Gregg Nelson

POLE exonuclease domain mutation predicts long progression-free survival in grade 3 endometrioid carcinoma of the endometrium.

OBJECTIVE POLE exonuclease domain mutations were recently found to occur in a subset of endometrial carcinomas and result in defective proof-reading function during DNA replication. The aim of this study is to further characterize the clinical and pathologic significance of POLE exonuclease domain mutations in high-grade endometrial carcinomas. METHODS We assessed for mutations in the exonuclease domain of POLE by Sanger sequencing in 53 grade 3 endometrioid, 25 serous, 16 clear cell and 5 dedifferentiated carcinomas. We correlated POLE mutation status with clinicopathologic features and molecular parameters. Univariate and multivariate survival analyses were performed using Kaplan-Meier and cox regression analyses. RESULTS POLE exonuclease domain mutations were identified in 8 of 53 (15%) grade 3 endometrioid carcinomas and not in any other histotypes examined. Only 1 of the 8 grade 3 endometrioid carcinomas with POLE exonuclease domain mutation displayed deficient mismatch repair protein expression by immunohistochemistry (MSH6 loss), compared to 21 of 45 grade 3 endometrioid carcinomas with wild-type exonuclease domain. When analyzed together with published grade 3 endometrioid carcinomas by The Cancer Genome Atlas, the presence of POLE exonuclease domain mutation was associated with significantly better progression-free survival in univariate (p=0.025) and multivariate (p=0.010) analyses, such that none of the patients with POLE mutated tumors experienced disease progression CONCLUSIONS POLE exonuclease domain mutations occur in a subset of grade 3 endometrioid carcinomas and are associated with good clinical outcome. It can serve as an important prognostic molecular marker to guide the management of patients with grade 3 endometrioid carcinomas.

Guidelines for postoperative care in gynecologic/oncology surgery: Enhanced Recovery After Surgery (ERAS®) Society recommendations — Part II

Open Access article, to access on the publishers site, click on the Additional Link above. Open Access under a CC-BY-NC-DD 4.0 license

Prognostic role and implications of mutation status of tumor suppressor gene ARID1A in cancer: a systematic review and meta-analysis

Loss of the tumor suppressor gene AT-rich interactive domain-containing protein 1A (ARID1A) has been demonstrated in several cancers, but its prognostic role is unknown. We aimed to investigate the risk associated with loss of ARID1A (ARID1A−) for all-cause mortality, cancer-specific mortality and recurrence of disease in subjects with cancer. PubMed and SCOPUS search from database inception until 01/31/2015 without language restriction was conducted, contacting authors for unpublished data. Eligible were prospective studies reporting data on prognostic parameters in subjects with cancer, comparing participants with presence of ARID1A (ARID1A+) vs. ARID1A−, assessed either via immunohistochemistry (loss of expression) or with genetic testing (presence of mutation). Data were summarized using risk ratios (RR) for number of deaths/recurrences and hazard ratios (HR) for time-dependent risk related to ARID1A− adjusted for potential confounders. Of 136 hits, 25 studies with 5,651 participants (28 cohorts; ARID1A−: n = 1,701; ARID1A+: n = 3,950), with a mean follow-up period of 4.7 ± 1.8 years, were meta-analyzed. Compared to ARID1A+, ARID1A− significantly increased cancer-specific mortality (studies = 3; RR = 1.55, 95% confidence interval (CI) = 1.19–2.00, I2 = 31%). Using HRs adjusted for potential confounders, ARID1A− was associated with a greater risk of cancer-specific mortality (studies = 2; HR = 2.55, 95%CI = 1.19–5.45, I2 = 19%) and cancer recurrence (studies = 10; HR = 1.93, 95%CI = 1.22–3.05, I2 = 76%). On the basis of these results, we have demonstrated that loss of ARID1A shortened time to cancer-specific mortality, and to recurrence of cancer when adjusting for potential confounders. For its role, this gene should be considered as an important potential target for personalized medicine in cancer treatment.

MMR deficiency is common in high-grade endometrioid carcinomas and is associated with an unfavorable outcome

OBJECTIVE To assess the prevalence of MMR deficiency (dMMR) in contemporary reclassified high-grade endometrial carcinomas and correlate dMMR with molecular alterations and patient outcome. METHODS In this study we evaluated the expression of MLH1, MSH2, PMS2 and MSH6 assessed by two different methods in a series of 102 high-grade endometrial carcinomas. The series was comprised of 64 high-grade endometrioid carcinomas (HGEC), 27 serous (ESC), and 11 clear cell (CCC) carcinomas. Absence of expression in any of the proteins was considered dMMR. dMMR was correlated with clinicopathological parameters using a Chi-square test. Univariate and multivariate survival analysis was performed using Kaplan-Meier and Cox regression analyses. RESULTS The overall prevalence of dMMR was 28% (29/102) and was seen in 29/64 (45%) HGEC but not detected in any of the ESC and CCC. Within HGEC, dMMR was associated with loss of ARID1A (p=0.0099), loss of PTEN (p=0.044) and wild-type TP53 (p=0.024) expression. dMMR was associated with increased risk for disease specific death by univariate analysis (p=0.013) among stage III/IV HGEC but not in multivariate analysis (p=0.12). CONCLUSIONS Among high-grade endometrial carcinomas, dMMR is restricted to HGEC and could be used as an adjunct diagnostic tool to refute a diagnosis of ESC. The association with dMMR in HGEC with ARID1A/PTEN alterations, TP53 wild type expression pattern and unfavorable outcome suggests that different oncogenetic pathways within HGEC are present.

Quantification of ER/PR expression in ovarian low-grade serous carcinoma

OBJECTIVE Case reports suggest that hormonal therapy may be a useful treatment option for low-grade serous carcinomas (LGSC) but the clinical value remains uncertain. We hypothesized that LGSCs show a constitutive high hormone receptor expression and that type diagnosis may be sufficient to initiate hormonal therapy. METHODS We assessed ER and PR expression on 27 LGSC, 69 high-grade serous carcinomas (HGSC), 36 serous borderline tumors (SBOT), and five normal fallopian tubes using three different platforms/antibodies on tissue microarrays. Staining from the Leica Bond Max and DAKO PharmDx platforms was evaluated using the Allred score. Quantitative fluorescence immunohistochemistry was performed using the HistoRx AQUAnalysis platform. A second cohort of 12 LGSC and 183 HGSC was assessed using the HistoRx AQUAnalysis platform. Welch ANOVA or Fishers Exact Test was used to compare differences in the histological types for each platform. Nonparametric bivariate density plots were used to graphically demonstrate the relationship between ER and PR for the various histological types. RESULTS LGSC have higher ER and PR expression compared to HGSC but significantly less than FT and SBOT. Nonparametric bivariate density revealed two populations of LGSC: one fifth of LGSC are ER high/PR high expressers similar to SBOT but the majority show low ER/PR expression more like HGSC. CONCLUSIONS Quantitative assessment of ER/PR expression using the HistoRx AQUAnalysis platform may be useful as a predictive diagnostic for hormonal therapy in LGSC, assuming that only the fraction of double high expressers benefit from hormonal treatment.

The diagnostic utility of TP53 and CDKN2A to distinguish ovarian high-grade serous carcinoma from low-grade serous ovarian tumors

Low-grade serous carcinomas and serous borderline tumors, combined herein and referred to as low-grade serous tumors, show distinct molecular alterations and clinical behaviors compared with high-grade serous carcinomas. The discrimination between low-grade serous tumors and high-grade serous carcinomas can be challenging on small tissue samples, such as cell blocks of paracentesis fluid or biopsies from omental disease. The purpose of this study was to test the ability of TP53 and CDKN2A immunohistochemistry to distinguish between high-grade serous carcinomas and low-grade serous tumors on small tissue samples. Tissue microarrays containing 582 high-grade serous carcinomas, 45 low-grade serous carcinomas, and 49 serous borderline tumors, confirmed by contemporary histopathological review, were stained for TP53 and CDKN2A (DO7 and E6H4 antibody clones, respectively). TP53 was scored as completely absent, wild-type pattern or overexpressed (>60%), and CDKN2A was scored as either negative/patchy (<90%) or block expression (>90%). The combination of the two markers, ie, the TP53 wild-type pattern and CDKN2A patchy expression, had sensitivity for low-grade serous tumors of 89%, a specificity of 93%, a positive predictive value of 68%, and a negative predictive value of 98%. These markers can, therefore, be used on small biopsies/cell blocks to refute a diagnosis of low-grade serous tumors. These findings may inform emerging neoadjuvant therapeutic strategies in advanced ovarian cancers and may be crucial for future clinical trials on molecular-based therapies.

Evidence for a time-dependent association between FOLR1 expression and survival from ovarian carcinoma: implications for clinical testing. An Ovarian Tumour Tissue Analysis consortium study

Background:Folate receptor 1 (FOLR1) is expressed in the majority of ovarian carcinomas (OvCa), making it an attractive target for therapy. However, clinical trials testing anti-FOLR1 therapies in OvCa show mixed results and require better understanding of the prognostic relevance of FOLR1 expression. We conducted a large study evaluating FOLR1 expression with survival in different histological types of OvCa.Methods:Tissue microarrays composed of tumour samples from 2801 patients in the Ovarian Tumour Tissue Analysis (OTTA) consortium were assessed for FOLR1 expression by centralised immunohistochemistry. We estimated associations for overall (OS) and progression-free (PFS) survival using adjusted Cox regression models. High-grade serous ovarian carcinomas (HGSC) from The Cancer Genome Atlas (TCGA) were evaluated independently for association between FOLR1 mRNA upregulation and survival.Results:FOLR1 expression ranged from 76% in HGSC to 11% in mucinous carcinomas in OTTA. For HGSC, the association between FOLR1 expression and OS changed significantly during the years following diagnosis in OTTA (Pinteraction=0.01, N=1422) and TCGA (Pinteraction=0.01, N=485). In OTTA, particularly for FIGO stage I/II tumours, patients with FOLR1-positive HGSC showed increased OS during the first 2 years only (hazard ratio=0.44, 95% confidence interval=0.20–0.96) and patients with FOLR1-positive clear cell carcinomas (CCC) showed decreased PFS independent of follow-up time (HR=1.89, 95% CI=1.10–3.25, N=259). In TCGA, FOLR1 mRNA upregulation in HGSC was also associated with increased OS during the first 2 years following diagnosis irrespective of tumour stage (HR: 0.48, 95% CI: 0.25–0.94).Conclusions:FOLR1-positive HGSC tumours were associated with an increased OS in the first 2 years following diagnosis. Patients with FOLR1-negative, poor prognosis HGSC would be unlikely to benefit from anti-FOLR1 therapies. In contrast, a decreased PFS interval was observed for FOLR1-positive CCC. The clinical efficacy of FOLR1-targeted interventions should therefore be evaluated according to histology, stage and time following diagnosis.

Uterine sarcoma and aromatase inhibitors: Tom Baker Cancer Centre experience and review of the literature.

Objectives Uterine sarcomas are a rare group of mesenchymal tumors with a poor prognosis and aggressive biology. Standard treatment involves surgical staging. The role of further adjuvant treatment is unclear. The goals of this study were to determine the response rates to treatment of patients with uterine sarcomas and to review the currently available literature on the use of aromatase inhibitors (AIs). Materials and Methods We performed a retrospective analysis on all patients with uterine sarcoma treated with an AI between 2000 and 2010 at the Tom Baker Cancer Centre in Calgary, Alberta. Results Four patients with endometrial stromal sarcoma and 3 patients with leiomyosarcoma received treatment with an AI. A literature search resulted in 10 case reports and 4 retrospective studies of patients with endometrial stromal sarcoma and 1 case report and 2 retrospective studies of patients with leiomyosarcoma. On the basis of the available literature, combined with the current findings, the overall response rate of endometrial stromal sarcoma to AIs is 67% (complete response of 7% and partial response of 60%), and the partial response rate of leiomyosarcoma to AIs is 11%, with no reported complete responses. Conclusions Aromatase inhibitors are a well-tolerated class of medications that are effective in the treatment of endometrial stromal sarcomas. These medications may also have a role to help stabilize disease progression in the treatment of leiomyosarcoma. More large, prospective, multicentered trials will be needed to clarify this issue.

An economic evaluation of the Enhanced Recovery After Surgery (ERAS) multisite implementation program for colorectal surgery in Alberta

BACKGROUND In February 2013, Alberta Health Services established an Enhanced Recovery After Surgery (ERAS) implementation program for adopting the ERAS Society colorectal guidelines into 6 sites (initial phase) that perform more than 75% of all colorectal surgeries in the province. We conducted an economic evaluation of this initiative to not only determine its cost-effectiveness, but also to inform strategy for the spread and scale of ERAS to other surgical protocols and sites. METHODS We assessed the impact of ERAS on patients’ health services utilization (HSU; length of stay [LOS], readmissions, emergency department visits, general practitioner and specialist visits) within 30 days of discharge by comparing pre- and post-ERAS groups using multilevel negative binomial regressions. We estimated the net health care costs/savings and the return on investment (ROI) associated with those impacts for post-ERAS patients using a decision analytic modelling technique. RESULTS We included 331 pre- and 1295 post-ERAS patients in our analyses. ERAS was associated with a reduction in all HSU outcomes except visits to specialists. However, only the reduction in primary LOS was significant. The net health system savings were estimated at

Dose-Response Association of CD8+ Tumor-Infiltrating Lymphocytes and Survival Time in High-Grade Serous Ovarian Cancer.

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