Publications by authors named "Marcus Q Bernardini"

82 Publications

Maximizing cancer prevention through genetic navigation for Lynch syndrome detection in women with newly diagnosed endometrial and nonserous/nonmucinous epithelial ovarian cancer.

Cancer 2021 May 13. Epub 2021 May 13.

Division of Gynecologic Oncology, Princess Margaret Cancer Centre/University Health Network/Sinai Health Systems, Toronto, Ontario, Canada.

Background: Despite recommendations for reflex immunohistochemistry (IHC) for mismatch repair (MMR) proteins to identify Lynch syndrome (LS), the uptake of genetic assessment by those who meet referral criteria is low. The authors implemented a comprehensive genetic navigation program to increase the uptake of genetic testing for LS in patients with endometrial cancer (EC) or nonserous/nonmucinous ovarian cancer (OC).

Methods: Participants with newly diagnosed EC or OC were prospectively recruited from 3 cancer centers in Ontario, Canada. Family history questionnaires were used to assess LS-specific family history. Reflex IHC for MMR proteins was performed with the inclusion of clinical directives in pathology reports. A trained genetic navigator initiated a genetic referral on behalf of the treating physician and facilitated genetic referrals to the closest genetics center.

Results: A total of 841 participants (642 with EC, 172 with OC, and 27 with synchronous EC/OC) consented to the study; 194 (23%) were MMR-deficient by IHC. Overall, 170 women (20%) were eligible for a genetic assessment for LS: 35 on the basis of their family history alone, 24 on the basis of their family history and IHC, 82 on the basis of IHC alone, and 29 on the basis of clinical discretion. After adjustments for participants who died (n = 6), 149 of 164 patients (91%) completed a genetic assessment, and 111 were offered and completed genetic testing. Thirty-four women (4.0% of the total cohort and 30.6% of those with genetic testing) were diagnosed with LS: 5 with mutL homolog 1 (MLH1), 9 with mutS homolog 2 (MSH2), 15 with mutS homolog 6 (MSH6), and 5 with PMS2.

Conclusions: The introduction of a navigated genetic program resulted in a high rate of genetic assessment (>90%) in patients with gynecologic cancer at risk for LS.
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http://dx.doi.org/10.1002/cncr.33625DOI Listing
May 2021

Gynecologic oncology treatment modifications or delays in response to the COVID-19 pandemic in a publicly funded versus privately funded North American tertiary cancer center.

Gynecol Oncol 2021 Apr 28. Epub 2021 Apr 28.

Division of Gynecologic Oncology, Department of Surgical Oncology, Princess Margaret Cancer Center, University of Toronto, Toronto, ON, Canada; Department of Obstetrics and Gynecology, University of Toronto, Toronto, ON, Canada. Electronic address:

Objective: To compare gynecologic oncology surgical treatment modifications and delays during the first wave of the COVID-19 pandemic between a publicly funded Canadian versus a privately funded American cancer center.

Methods: This is a retrospective cohort study of all planned gynecologic oncology surgeries at University Health Network (UHN) in Toronto, Canada and Brigham and Women's Hospital (BWH) in Boston, USA, between March 22,020 and July 302,020. Surgical treatment delays and modifications at both centers were compared to standard recommendations. Multivariable logistic regression was performed to adjust for confounders.

Results: A total of 450 surgical gynecologic oncology patients were included; 215 at UHN and 235 at BWH. There was a significant difference in median time from decision-to-treat to treatment (23 vs 15 days, p < 0.01) between UHN and BWH and a significant difference in treatment delays (32.56% vs 18.29%; p < 0.01) and modifications (8.37% vs 0.85%; p < 0.01), respectively. On multivariable analysis adjusting for age, race, treatment site and surgical priority status, treatment at UHN was an independent predictor of treatment modification (OR = 9.43,95% CI 1.81-49.05, p < 0.01). Treatment delays were higher at UHN (OR = 1.96,95% CI 1.14-3.36 p = 0.03) and for uterine disease (OR = 2.43, 95% CI 1.11-5.33, p = 0.03).

Conclusion: During the first wave of COVID-19 pandemic, gynecologic oncology patients treated at a publicly funded Canadian center were 9.43 times more likely to have a surgical treatment modification and 1.96 times more likely to have a surgical delay compared to an equal volume privately funded center in the United States.
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http://dx.doi.org/10.1016/j.ygyno.2021.04.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8080163PMC
April 2021

The Prevent Ovarian Cancer Program (POCP): Identification of women at risk for ovarian cancer using complementary recruitment approaches.

Gynecol Oncol 2021 Apr 13. Epub 2021 Apr 13.

Gynecologic Oncology, The University Health Network, Toronto, Canada; Department of Obstetrics and Gynecology, University of Toronto, Toronto, Canada. Electronic address:

Background: Up to 20% of high-grade serous ovarian carcinomas (HGSOC) are hereditary; however, historical uptake of genetic testing is low. We used a unique combination of approaches to identify women in Ontario, Canada, with a first-degree relative (FDR) who died from HGSOC without prior genetic testing, and offer them multi-gene panel testing.

Methods: From May 2015-Sept 2019, genetic counseling and testing was provided to eligible participants. Two recruitment strategies were employed, including self-identification in response to an outreach campaign and direct targeting of FDRs of deceased HGSOC patients treated at our institution. The rate of pathogenic variants (PV) in established/potential ovarian cancer risk genes and the benefits/challenges of each approach were assessed.

Results: A total of 564 women enrolled in response to our outreach campaign (n = 473) or direct recruitment (n = 91). Mean age at consent was 52 years and 96% did not meet provincial testing criteria. Genetic results were provided to 528 individuals from 458 families. The rate of PVs in ovarian cancer risk genes was highest when FDRs were diagnosed with HGSOC <60 years (9.4% vs. 3.9% ≥ 60y, p = 0.0160). Participants in the outreach vs. direct recruitment cohort had a similar rate of PVs; however, uptake of genetic testing (97% vs. 89%; p = 0.0036) and study completion (95% vs. 87%; p = 0.0062) rates were higher in the former. Eleven participants with pathogenic variants have completed risk-reducing gynecologic surgery, with one stage I HGSOC and two breast cancers identified.

Conclusion: Overall PV rates in this large cohort were lower than expected; however, we provide evidence that genetic testing criteria in Ontario should include individuals with a deceased FDR diagnosed with HGSOC <60 years of age.
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http://dx.doi.org/10.1016/j.ygyno.2021.04.011DOI Listing
April 2021

Evaluation of treatment effects in patients with endometrial cancer and POLE mutations: An individual patient data meta-analysis.

Cancer 2021 Apr 1. Epub 2021 Apr 1.

Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, British Columbia, Canada.

Background: Endometrial cancers (ECs) with somatic mutations in DNA polymerase epsilon (POLE) are characterized by unfavorable pathological features, which prompt adjuvant treatment. Paradoxically, women with POLE-mutated EC have outstanding clinical outcomes, and this raises concerns of overtreatment. The authors investigated whether favorable outcomes were independent of treatment.

Methods: A PubMed search for POLE and endometrial was restricted to articles published between March 1, 2012, and March 1, 2018, that provided individual patient data (IPD), adjuvant treatment, and survival. Following the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) reporting guidelines for IPD, the authors used univariate and multivariate one-stage meta-analyses with mixed effects Cox models (random effects for study cohorts) to infer the associations of treatment, traditional prognostic factors, and outcome, which was defined as the time from first diagnosis to any adverse event (progression/recurrence or death from EC).

Results: Three hundred fifty-nine women with POLE-mutated EC were identified; 294 (82%) had pathogenic mutations. Worse outcomes were demonstrated in patients with nonpathogenic POLE mutations (hazard ratio, 3.42; 95% confidence interval, 1.47-7.58; log-rank P < .01). Except for stage (P < .01), traditional prognosticators were not associated with progression/recurrence or death from disease. Adverse events were rare (11 progressions/recurrences and 3 disease-specific deaths). Salvage rates in patients who experienced recurrence were high and sustained, with 8 of 11 alive without evidence of disease (range, 5.5-14.2 years). Adjuvant treatment was not associated with outcome.

Conclusions: Clinical outcomes for ECs with pathogenic POLE mutations are not associated with most traditional risk parameters, and patients do not appear to benefit from adjuvant therapy. The observed low rates of recurrence/progression and the high and sustained salvage rates raise the possibility of safely de-escalating treatment for these patients.

Lay Summary: Ten percent of all endometrial cancers have mutations in the DNA repair gene DNA polymerase epsilon (POLE). Women who have endometrial cancers with true POLE mutations experience almost no recurrences or deaths from their cancer even when their tumors appear to have very unfavorable characteristics. Additional therapy (radiation and chemotherapy) does not appear to improve outcomes for women with POLE-mutated endometrial cancer, and this supports the move to less therapy and less associated toxicity. Diligent classification of endometrial cancers by molecular features provides valuable information to inform prognosis and to direct treatment/no treatment.
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http://dx.doi.org/10.1002/cncr.33516DOI Listing
April 2021

Understanding the clinical implication of mismatch repair deficiency in endometrioid endometrial cancer through a prospective study.

Gynecol Oncol 2021 Apr 19;161(1):221-227. Epub 2021 Jan 19.

Division of Gynecologic Oncology, Princess Margaret Cancer Centre, University Health Network/Sinai Health Systems, Toronto, Ontario, Canada; Department of Obstetrics and Gynaecology, University of Toronto, Toronto, Canada; Zane Cohen Centre for Digestive Diseases, Familial Gastrointestinal Cancer Registry, Mount Sinai Hospital, Toronto, Ontario, Canada. Electronic address:

Objectives: Findings on impact of mismatch repair deficiency (MMRd) on patient outcomes in endometrial cancer (EC) have been inconsistent to date. The objective of this study was to compare the oncologic outcomes and recurrence patterns between MMRd and MMR-intact (MMRi) endometrioid EC (EEC).

Methods: Between 2015 and 2018, we prospectively recruited 492 EEC cases from three cancer centers in Ontario, Canada. Tumors were reflexively assessed for MMR protein expression by immunohistochemistry (IHC). Clinicopathological, survival and recurrence patterns were compared between MMRd and MMRi cases.

Results: Of 492 EEC, 348 were MMRi (71%) and 144 were MMRd (29%) with median follow-up of 16.8 months (0-69.6). MMRd tumors tended to be grade 2 or 3 (56% vs. 29%, p < 0.001), with propensity for lymphovascular space invasion (28% vs. 18%, p = 0.024), lymph node involvement (7% vs. 5%, p < 0.001) and received more adjuvant treatment (46% vs. 33%, p = 0.027). This group also had significantly lower 3-year recurrence-free survival (78% vs. 90%, p = 0.014) although there was no difference in OS (p = 0.603). MMRd cases were more likely to recur in retroperitoneal lymph nodes (p = 0.045). Upon subgroup analysis, MLH1 methylated tumors had the worst prognostic features and survival outcomes.

Conclusions: MLH1 methylated EECs exhibit more aggressive features compared to other MMRd and MMRi EECs. This may indicate an inherent difference in tumor biology, suggesting the importance of individualized management based on EC molecular phenotype.
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http://dx.doi.org/10.1016/j.ygyno.2021.01.002DOI Listing
April 2021

Risk of second malignancy in patients with ovarian clear cell carcinoma.

Int J Gynecol Cancer 2021 Apr 18;31(4):545-552. Epub 2020 Dec 18.

Gynecologic Oncology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada.

Objective: Ovarian clear cell carcinoma has unique clinical and molecular features compared with other epithelial ovarian cancer histologies. Our objective was to describe the incidence of second primary malignancy in patients with ovarian clear cell carcinoma.

Methods: Retrospective cohort study of patients with ovarian clear cell carcinoma at two tertiary academic centers in Toronto, Canada between May 1995 and June 2017. Demographic, histopathologic, treatment, and survival details were obtained from chart review and a provincial cancer registry. We excluded patients with histologies other than pure ovarian clear cell carcinoma (such as mixed clear cell histology), and those who did not have their post-operative follow-up at these institutions.

Results: Of 209 patients with ovarian clear cell carcinoma, 54 patients developed a second primary malignancy (25.8%), of whom six developed two second primary malignancies. Second primary malignancies included: breast (13), skin (9), gastrointestinal tract (9), other gynecologic malignancies (8), thyroid (6), lymphoma (3), head and neck (4), urologic (4), and lung (4). Eighteen second primary malignancies occurred before the index ovarian clear cell carcinoma, 35 after ovarian clear cell carcinoma, and 7 were diagnosed concurrently. Two patients with second primary malignancies were diagnosed with Lynch syndrome. Smoking and radiation therapy were associated with an increased risk of second primary malignancy on multivariable analysis (OR 3.69, 95% CI 1.54 to 9.07, p=0.004; OR 4.39, 95% CI 1.88 to 10.6, p=0.0008, respectively). However, for patients developing second primary malignancies after ovarian clear cell carcinoma, radiation therapy was not found to be a significant risk factor (p=0.17). There was no significant difference in progression-free survival (p=0.85) or overall survival (p=0.38) between those with second primary malignancy and those without.

Conclusion: Patients with ovarian clear cell carcinoma are at increased risk of second primary malignancies, most frequently non-Lynch related. A subset of patients with ovarian clear cell carcinoma may harbor mutations rendering them susceptible to second primary malignancies. Our results may have implications for counseling and consideration for second primary malignancy screening.
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http://dx.doi.org/10.1136/ijgc-2020-001946DOI Listing
April 2021

Does Radical Hysterectomy for Clinically Apparent Stage II Endometrial Cancer Affect Risk of Local Recurrence?

J Obstet Gynaecol Can 2021 May 4;43(5):564-570. Epub 2021 Jan 4.

Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University of Toronto, Toronto, ON; Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, ON.

Objective: Compare recurrence-free survival (RFS) and morbidity between radical hysterectomy (RH) and simple hysterectomy (SH) for clinically diagnosed stage II endometrial cancer.

Methods: A multicentre, retrospective study, from 2000 to 2015, involving patients with endometrial cancer with cervical involvement preoperatively and stromal invasion on final pathology. Wilcoxon rank-sum test, Fisher exact test, Kaplan-Meier survival functions, and Cox proportional hazards models were used for analysis.

Results: Ninety of 1613 patients had clinical stage II endometrial cancer; 57 underwent RH and 33 underwent SH, with no difference in adjuvant treatment or morbidity. About half of patients (51%) had pathologic stage III-IV disease. Mean follow-up was 3.3 and 3.8 years for SH and RH, respectively. Thirty-three percent of patients with RH and SH experienced a recurrence. Most recurrences were distant: 90% with SH and 79% with RH. There was no difference in RFS between groups (2-year: SH 65% vs. RH 75%; 5-year: SH 54% vs. RH 63%; P = 0.72). Controlling for stage, adjuvant treatment, and margin status, RH was not associated with RFS (HR 0.62; 95% CI 0.28-1.35). Among 44 patients with pathologic stage II disease, 7 had a recurrence (4 SH and 3 RH); 6 of 7 had distant recurrences.

Conclusions: Fifty-one percent of patients with clinical stage II endometrial cancer had advanced disease on final pathology, highlighting the importance of surgical staging. RH was not associated with RFS or reduced morbidity. Most recurrences were distant. Although RH could be performed to achieve negative surgical margins, SH may be sufficient for central, small tumours given the high risk of advanced disease and distant recurrence. Research efforts should further elucidate the ideal management of these patients.
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http://dx.doi.org/10.1016/j.jogc.2020.12.017DOI Listing
May 2021

The impacts of neoadjuvant chemotherapy and of cytoreductive surgery on 10-year survival from advanced ovarian cancer.

Int J Gynaecol Obstet 2021 Jun 13;153(3):417-423. Epub 2021 Jan 13.

Division of Gynecologic Oncology, Princess Margaret Cancer Center, University Health Networks, Toronto, ON, Canada.

Objective: To compare the long-term survival outcomes for women with advanced ovarian cancer treated with chemotherapy either before or after surgery (neoadjuvant chemotherapy vs primary cytoreductive surgery) at a single tertiary cancer center.

Methods: Retrospective cohort study of 326 patients with Stage IIIC or IV high-grade serous ovarian cancer who received neoadjuvant chemotherapy or primary cytoreductive surgery between 2001 and 2011. Clinical treatments were recorded and 10-year survival rates were measured.

Results: A total of 183 women (56.1%) underwent primary cytoreductive surgery and 143 women (43.9%) received neoadjuvant chemotherapy. Women who received neoadjuvant chemotherapy were more likely to have no residual disease than those who underwent primary cytoreductive surgery (51.4% vs 41.5%; P = 0.030) but experienced inferior 10-year overall survival (9.1% vs 19.3%; P < 0.001). Among those who had primary cytoreductive surgery, those with no residual disease had superior 10-year overall survival than those who had any evidence of residual disease (36.0% vs 7.2%; P < 0.001).

Conclusion: Among women with advanced ovarian cancer, those who underwent primary cytoreductive surgery had better survival than those who received neoadjuvant chemotherapy. Neoadjuvant chemotherapy should be reserved for those in whom optimal primary cytoreductive surgery is not feasible.
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http://dx.doi.org/10.1002/ijgo.13542DOI Listing
June 2021

Assessment of Sentinel Lymph Node Biopsy vs Lymphadenectomy for Intermediate- and High-Grade Endometrial Cancer Staging.

JAMA Surg 2021 Feb;156(2):157-164

Department of Obstetrics and Gynaecology, University of Toronto, Toronto, Ontario, Canada.

Importance: Whether sentinel lymph node biopsy (SLNB) can replace lymphadenectomy for surgical staging in patients with high-grade endometrial cancer (EC) is unclear.

Objective: To examine the diagnostic accuracy of, performance characteristics of, and morbidity associated with SLNB using indocyanine green in patients with intermediate- and high-grade EC.

Design, Setting, And Participants: In this prospective, multicenter cohort study (Sentinel Lymph Node Biopsy vs Lymphadenectomy for Intermediate- and High-Grade Endometrial Cancer Staging [SENTOR] study), accrual occurred from July 1, 2015, to June 30, 2019, with early stoppage because of prespecified accuracy criteria. The study included patients with clinical stage I grade 2 endometrioid or high-grade EC scheduled to undergo laparoscopic or robotic hysterectomy with an intent to complete staging at 3 designated cancer centers in Toronto, Ontario, Canada.

Exposures: All patients underwent SLNB followed by lymphadenectomy as the reference standard. Patients with grade 2 endometrioid EC underwent pelvic lymphadenectomy (PLND) alone, and patients with high-grade EC underwent PLND and para-aortic lymphadenectomy (PALND).

Main Outcomes And Measures: The primary outcome was sensitivity of the SLNB algorithm. Secondary outcomes were additional measures of diagnostic accuracy, sentinel lymph node detection rates, and adverse events.

Results: The study enrolled 156 patients (median age, 65.5 years; range, 40-86 years; median body mass index [calculated as weight in kilograms divided by height in meters squared], 27.5; range, 17.6-49.3), including 126 with high-grade EC. All patients underwent SLNB and PLND, and 101 patients (80%) with high-grade EC also underwent PALND. Sentinel lymph node detection rates were 97.4% per patient (95% CI, 93.6%-99.3%), 87.5% per hemipelvis (95% CI, 83.3%-91.0%), and 77.6% bilaterally (95% CI, 70.2%-83.8%). Of 27 patients (17%) with nodal metastases, 26 patients were correctly identified by the SLNB algorithm, yielding a sensitivity of 96% (95% CI, 81%-100%), a false-negative rate of 4% (95% CI, 0%-19%), and a negative predictive value of 99% (95% CI, 96%-100%). Only 1 patient (0.6%) was misclassified by the SLNB algorithm. Seven of 27 patients with node-positive cancer (26%) were identified outside traditional PLND boundaries or required immunohistochemistry for diagnosis.

Conclusions And Relevance: In this prospective cohort study, SLNB had acceptable diagnostic accuracy for patients with high-grade EC at increased risk of nodal metastases and improved the detection of node-positive cases compared with lymphadenectomy. The findings suggest that SLNB is a viable option for the surgical staging of EC.
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http://dx.doi.org/10.1001/jamasurg.2020.5060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7658802PMC
February 2021

Cross-Cancer Genome-Wide Association Study of Endometrial Cancer and Epithelial Ovarian Cancer Identifies Genetic Risk Regions Associated with Risk of Both Cancers.

Cancer Epidemiol Biomarkers Prev 2021 01 3;30(1):217-228. Epub 2020 Nov 3.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.

Background: Accumulating evidence suggests a relationship between endometrial cancer and ovarian cancer. Independent genome-wide association studies (GWAS) for endometrial cancer and ovarian cancer have identified 16 and 27 risk regions, respectively, four of which overlap between the two cancers. We aimed to identify joint endometrial and ovarian cancer risk loci by performing a meta-analysis of GWAS summary statistics from these two cancers.

Methods: Using LDScore regression, we explored the genetic correlation between endometrial cancer and ovarian cancer. To identify loci associated with the risk of both cancers, we implemented a pipeline of statistical genetic analyses (i.e., inverse-variance meta-analysis, colocalization, and M-values) and performed analyses stratified by subtype. Candidate target genes were then prioritized using functional genomic data.

Results: Genetic correlation analysis revealed significant genetic correlation between the two cancers ( = 0.43, = 2.66 × 10). We found seven loci associated with risk for both cancers ( < 2.4 × 10). In addition, four novel subgenome-wide regions at 7p22.2, 7q22.1, 9p12, and 11q13.3 were identified ( < 5 × 10). Promoter-associated HiChIP chromatin loops from immortalized endometrium and ovarian cell lines and expression quantitative trait loci data highlighted candidate target genes for further investigation.

Conclusions: Using cross-cancer GWAS meta-analysis, we have identified several joint endometrial and ovarian cancer risk loci and candidate target genes for future functional analysis.

Impact: Our research highlights the shared genetic relationship between endometrial cancer and ovarian cancer. Further studies in larger sample sets are required to confirm our findings.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-0739DOI Listing
January 2021

Tumor site discordance in mismatch repair deficiency in synchronous endometrial and ovarian cancers.

Int J Gynecol Cancer 2020 12 20;30(12):1951-1958. Epub 2020 Oct 20.

Gynecologic Oncology, Princess Margaret Hospital Cancer Centre, Toronto, Ontario, Canada

Objectives: For synchronous endometrial and ovarian cancers, most centers rely on mismatch repair testing of the endometrial cancer to identify Lynch syndrome, and neglect the ovarian tumor site completely. We examined the mismatch repair immunohistochemistry and microsatellite instability results from the endometrium and ovary to assess discordance between the tumor sites and between tests.

Methods: 30 women with newly diagnosed synchronous endometrial and ovarian cancer were prospectively recruited from three cancer centers in Ontario, Canada. Both tumor sites were assessed for mismatch repair deficiency by immunohistochemistry and microsatellite instability test; discordance in results between tumor sites and discordance between test results at each site was examined. Cases with discordant results had tumors sequenced with a targeted panel in order to reconcile the findings. All women underwent mismatch repair gene germline testing.

Results: Of 30 patients, 11 (37%) were mismatch repair deficient or microsatellite instable at either tumor site, with 5 (17%) testing positive for Lynch syndrome. Mismatch repair immunohistochemistry expression was discordant between endometrial and ovarian tumor sites in 2 of 27 patients (7%) while microsatellite instability results were discordant in 2 of 25 patients (8%). Relying on immunohistochemistry or microsatellite instability alone on the endometrial tumor would have missed one and three cases of Lynch syndrome, respectively. One patient with Lynch syndrome with a pathogenic variant was not detected by either immunohistochemistry or microsatellite instability testing. The rate of discordance between immunohistochemistry and microsatellite instability test was 3.8% in the ovary and 12% in the endometrium.

Conclusions: There was discordance in immunohistochemistry and microsatellite instability results between tumor sites and between tests within each site. Endometrial tumor testing with mismatch repair immunohistochemistry performed well, but missed one case of Lynch syndrome. Given the high incidence of Lynch syndrome (17%), consideration may be given to germline testing in all patients with synchronous endometrial and ovarian cancers.
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http://dx.doi.org/10.1136/ijgc-2020-001927DOI Listing
December 2020

Survival after minimally invasive surgery in early cervical cancer: is the intra-uterine manipulator to blame?

Int J Gynecol Cancer 2020 12 9;30(12):1864-1870. Epub 2020 Oct 9.

Gynecologic Oncology, Princess Margaret Hospital Cancer Centre, Toronto, Ontario, Canada

Objectives: Minimally invasive radical hysterectomy is associated with decreased survival in patients with early cervical cancer. The objective of this study was to determine whether the use of an intra-uterine manipulator at the time of laparoscopic or robotic radical hysterectomy is associated with inferior oncologic outcomes.

Methods: A retrospective cohort study was carried out of all patients with cervical cancer (squamous cell carcinoma, adenocarcinoma or adenosquamous carcinoma) International Federation of Gynecology and Obstetrics 2009 stages IA1 (with positive lymphovascular space invasion) to IIA who underwent minimally invasive radical hysterectomy at two academic centers between January 2007 and December 2017. Treatment, tumor characteristics, and survival data were retrieved from hospital records.

Results: A total of 224 patients were identified at the two centers; 115 had surgery with the use of an intra-uterine manipulator while 109 did not; 53 were robotic and 171 were laparoscopic. Median age was 44 years (range 38-54) and median body mass index was 25.8 kg/m (range 16.6-51.5). Patients in whom an intra-uterine manipulator was not used at the time of minimally invasive radical hysterectomy were more likely to have residual disease at hysterectomy (p<0.001), positive lymphovascular space invasion (p=0.02), positive margins (p=0.008), and positive lymph node metastasis (p=0.003). Recurrence-free survival at 5 years was 80% in the no intra-uterine manipulator group and 94% in the intra-uterine manipulator group. After controlling for the presence of residual cancer at hysterectomy, tumor size and high-risk pathologic criteria (positive margins, parametria or lymph nodes), the use of an intra-uterine manipulator was no longer significantly associated with worse recurrence-free survival (HR 0.4, 95% CI 0.2 to 1.0, p=0.05). The only factor which was consistently associated with recurrence-free survival was tumor size (HR 2.1, 95% CI 1.5 to 3.0, for every 10 mm increase, p<0.001).

Conclusion: After controlling for adverse pathological factors, the use of an intra-uterine manipulator in patients with early cervical cancer who underwent minimally invasive radical hysterectomy was not an independent factor associated with rate of recurrence.
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http://dx.doi.org/10.1136/ijgc-2020-001816DOI Listing
December 2020

High-throughput approaches for precision medicine in high-grade serous ovarian cancer.

J Hematol Oncol 2020 10 9;13(1):134. Epub 2020 Oct 9.

Department of Medical Biophysics, University of Toronto, Toronto, Canada.

High-grade serous carcinoma (HGSC) is the most prevalent and aggressive subtype of ovarian cancer. The large degree of clinical heterogeneity within HGSC has justified deviations from the traditional one-size-fits-all clinical management approach. However, the majority of HGSC patients still relapse with chemo-resistant cancer and eventually succumb to their disease, evidence that further work is needed to improve patient outcomes. Advancements in high-throughput technologies have enabled novel insights into biological complexity, offering a large potential for informing precision medicine efforts. Here, we review the current landscape of clinical management for HGSC and highlight applications of high-throughput biological approaches for molecular subtyping and the discovery of putative blood-based biomarkers and novel therapeutic targets. Additionally, we present recent improvements in model systems and discuss how their intersection with high-throughput platforms and technological advancements is positioned to accelerate the realization of precision medicine in HGSC.
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http://dx.doi.org/10.1186/s13045-020-00971-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7547483PMC
October 2020

Performance characteristics of screening strategies to identify Lynch syndrome in women with ovarian cancer.

Cancer 2020 11 18;126(22):4886-4894. Epub 2020 Aug 18.

Division of Gynecologic Oncology, Princess Margaret Cancer Centre, University Health Network, Sinai Health Systems, Toronto, Ontario, Canada.

Background: For women with ovarian cancer (OC), the optimal screening strategy to identify Lynch syndrome (LS) has not been determined. In the current study, the authors compared the performance characteristics of various strategies combining mismatch repair (MMR) immunohistochemistry (IHC), microsatellite instability testing (MSI), and family history for the detection of LS.

Methods: Women with nonserous and/or nonmucinous ovarian cancer were recruited prospectively from 3 cancer centers in Ontario, Canada. All underwent germline testing for LS and completed a family history assessment. Tumors were assessed using MMR IHC and MSI. The sensitivity, specificity, and positive and negative predictive values of screening strategies were compared with the gold standard of a germline result.

Results: Of 215 women, germline data were available for 189 (88%); 13 women (7%) had pathogenic germline variants with 7 women with mutS homolog 6 (MSH6); 3 women with mutL homolog 1 (MLH1); 2 women with PMS1 homolog 2, mismatch repair system component (PMS2); and 1 woman with mutS homolog 2 (MSH2). A total of 28 women had MMR-deficient tumors (13%); of these, 11 had pathogenic variants (39%). Sequential IHC (with MLH1 promoter methylation analysis on MLH1-deficient tumors) followed by MSI for nonmethylated and/or MMR-intact patients was the most sensitive (92.3%; 95% confidence interval, 64%-99.8%) and specific (97.7%; 95% confidence interval, 94.2%-99.4%) approach, missing 1 case of LS. IHC with MLH1 promoter methylation analysis missed 2 patients of LS. Family history was found to have the lowest sensitivity at 55%.

Conclusions: Sequential IHC (with MLH1 promoter methylation analysis) followed by MSI was found to be most sensitive. However, IHC with MLH1 promoter methylation analysis also performed well and is likely more cost-effective and efficient in the clinical setting. The pretest probability of LS is high in patients with MMR deficiency and warrants universal screening for LS.
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http://dx.doi.org/10.1002/cncr.33144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693219PMC
November 2020

Preoperative neutrophil-to-lymphocyte ratio predicts 30 day postoperative morbidity and survival after primary surgery for ovarian cancer.

Int J Gynecol Cancer 2020 09 11;30(9):1378-1383. Epub 2020 Aug 11.

Gynecologic Oncology, Princess Margaret Hospital Cancer Centre, Toronto, Ontario, Canada.

Objective: The preoperative neutrophil-to-lymphocyte ratio has been found to be an independent prognostic indicator for perioperative complications and survival outcomes in patients undergoing oncologic surgery for several malignancies. The objective of this study was to evaluate the role of the preoperative neutrophil-to-lymphocyte ratio in predicting 30-day postoperative morbidity and overall survival in advanced-stage high-grade serous ovarian cancer patients after primary surgery.

Methods: A retrospective study was conducted on consecutive patients who underwent primary surgery for high-grade serous ovarian cancer between January 2008 and December 2016 at a single tertiary academic institution in Toronto, Canada. Optimal thresholds for preoperative neutrophil-to-lymphocyte ratio were determined using receiver-operator characteristic curve analysis. Cox-proportional hazard models, Kaplan-Meier, and logistic regression analyses were performed.

Results: Of 505 patients with ovarian cancer during the study period, 199 met the inclusion criteria. Receiver-operator characteristic curve analysis generated optimal preoperative neutrophil-to-lymphocyte ratio thresholds of 2.3 and 2.9 for 30-day postoperative morbidity and survival outcomes, respectively. A neutrophil-to-lymphocyte ratio ≥2.3 was predictive of a composite outcome of 30-day postoperative complications (odds ratio 7.3, 95% confidence interval 2.44 to 21.81; p=0.0004), after adjusting for longer operative time and intraoperative complications. Postoperative complications included superficial surgical site infections (p=0.007) and urinary tract infections (p=0.004). A neutrophil-to-lymphocyte ratio ≥29 was associated with worse 5-year overall survival (57.8% vs 77.7%, p=0.003), and suggested no statistically significant difference in progression-free survival (33.8% vs 40.7%, p=0.054). On multivariable analysis, the neutrophil-to-lymphocyte ratio remained an independent predictor for overall survival (p=0.02) when adjusting for suboptimal cytoreduction (p≤0.0001).

Discussion: A preoperative neutrophil-to-lymphocyte ratio ≥2.3 and ≥2.9 is associated with greater risk of 30-day postoperative morbidity and worse overall survival, respectively. This marker may be used in conjunction with other risk assessment strategies to preoperatively identify high-risk patients. Further prospective study is required to investigate its role in clinical decision-making.
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http://dx.doi.org/10.1136/ijgc-2020-001378DOI Listing
September 2020

Quality of life in patients with cervical cancer after open versus minimally invasive radical hysterectomy (LACC): a secondary outcome of a multicentre, randomised, open-label, phase 3, non-inferiority trial.

Lancet Oncol 2020 06;21(6):851-860

Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Background: In the phase 3 LACC trial and a subsequent population-level review, minimally invasive radical hysterectomy was shown to be associated with worse disease-free survival and higher recurrence rates than was open radical hysterectomy in patients with early stage cervical cancer. Here, we report the results of a secondary endpoint, quality of life, of the LACC trial.

Methods: The LACC trial was a randomised, open-label, phase 3, non-inferiority trial done in 33 centres worldwide. Eligible participants were women aged 18 years or older with International Federation of Gynaecology and Obstetrics (FIGO) stage IA1 with lymphovascular space invasion, IA2, or IB1 adenocarcinoma, squamous cell carcinoma, or adenosquamous carcinoma of the cervix, with an Eastern Cooperative Oncology Group performance status of 0 or 1, who were scheduled to have a type 2 or 3 radical hysterectomy. Participants were randomly assigned (1:1) to receive open or minimally invasive radical hysterectomy. Randomisation was done centrally using a computerised minimisation program, stratified by centre, disease stage according to FIGO guidelines, and age. Neither participants nor investigators were masked to treatment allocation. The primary endpoint of the LACC trial was disease-free survival at 4·5 years, and quality of life was a secondary endpoint. Eligible patients completed validated quality-of-life and symptom assessments (12-item Short Form Health Survey [SF-12], Functional Assessment of Cancer Therapy-Cervical [FACT-Cx], EuroQoL-5D [EQ-5D], and MD Anderson Symptom Inventory [MDASI]) before surgery and at 1 and 6 weeks and 3 and 6 months after surgery (FACT-Cx was also completed at additional timepoints up to 54 months after surgery). Differences in quality of life over time between treatment groups were assessed in the modified intention-to-treat population, which included all patients who had surgery and completed at least one baseline (pretreatment) and one follow-up (at any timepoint after surgery) questionnaire, using generalised estimating equations. The LACC trial is registered with ClinicalTrials.gov, NCT00614211.

Findings: Between Jan 31, 2008, and June 22, 2017, 631 patients were enrolled; 312 assigned to the open surgery group and 319 assigned to the minimally invasive surgery group. 496 (79%) of 631 patients had surgery completed at least one baseline and one follow-up quality-of-life survey and were included in the modified intention-to-treat analysis (244 [78%] of 312 patients in the open surgery group and 252 [79%] of 319 participants in the minimally invasive surgery group). Median follow-up was 3·0 years (IQR 1·7-4·5). At baseline, no differences in the mean FACT-Cx total score were identified between the open surgery (129·3 [SD 18·8]) and minimally invasive surgery groups (129·8 [19·8]). No differences in mean FACT-Cx total scores were identified between the groups 6 weeks after surgery (128·7 [SD 19·9] in the open surgery group vs 130·0 [19·8] in the minimally invasive surgery group) or 3 months after surgery (132·0 [21·7] vs 133·0 [22·1]).

Interpretation: Since recurrence rates are higher and disease-free survival is lower for minimally invasive radical hysterectomy than for open surgery, and postoperative quality of life is similar between the treatment groups, gynaecological oncologists should recommend open radical hysterectomy for patients with early stage cervical cancer.

Funding: MD Anderson Cancer Center and Medtronic.
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http://dx.doi.org/10.1016/S1470-2045(20)30081-4DOI Listing
June 2020

Cognitive markers of dementia risk in middle-aged women with bilateral salpingo-oophorectomy prior to menopause.

Neurobiol Aging 2020 10 29;94:1-6. Epub 2020 Apr 29.

Department of Psychology, University of Toronto, Toronto, Ontario, Canada; Rotman Research Institute, Toronto, Ontario, Canada; Tema Genus, Linköping University, Linköping, Sweden.

Oophorectomy prior to menopause is associated with late-life dementia. Memory decline may start within 6 months after oophorectomy in middle-aged women, suggested by lower verbal and working memory performance. Unknown is whether such changes persist beyond 6 months, and whether they are reversed by estradiol. Short-term benefits of estradiol on verbal memory following oophorectomy were observed in one study, but longer term effects remain unknown. In the present study, middle-aged BRCA1/2 mutation carriers with early oophorectomy at least 1 year prior to study onset were tested on verbal and working memory with results stratified by (1) current estradiol use (n = 22) or (2) no history of estradiol use (n = 24), and compared to age-matched premenopausal controls (n = 25). Both memory abilities were adversely affected by oophorectomy, but only working memory was maintained by estradiol. Estrogen metabolite levels correlated with working memory, suggesting a role for estradiol in preserving this ability. Memory decline appears to persist after early oophorectomy, particularly for women who do not take estradiol.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.04.019DOI Listing
October 2020

Distinct fibroblast functional states drive clinical outcomes in ovarian cancer and are regulated by TCF21.

J Exp Med 2020 08;217(8)

Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.

Recent studies indicate that cancer-associated fibroblasts (CAFs) are phenotypically and functionally heterogeneous. However, little is known about CAF subtypes, the roles they play in cancer progression, and molecular mediators of the CAF "state." Here, we identify a novel cell surface pan-CAF marker, CD49e, and demonstrate that two distinct CAF states, distinguished by expression of fibroblast activation protein (FAP), coexist within the CD49e+ CAF compartment in high-grade serous ovarian cancers. We show for the first time that CAF state influences patient outcomes and that this is mediated by the ability of FAP-high, but not FAP-low, CAFs to aggressively promote proliferation, invasion and therapy resistance of cancer cells. Overexpression of the FAP-low-specific transcription factor TCF21 in FAP-high CAFs decreases their ability to promote invasion, chemoresistance, and in vivo tumor growth, indicating that it acts as a master regulator of the CAF state. Understanding CAF states in more detail could lead to better patient stratification and novel therapeutic strategies.
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http://dx.doi.org/10.1084/jem.20191094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7398174PMC
August 2020

The use of indocyanine green fluorescence angiography to assess anastomotic perfusion following bowel resection in surgery for gynecologic malignancies - A report of 100 consecutive anastomoses.

Gynecol Oncol 2020 08 15;158(2):402-406. Epub 2020 May 15.

Department of Obstetrics and Gynecology, University of Toronto, Toronto, ON, Canada; Division of Gynecologic Oncology, Department of Surgical Oncology, Princess Margaret Cancer Center, University Health Network, Toronto, ON, Canada. Electronic address:

Objective: Real-time intraoperative assessment of anastomotic perfusion with indocyanine green fluorescence angiography (ICG-FA) is a recent technique that is found to assist intraoperative decision-making and decrease risk of anastomotic leak in the General Surgery literature. No studies to date evaluate its use in Gynecologic Oncology. Our objectives were to assess the safety and feasibility of ICG-FA use and to describe the intraoperative assessment of anastomotic perfusion with ICG-FA.

Methods: A retrospective study of a prospectively-collected database of patients with a gynecologic malignancy who underwent a bowel resection at Princess Margaret Cancer Centre in Toronto, Canada, between November 1, 2017 and December 15, 2019 was conducted. ICG-FA was administered intravenously, and a near infrared imaging system (Pinpoint, Novadaq, Canada; SPY-PHI, Stryker, USA) was used to objectively assess bowel perfusion.

Results: ICG-FA was used to assess a total of 100 bowel anastomoses in 82 consecutive surgeries: 56 low anterior resections, 19 small bowel resections, 15 right hemi-colectomies, 6 left hemi-colectomies, 3 transverse colectomies, and 1 total colectomy. Fifty-five end-to end, 44 side-to-side and 1 end-to-side anastomoses were assessed. ICG angiography was successful in all patients, allowing complete visualization of anastomotic perfusion in all cases. Hypoperfusion detected by ICG-FA resulted in change in operative plan for three patients (two anastomotic revisions and one diverting ileostomy). There were no adverse reactions to ICG. In this cohort, there was one postoperative anastomotic leak.

Conclusions: ICG-FA enables objective and accurate intraoperative evaluation of anastomotic perfusion in surgeries for gynecologic malignancies. Its implementation and routine use were found to be safe and well-tolerated without side effects in our study cohort. ICG-FA can be used with other risk-assessment strategies to guide operative decision-making in Gynecologic Oncology.
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http://dx.doi.org/10.1016/j.ygyno.2020.05.008DOI Listing
August 2020

Equivalent Survival of p53 Mutated Endometrial Endometrioid Carcinoma Grade 3 and Endometrial Serous Carcinoma.

Int J Gynecol Pathol 2021 Mar;40(2):116-123

TP53 status is the most important prognostic biomarker in endometrial carcinoma. We asked the question whether p53 mutated endometrial endometrioid carcinomas grade 3 (EEC3) or endometrial serous carcinomas (ESC), the latter ubiquitously harboring TP53 mutation, have different outcomes. TP53 mutation status was assessed by surrogate p53 immunohistochemistry on 326 EEC3 and ESC from 2 major cancer centers in Canada. Mutant-type p53 expression, including overexpression, complete absence, or cytoplasmic expression, was distinguished from the wild-type pattern. Statistical associations with clinico-pathological parameter, other key biomarkers, and survival analyses were performed. P53 mutant-type immunohistochemistry was observed in all 126 ESC and in 47/200 (23.5%) EEC3. ESC and p53 mutated EEC3 had an unfavorable outcome compared with p53 wild-type EEC3 (hazard ratio=2.37, 95% confidence interval=1.48-3.80, P=0.003, hazard ratio=2.19, 95% confidence interval=1.16-4.12, P=0.016, respectively) in multivariable analyses adjusted for age, stage, center, and presence of lymph-vascular invasion. There was no significant difference in survival between ESC and p53 mutated EEC3 in multivariable analysis. Furthermore, p53 mutated EEC3 and ESC almost completely overlapped in univariate survival analysis when mismatch repair (MMR)-deficient cases were excluded, which suggests that EEC3 harboring combined MMR deficiency and TP53 mutations behave more according to the MMR status. Significant differences between p53 mutated MMR-proficient EEC3 and ESC in PTEN and p16 expression status remained. p53 mutated, MMR-proficient EEC3 and ESC have overlapping survival significantly different from p53 wild-type EEC3, which justifies a similar treatment with current non-targeted standard therapy. Although this is so, separate classification should continue due to biological differences that will become important for future targeted therapy.
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http://dx.doi.org/10.1097/PGP.0000000000000674DOI Listing
March 2021

IL6 Induces an IL22 CD8 T-cell Subset with Potent Antitumor Function.

Cancer Immunol Res 2020 03 21;8(3):321-333. Epub 2020 Jan 21.

Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada.

CD8 T cells can be polarized into several different subsets as defined by the cytokines they produce and the transcription factors that govern their differentiation. Here, we identified the polarizing conditions to induce an IL22-producing CD8 Tc22 subset, which is dependent on IL6 and the aryl hydrocarbon receptor transcription factor. Further characterization showed that this subset was highly cytolytic and expressed a distinct cytokine profile and transcriptome relative to other subsets. In addition, polarized Tc22 were able to control tumor growth as well as, if not better than, the traditional IFNγ-producing Tc1 subset. Tc22s were also found to infiltrate the tumors of human patients with ovarian cancer, comprising up to approximately 30% of expanded CD8 tumor-infiltrating lymphocytes (TIL). Importantly, IL22 production in these CD8 TILs correlated with improved recurrence-free survival. Given the antitumor properties of Tc22 cells, it may be prudent to polarize T cells to the Tc22 lineage when using chimeric antigen receptor (CAR)-T or T-cell receptor (TCR) transduction-based immunotherapies.
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http://dx.doi.org/10.1158/2326-6066.CIR-19-0521DOI Listing
March 2020

High expression of B7-H3 on stromal cells defines tumor and stromal compartments in epithelial ovarian cancer and is associated with limited immune activation.

J Immunother Cancer 2019 12 31;7(1):357. Epub 2019 Dec 31.

Department of Immunology, University of Toronto, Toronto, Ontario, Canada.

Background: B7-H3 and B7-H4 are highly expressed by many human malignancies making them attractive immunotherapeutic targets. However, their expression patterns and immune contexts in epithelial ovarian cancer have not been well characterized.

Methods: We used flow cytometry, immunohistochemistry, and genomic analyses to determine the patterns of B7-H3, B7-H4, and PD-L1 expression by tumor, stromal, and immune cells in the ovarian tumor microenvironment (TME). We analyzed immune cell frequency and expression of PD-1, TIM3, LAG3, ICOS, TIA-1, granzyme B, 2B4, CD107a, and GITR on T cells; CD20, CD22, IgD, BTLA, and CD27 on B cells; CD16 on monocytes; and B7-H3, B7-H4, PD-L1, PD-L2, ICOSL, CD40, CD86, and CLEC9a on antigen-presenting cells by flow cytometry. We determined intratumoral cellular location of immune cells using immunohistochemistry. We compared differences in immune infiltration in tumors with low or high tumor-to-stroma ratio and in tumors from the same or unrelated patients.

Results: On non-immune cells, B7-H4 expression was restricted to tumor cells whereas B7-H3 was expressed by both tumor and stromal cells. Stromal cells of the ovarian TME expressed high levels of B7-H3 compared to tumor cells. We used this differential expression to assess the tumor-to-stroma ratio of ovarian tumors and found that high tumor-to-stroma ratio was associated with increased expression of CD16 by monocytes, increased frequencies of PD-1 CD8 T cells, increased PD-L1 expression by APCs, and decreased CLEC9a expression by APCs. We found that expression of PD-L1 or CD86 on APCs and the proportion of PD-1 CD4 T cells were strongly correlated on immune cells from tumors within the same patient, whereas expression of CD40 and ICOSL on APCs and the proportion of PD-1 CD8 T cells were not.

Conclusions: This study provides insight into the expression patterns of B7-H3 and B7-H4 in the ovarian TME. Further, we demonstrate an association between the tumor-to-stroma ratio and the phenotype of tumor-infiltrating immune cells. We also find that some but not all immune parameters show consistency between peritoneal metastatic sites. These data have implications for the design of immunotherapies targeting these B7 molecules in epithelial ovarian cancer.
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http://dx.doi.org/10.1186/s40425-019-0816-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6937725PMC
December 2019

Tumor cell expression of B7-H4 correlates with higher frequencies of tumor-infiltrating APCs and higher CXCL17 expression in human epithelial ovarian cancer.

Oncoimmunology 2019;8(12):e1665460. Epub 2019 Sep 30.

Department of Immunology, University of Toronto, Toronto, Ontario, Canada.

B7-H4, an immune suppressive member of the B7 family, is highly expressed in a wide variety of human malignancies making it an attractive immunotherapeutic target. However, the association between B7-H4 expression in the tumor microenvironment and the immune infiltrate has not been comprehensively examined. To evaluate the immune tumor microenvironment, we analyzed epithelial ovarian tumors from 28 patients using flow cytometry, immunohistochemistry, functional, and genomic analyses. We determined B7-H4 expression patterns and compared the immune infiltrates of tumors with high and low surface expression of B7-H4. Frequencies and phenotypes of tumor and immune cells were determined using multiple flow cytometry panels. Immunohistochemistry was used to analyze cellular infiltration and location. Publicly available datasets were interrogated to determine intratumoral cytokine and chemokine expression. We found that B7-H4 was predominantly expressed by tumor cells in the epithelial ovarian tumor microenvironment. Surface expression of B7-H4 on tumor cells was correlated with higher levels of infiltrating mature antigen-presenting cells. Further, expression of CXCL17, a monocyte and dendritic cell chemoattractant, correlated strongly with B7-H4 expression. T cells expressed activation markers, but T cells expressing a combination of markers associated with T cell activation/exhaustion phenotype were not prevalent. Overall, our data suggest that B7-H4 is associated with a pro-inflammatory tumor microenvironment.
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http://dx.doi.org/10.1080/2162402X.2019.1665460DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6844312PMC
September 2019

An Orthotopic Endometrial Cancer Model with Retroperitoneal Lymphadenopathy Made From In Vivo Propagated and Cultured VX2 Cells.

J Vis Exp 2019 09 12(151). Epub 2019 Sep 12.

Department of Medical Biophysics, University of Toronto; Princess Margaret Cancer Center, University Health Network;

Endometrial cancer is the most common gynecologic malignancy in North America and the incidence is rising worldwide. Treatment consists of surgery with or without adjuvant therapy depending on lymph node involvement as determined by lymphadenectomy. Lymphadenectomy is a morbid procedure, which has not been shown to have a therapeutic benefit in many patients, and thus a new method to diagnose lymph node metastases is required. To test novel imaging agents, a reliable model of endometrial cancer with retroperitoneal lymph node metastases is needed. The VX2 endometrial cancer model has been described frequently in the literature; however, significant variation exists with respect to the method of model establishment. Furthermore, no studies have reported on the use of cultured VX2 cells to create this model as only cells propagated in vivo have been previously used. Herein, we present a standardized surgical method and post-operative monitoring method for the establishment of the VX2 endometrial cancer model and report on the first use of cultured VX2 cells to create this model.
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http://dx.doi.org/10.3791/59340DOI Listing
September 2019

Molecular characterization of gastric-type endocervical adenocarcinoma using next-generation sequencing.

Mod Pathol 2019 12 15;32(12):1823-1833. Epub 2019 Jul 15.

Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.

Gastric-type endocervical adenocarcinoma is an uncommon aggressive type of endocervical adenocarcinoma that is not associated with human papillomavirus (HPV). At present, this tumor is classified under the spectrum of mucinous carcinoma of the uterine cervix. The clinical stage of gastric-type endocervical adenocarcinoma at the time of diagnosis is usually more advanced compared to the HPV-associated endocervical adenocarcinoma. Widespread dissemination to unusual sites, such as omentum, peritoneum, and distant organs, can be present. Owing to its rare incidence, diagnostic dilemmas, and aggressive behavior, clinical management can be challenging. In this study, we aimed to elucidate the molecular characteristics of these tumors by using next-generation sequencing (NGS) to assess 161 unique cancer-driver genes for single-nucleotide and copy-number variations, gene fusions, and insertions/deletions within gastric-type endocervical adenocarcinoma tumors. In total, 92 variants were detected across the 14 samples tested (7 variants on average per tumor). TP53 was the most recurrently mutated gene followed by MSH6, CDKN2A/B, POLE, SLX4, ARID1A, STK11, BRCA2, and MSH2. Abnormal p53 expression was observed in nine cases by immunohistochemistry, of which TP53 variants were present in four cases. MDM2 gene amplification in 12q15 (69202190-69233452) locus was seen in two cases that express normal p53 levels by immunohistochemistry. Four cases had STK11 null (frameshift/nonsense) variants, three of which were previously reported in Peutz-Jeghers syndrome. Overall, genes that are implicated in DNA damage, repair, cell cycle, Fanconi anemia pathway, and the PI3K-AKT signaling pathways were found to be mutated. Of note, genes known to have acquired and/or inherited variants in endometrial tumors were enriched within our cohort. In conclusion, our study shows the genetic heterogeneity of gastric-type endocervical adenocarcinoma with some potentially actionable molecular alterations, which highlights the importance of further molecular characterization for better identification of this rare entity, and hence better clinical management.
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http://dx.doi.org/10.1038/s41379-019-0305-xDOI Listing
December 2019

Patterns of recurrence and impact on survival in patients with clear cell ovarian carcinoma.

Int J Gynecol Cancer 2019 09 3;29(7):1164-1169. Epub 2019 Jul 3.

Gynecologic Oncology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada.

Background: Patients with recurrent clear cell ovarian cancer have poor prognosis and limited effective systemic treatment options.

Objectives: To characterize patterns of recurrence and compare overall survival and post-recurrence survival parameters in patients with recurrent ovarian clear cell carcinoma.

Methods: Clinical data on patients with ovarian clear cell carcinoma between June 1995 and August 2014 were collected. Patients with clear cell ovarian cancer recurrence were included in this study. Patients with different histologic sub-type, persistent or progressive disease on completion of the initial treatment were excluded. Descriptive statistics, univariate and multivariable analyses, and Kaplan-Meier survival probability estimates were completed. The log-rank test was used to quantify survival differences on univariable analysis. To search for significant covariates related to the overall survival and post-recurrence survival, a univariable Cox proportional hazard model was performed.

Results: A total of 209 patients met inclusion criteria. Of these, 61 (29%) patients who were free of disease at completion of the initial treatment had recurrence. Patterns of recurrence were as follows: 38 (62%) patients had multiple-site recurrence, 12 (20%) had single-site recurrence, and 11 (18%) had nodal recurrence only. The median overall survival was 44.7 months (95% CI 33.4 to 64.2) and was significantly associated with pattern of recurrence (p=0.005). The median post-recurrence survival was 18.4 months (95% CI 12.5 to 26.7): 54.4 months (95% CI 11 to 125.5) in single-site recurrence, 13.7 months (95% CI 6.8 to 16.5) in multiple-site recurrence, and 30.1 (95% CI 7.2 to 89) months in nodal recurrence (p=0.0002). In the multivariable analysis, pattern of recurrence was a predictor of post-recurrence survival.Six patients (9.8%) had a prolonged disease-free interval after recurrence (disease-free for more than 30 months after completion of treatment for recurrence). Prolonged recurrences were noted in 4 (33%) of 12 patients with single-site recurrence, 1 (9%) of 11 patients with nodal recurrence, and in 1 (2.7%) of 38 patients with multiple-site recurrence. Three of the six patients with a prolonged disease-free interval after recurrence were treated surgically at the time of recurrence.

Conclusion: Ovarian clear cell carcinoma predominantly recurs in multiple sites and it is associated with a high mortality rate and short post-recurrence survival. When recurrences are limited to a single site, or only to lymph nodes, the median post-recurrence survival is longer. Disease-free interval after recurrence is longer in patients with single-site recurrence who are treated surgically at the time of recurrence.
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http://dx.doi.org/10.1136/ijgc-2019-000287DOI Listing
September 2019

Barriers to care for women with low-grade endometrial cancer and morbid obesity: a qualitative study.

BMJ Open 2019 06 27;9(6):e026872. Epub 2019 Jun 27.

Obstetrics and Gynaecology, University of Toronto, Toronto, Ontario, Canada.

Objective: Obesity is a major risk factor for low-grade endometrial cancer. The surgical management of patients with obesity is challenging, and they may face unique barriers to accessing care. We completed a qualitative study to understand the experiences of low-grade endometrial cancer patients with morbid obesity, from symptom onset to diagnosis to surgery.

Design: Semi-structured interviews were performed with endometrial cancer patients with morbid obesity (body mass index (BMI) 40 kg/m) referred for primary surgery. Transcribed interviews were coded line-by-line and analysed using an interpretive descriptive approach that drew on labelling theory to understand patients' experiences. Thematic sufficiency was confirmed after 15 interviews.

Setting: Two tertiary care centres in Toronto, Ontario, Canada.

Participants: Fifteen endometrial cancer patients with a median age of 61 years (range: 50-74) and a median BMI of 50 kg/m (range: 44-70) were interviewed.

Results: Thematic analysis identified that (1) both patients and providers lack knowledge on endometrial cancer and its presenting symptoms and risk factors; (2) patients with morbid obesity are subject to stigma and poor communication in the healthcare system and (3, 4) although clinical, administrative, financial, geographic and facility-related barriers exist, quality care for patients with morbid obesity is an achievable goal.

Conclusions: Improved education on the prevention and identification of endometrial cancer is needed for both patients and providers. Delivery of cancer care to patients with morbid obesity may be improved through provider awareness of the impact of weight stigma and establishing streamlined care pathways at centres equipped to manage surgical complexity.
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http://dx.doi.org/10.1136/bmjopen-2018-026872DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6597640PMC
June 2019

Use of Porphysomes to detect primary tumour, lymph node metastases, intra-abdominal metastases and as a tool for image-guided lymphadenectomy: proof of concept in endometrial cancer.

Theranostics 2019 13;9(9):2727-2738. Epub 2019 Apr 13.

Institute of Medical Science, University of Toronto, Toronto, ON, Canada.

: To investigate Porphysome fluorescence image-guided resection (PYRO-FGR) for detection of uterine tumour, metastatic lymph nodes and abdominal metastases in a model of endometrial cancer. : White New Zealand rabbits were inoculated with VX2 cells via intra-myometrial injection. At 30 days, Porphysomes were administered intravenously. At 24 h the abdomen was imaged and fluorescent tissue identified (PYRO-FGR). After complete resection of fluorescent tissue, fluorescence-negative lymph nodes and peritoneal biopsies were removed. Histopathology including ultra-staging and analysis by a pathologist was used to detect tumour. Fluorescence signal to background ratio (SBR) was calculated and VX2 (+) tissue compared to VX2 (-) tissue. Biodistribution was calculated and Porphysome accumulation in fluorescent VX2 (+) tissue compared to fluorescent VX2 (-) and non-fluorescent VX2 (-) tissue. : Of 17 VX2 models, 10 received 4 mg/kg of Porphysomes and 7 received 1 mg/kg. Seventeen tumours (UT), 81 lymph nodes (LN) and 54 abdominal metastases (AM) were fluorescence-positive and resected. Of these, 17 UT, 60 LN and 45 AM were VX2 (+), while 16 LN and 5 AM were VX2 (-). Nine specimens were excluded from analysis. Thirty-one LN and 53 peritoneal biopsies were fluorescence-negative and resected. Of these, all LN and 51/53 biopsies were VX2 (-) with only 2 false-negative biopsies. Sensitivity and specificity of PYRO-FGR for VX2 (+) tissue was 98.4% / 80.0% overall, 100% / 100% for UT, 100% / 66.0 % for LN and 95.7% / 91.4% for AM. Increased SBR and biodistribution was observed in VX2 (+) tissue vs. VX2 (-) tissue. : Porphysomes are a highly sensitive imaging agent for intra-operative detection and resection of uterine tumour, metastatic lymph nodes and abdominal metastases.
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http://dx.doi.org/10.7150/thno.31225DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6525988PMC
June 2020

Laparoscopic and robotic hysterectomy in endometrial cancer patients with obesity: a systematic review and meta-analysis of conversions and complications.

Am J Obstet Gynecol 2019 11 10;221(5):410-428.e19. Epub 2019 May 10.

Department of Surgery, Toronto, Ontario, Canada; Division of General Surgery, St. Michael's Hospital, Toronto, Ontario, Canada. Electronic address:

Objective Data: Robotic assistance may facilitate completion of minimally invasive hysterectomy, which is the standard of care for the treatment of early-stage endometrial cancer, in patients for whom conventional laparoscopy is challenging. The aim of this systematic review was to assess conversion to laparotomy and perioperative complications after laparoscopic and robotic hysterectomy in patients with endometrial cancer and obesity (body mass index, ≥30 kg/m).

Study: We systematically searched MEDLINE, EMBASE, and Evidence-Based Medicine Reviews (January 1, 2000, to July 18, 2018) for studies of patients with endometrial cancer and obesity (body mass index, ≥30 kg/m) who underwent primary hysterectomy.

Study Appraisal And Synthesis Methods: We determined the pooled proportions of conversion, organ/vessel injury, venous thromboembolism, and blood transfusion. We assessed risk of bias with the Institute of Health Economics Quality Appraisal Checklist for single-arm studies, and Newcastle-Ottawa Quality Scale for double-arm studies.

Results: We identified 51 observational studies that reported on 10,800 patients with endometrial cancer and obesity (study-level body mass index, 31.0-56.3 kg/m). The pooled proportions of conversion from laparoscopic and robotic hysterectomy were 6.5% (95% confidence interval, 4.3-9.9) and 5.5% (95% confidence interval, 3.3-9.1), respectively, among patients with a body mass index of ≥30 kg/m, and 7.0% (95% confidence interval, 3.2-14.5) and 3.8% (95% confidence interval, 1.4-9.9) among patients with body mass index of ≥40 kg/m. Inadequate exposure because of adhesions/visceral adiposity was the most common reason for conversion for both laparoscopic (32%) and robotic hysterectomy (61%); however, intolerance of the Trendelenburg position caused 31% of laparoscopic conversions and 6% of robotic hysterectomy conversions. The pooled proportions of organ/vessel injury (laparoscopic, 3.5% [95% confidence interval, 2.2-5.5]; robotic hysterectomy, 1.2% [95% confidence interval, 0.4-3.4]), venous thromboembolism (laparoscopic, 0.5% [95% confidence interval, 0.2-1.2]; robotic hysterectomy, 0.5% [95% confidence interval, 0.1-2.0]), and blood transfusion (laparoscopic, 2.8% [95% confidence interval, 1.5-5.1]; robotic hysterectomy, 2.1% [95% confidence interval, 1.6-3.8]) were low and not appreciably different between arms.

Conclusion: Robotic and laparoscopic hysterectomy have similar rates perioperative complications in patients with endometrial cancer and obesity, but robotic hysterectomy may reduce conversions because of positional intolerance in patients with morbid obesity. Existing literature is limited by selection and confounding bias, and randomized trials are needed to inform practice standards in this population.
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http://dx.doi.org/10.1016/j.ajog.2019.05.004DOI Listing
November 2019

Evaluation of vitamin D biosynthesis and pathway target genes reveals UGT2A1/2 and EGFR polymorphisms associated with epithelial ovarian cancer in African American Women.

Cancer Med 2019 05 18;8(5):2503-2513. Epub 2019 Apr 18.

Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, New York.

An association between genetic variants in the vitamin D receptor (VDR) gene and epithelial ovarian cancer (EOC) was previously reported in women of African ancestry (AA). We sought to examine associations between genetic variants in VDR and additional genes from vitamin D biosynthesis and pathway targets (EGFR, UGT1A, UGT2A1/2, UGT2B, CYP3A4/5, CYP2R1, CYP27B1, CYP24A1, CYP11A1, and GC). Genotyping was performed using the custom-designed 533,631 SNP Illumina OncoArray with imputation to the 1,000 Genomes Phase 3 v5 reference set in 755 EOC cases, including 537 high-grade serous (HGSOC), and 1,235 controls. All subjects are of African ancestry (AA). Logistic regression was performed to estimate odds ratios (OR) and 95% confidence intervals (CI). We further evaluated statistical significance of selected SNPs using the Bayesian False Discovery Probability (BFDP). A significant association with EOC was identified in the UGT2A1/2 region for the SNP rs10017134 (per allele OR = 1.4, 95% CI = 1.2-1.7, P = 1.2 × 10 , BFDP = 0.02); and an association with HGSOC was identified in the EGFR region for the SNP rs114972508 (per allele OR = 2.3, 95% CI = 1.6-3.4, P = 1.6 × 10 , BFDP = 0.29) and in the UGT2A1/2 region again for rs1017134 (per allele OR = 1.4, 95% CI = 1.2-1.7, P = 2.3 × 10 , BFDP = 0.23). Genetic variants in the EGFR and UGT2A1/2 may increase susceptibility of EOC in AA women. Future studies to validate these findings are warranted. Alterations in EGFR and UGT2A1/2 could perturb enzyme efficacy, proliferation in ovaries, impact and mark susceptibility to EOC.
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http://dx.doi.org/10.1002/cam4.1996DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6536963PMC
May 2019