Amanda Cuddy

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.

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.

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

PurposeSurveillance 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?MethodsSystematic 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.ResultsCitations (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).ConclusionsPatients’ 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.

Clinical and Genetic Implications of DNA Mismatch Repair Deficiency in Patients With Pancreatic Ductal Adenocarcinoma

This cohort study examines the behavior and outcomes of deficient DNA mismatch repair in patients at elevated risk for malignant neoplasms, including pancreatic ductal adenocarcinoma.

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.

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.

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

Surveillance imaging following colon cancer resection: Universal or risk-based?

307 Background: Current colon cancer surveillance guidelines recommend annual imaging for all patients following curative resection. The primary aim of this study is to evaluate variation in surveillance practices following colon cancer resection. METHODS A retrospective cohort study of patients ≥ 66 years old with stage I-III colon cancer that underwent surgical resection in the Surveillance, Epidemiology, and End Results-Medicare linked database (July 2001 through December 2007) with at least 3 years of follow-up was performed. Medicare claims for PET and CT scan of the chest, abdomen and pelvis performed after surgical resection were recorded and analyzed. In order to evaluate the use of definitive treatment (DT) for presumed recurrent disease, we identified patients who had undergone lung, liver, or colorectal resection during follow-up. RESULTS Of 22,544 patients who underwent primary resection of colon cancer, 13,753 (61.0%) underwent PET and/or CT after resection and 1,109 (4.52%) underwent at least 1 DT. The mean number of imaging performed for patients who did not undergo DT was 1.68. Within this group, the utilization of PET and/or CT varied by stage, with 14.1%, 22.4%, and 42.2% of patients with stage I, II, and III disease undergoing imaging, respectively. The most significant factor associated with PET and/or CT was tumor stage with an odds ratio of 1.86 (95% CI 1.70-2.02, P<0.001) for stage II disease and 4.56 (95% CI 4.17-4.99, P<0.001) for stage III disease compared to stage I disease. Additional factors significantly associated with PET and/or CT included year of diagnosis and SEER region. Among patients who did undergo DT, the mean number of PET and/or CT performed was 5.37 but the majority of imaging studies were performed 4 months prior to DT (mean 2.95). CONCLUSIONS There is a high degree of variation in the use of surveillance imaging among elderly patients with localized colon cancer although some of this variation appears to be associated with stage at presentation. Our findings highlight discordance between clinical practice and surveillance guidelines. Further study is needed to understand the basis and appropriateness of clinical decision making that departs from guideline-based care.

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.

How are colorectal cancer (CRC) patients treated following cancer recurrence during follow-up?

645 Background: A major goal of surveillance following curative resection for CRC is identification of treatable recurrence. However, there is a paucity of data regarding optimal frequency or duration of surveillance or potential for salvage therapy following detection of recurrence. The aim of this study was to examine treatment patterns following recurrence of CRC. Methods: Patients ≥ 18 years who presented to 8 participating NCCN institutions between 2005-2012 with resected stage I, II, or III CRC were identified. Time to recurrence was determined by the Kaplan-Meier method and descriptive statistics were used to report treatments following recurrence. Results: Of 5653 patients who underwent resection for locoregional CRC (2984 colon, 2669 rectal and rectosigmoid), median age was 60 [IQR: 50-70]. 53.5% were male. With a median follow-up time after diagnosis of 23.5 months (11.0-45.2), 641 recurrences (6.9% local; 93.1% distant) were identified. Median time to local recurrence was 16.1 months [IQR: 12.5...