic Implications of DNA Mismatch Repair Deficiency in Biliary Tract Cancers Associated with Lynch Syndrome.

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.

Correction to: A systematic review of patient perspectives on surveillance after colorectal cancer treatment.

The original version of this article unfortunately contained a mistake. The online supplementary files are missing. The complete version of online supplementary materials are published with this erratum.

A systematic review of patient perspectives on surveillance after colorectal cancer treatment.

PURPOSE: Surveillance after colorectal cancer (CRC) treatment is routine, but intensive follow-up may offer little-to-no overall survival benefit. Given the growing population of CRC survivors, we aimed to systematically evaluate the literature for the patient perspective on two questions: (1) How do CRC patients perceive routine surveillance following curative treatment and what do they expect to gain from their surveillance testing or visits? (2) Which providers (specialists, nursing, primary care) are preferred by CRC survivors to guide post-treatment surveillance? METHODS: Systematic searches of PubMed MEDLINE, Embase, the CENTRAL Register of Controlled Trials, CINAHL, and PsycINFO were conducted. Studies were screened for inclusion by two reviewers, with discrepancies adjudicated by a third reviewer. Data were abstracted and evaluated utilizing validated reporting tools (CONSORT, STROBE, CASP) appropriate to study design. RESULTS: Citations (3691) were screened, 91 full-text articles reviewed, and 23 studies included in the final review: 15 quantitative and 8 qualitative. Overall, 12 studies indicated CRC patients perceive routine surveillance positively, expecting to gain reassurance of continued disease suppression. Negative perceptions described in six studies included anxiety and dissatisfaction related to quality of life or psychosocial issues during follow-up. Although 5 studies supported specialist-led care, 9 studies indicated patient willingness to have follow-up with non-specialist providers (primary care or nursing). CONCLUSIONS: Patients' perceptions of follow-up after CRC are predominantly positive, although unmet needs included psychosocial support and quality of life. IMPLICATIONS FOR CANCER SURVIVORS: Survivors perceived follow-up as reassuring, however, surveillance care should be more informative and focused on survivor-specific needs.

In Silico Systems Biology Analysis of Variants of Uncertain Significance in Lynch Syndrome Supports the Prioritization of Functional Molecular Validation.

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.

Can Microsatellite Status of Colorectal Cancer Be Reliably Assessed after Neoadjuvant Therapy?

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.

Identification of a novel PMS2 alteration c.505C>G (R169G) in trans with a PMS2 pathogenic mutation in a patient with constitutional mismatch repair deficiency.

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.

Role of microsatellite instability-low as a diagnostic biomarker of Lynch syndrome in colorectal cancer.

Lynch syndrome is the most common Mendelian disorder predisposing persons to hereditary colorectal cancer. Carriers of MSH6 mutations constitute less than 10% of the total of cases with Lynch syndrome and present with a weaker clinical phenotype, including low levels of microsatellite instability (MSI-L) in colorectal tumors. The frequency of MSH6 mutation carriers among patients presenting with MSI-L colorectal cancer has yet to be determined, as has the appropriate genetic workup in this context. We have reviewed here the clinicopathologic characteristics, immunohistochemistry, and genetic testing results for 71 patients at a single institution diagnosed with MSI-L colorectal cancers. Of 71 patients with MSI-L tumors, 21 underwent genetic testing for MSH6 mutations, three of whom presented with loss of staining of MSH6 and only one of whom carried a pathogenic germline MSH6 mutation in exon 4 (c.2677_2678delCT; p.Leu893Alafs*6). This latter patient had a significant family history of cancer and had a rectal primary tumor that showed instability only in mononucleotide markers. In this cohort of MSI-L patients, we detected no notable clinicopathologic or molecular characteristic that would help to distinguish a group most likely to harbor germline MSH6 mutations. Therefore, we conclude that the prevalence of MSH6 mutations among patients with MSI-L tumors is very low. Microsatellite instability analysis combined with immunohistochemistry of mismatch repair proteins adequately detects potential MSH6 mutation carriers among MSI-L colorectal cancers.