Sarah E. Ferguson

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

BackgroundDespite 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).MethodsParticipants 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.ResultsA 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.ConclusionsThe introduction of a navigated genetic program resulted in a high rate of genetic assessment (>90%) in patients with gynecologic cancer at risk for LS.

Association of bilateral salpingo-oophorectomy with all cause and cause specific mortality: population based cohort study

Abstract Objectives To determine if bilateral salpingo-oophorectomy, compared with ovarian conservation, is associated with all cause or cause specific death in women undergoing hysterectomy for non-malignant disease, and to determine how this association varies with age at surgery. Design Population based cohort study. Setting Ontario, Canada from 1 January 1996 to 31 December 2015, and follow-up to 31 December 2017. Participants 200 549 women (aged 30-70 years) undergoing non-malignant hysterectomy, stratified into premenopausal (<45 years), menopausal transition (45-49 years), early menopausal (50-54 years), and late menopausal (≥55 years) groups according to age at surgery; median follow-up was 12 years (interquartile range 7-17). Exposures Bilateral salpingo-oophorectomy versus ovarian conservation. Main outcomes measures The primary outcome was all cause death. Secondary outcomes were non-cancer and cancer death. Within each age group, overlap propensity score weighted survival models were used to examine the association between bilateral salpingo-oophorectomy and mortality outcomes, while adjusting for demographic characteristics, gynaecological conditions, and comorbidities. To account for comparisons in four age groups, P<0.0125 was considered statistically significant. Results Bilateral salpingo-oophorectomy was performed in 19%, 41%, 69%, and 81% of women aged <45, 45-49, 50-54, and ≥55 years, respectively. The procedure was associated with increased rates of all cause death in women aged <45 years (hazard ratio 1.31, 95% confidence interval 1.18 to 1.45, P<0.001; number needed to harm 71 at 20 years) and 45-49 years (1.16, 1.04 to 1.30, P=0.007; 152 at 20 years), but not in women aged 50-54 years (0.83, 0.72 to 0.97, P=0.018) or ≥55 years (0.92, 0.82 to 1.03, P=0.16). Findings in women aged <50 years were driven largely by increased non-cancer death. In secondary analyses identifying a possible change in the association between bilateral salpingo-oophorectomy and all cause death with advancing age at surgery, the hazard ratio gradually decreased during the menopausal transition and remained around 1 at all ages thereafter. Conclusion In this observational study, bilateral salpingo-oophorectomy at non-malignant hysterectomy appeared to be associated with increased all cause mortality in women aged <50 years, but not in those aged ≥50 years. While caution is warranted when considering bilateral salpingo-oophorectomy in premenopausal women without indication, this strategy for ovarian cancer risk reduction does not appear to be detrimental to survival in postmenopausal women.

Simple perinephric adipose tissue measurement for prediction of failed sentinel lymph node mapping in endometrial cancer

We aimed to evaluate whether pre-operative average perinephric fat is associated with sentinel lymph node (SLN) mapping, peri-operative complications, and survival in endometrial cancer. This was a retrospective cohort study of endometrial cancer patients who underwent surgical staging with SLN mapping between 2015 and 2021. Average perinephric fat was measured on axial sections of pre-operative computed tomography scans. Baseline characteristics and average perinephric fat measurements were compared between patients with successful mapping and those with bilateral failed mapping. We also compared peri-operative complications between patients with high and low average perinephric fat. Of the 297 participants included, 274 (92%) had at least unilateral successful SLN mapping, while 23 (8%) had bilateral failed SLN mapping. Median body mass index (34.7 vs 29.8 kg/m Increased average perinephric fat is associated with a higher risk of failed SLN mapping in endometrial cancer, without an associated increase in peri-operative complications. Incorporating this simple measurement into clinical practice may add value in identifying and counseling individuals at higher risk for failed mapping.

Sexual Health and Quality of Life in Patients With Low-Risk Early-Stage Cervical Cancer: Results From GCIG/CCTG CX.5/SHAPE Trial Comparing Simple Versus Radical Hysterectomy

PURPOSE Simple hysterectomy and pelvic node assessment (SHAPE) is a phase III randomized trial (ClinicalTrials.gov identifier: NCT01658930 ) reporting noninferiority of simple compared with radical hysterectomy for oncologic outcomes in low-risk cervical cancer. This study presents secondary outcomes of sexual health and quality of life (QOL) of the SHAPE trial. METHODS Participants were randomly assigned to receive either radical or simple hysterectomy. Sexual health was assessed up to 36 months postoperatively using the Female Sexual Function Index (FSFI) and Female Sexual Distress Scale-Revised and QOL using European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 and Cervical Cancer-Specific Module (QLQ-CX24) questionnaires. RESULTS Among participants with at least one QOL measure, clinical and pathologic characteristics were balanced and with no differences in preoperative baseline scores for sexual health or QOL between groups. FSFI total score met the cutoff for dysfunction up to 6 months ( P = .02) in the radical hysterectomy group. Group differences favored simple hysterectomy for FSFI subscales: desire and arousal at 3 months ( P ≤ .001) and pain and lubrication up to 12 months ( P ≤ .018). Both groups met the cutoff for sexual distress but was higher in radical hysterectomy at 3 months ( P = .018). For QLQ-CX24, symptom experience was significantly better up to 24 months ( P = .031) and body image better at 3, 24, and 36 months ( P ≤ .01) for simple hysterectomy. Sexual-vaginal functioning was significantly better up to 24 months ( P ≤ .022) and more sexual activity up to 36 months ( P = .024) in the simple hysterectomy arm. Global health status was significantly higher at 36 months for simple hysterectomy ( P = .025). CONCLUSION Simple hysterectomy was associated with lower rates of sexual dysfunction than radical hysterectomy, with a lower proportion of women having sustained sexual-vaginal dysfunction. These results further support the benefit of surgical de-escalation for low-risk cervical cancer.

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

BackgroundFor 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.MethodsWomen 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.ResultsOf 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%.ConclusionsSequential 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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Clinical Validation of Human Papilloma Virus Circulating Tumor DNA for Early Detection of Residual Disease After Chemoradiation in Cervical Cancer

PURPOSE Most cervical cancers are caused by human papilloma virus (HPV), and HPV circulating tumor DNA (ctDNA) may identify patients at highest risk of relapse. Our pilot study using digital polymerase chain reaction (dPCR) showed that detectable HPV ctDNA at the end of chemoradiation (CRT) is associated with inferior progression-free survival (PFS) and that a next-generation sequencing approach (HPV-seq) may outperform dPCR. We aimed to prospectively validate HPV ctDNA as a tool for early detection of residual disease. METHODS This prospective, multicenter validation study accrued patients with stage IB-IVA cervical cancer treated with CRT between 2017 and 2022. Participants underwent phlebotomy at baseline, end of CRT, 4-6 weeks post-CRT, and 3 months post-CRT for HPV ctDNA levels. Plasma HPV genotype–specific DNA levels were quantified using both dPCR and HPV-seq. The primary end point was 2-year PFS. RESULTS With a median follow-up of 2.2 (range, 0.5-5.5) years, there were 24 PFS events among the 70 patients with HPV+ cervical cancer. Patients with detectable HPV ctDNA on dPCR at the end of CRT, 4-6 weeks post-CRT, and 3 months post-CRT had significantly worse 2-year PFS compared with those with undetectable HPV ctDNA (77% v 51%, P = .03; 82% v 15%, P < .001; and 82% v 24%, P < .001, respectively); the median lead time to recurrence was 5.9 months. HPV-seq showed similar results as dPCR. On multivariable analyses, detectable HPV ctDNA on dPCR and HPV-seq remained independently associated with inferior PFS. CONCLUSION Persistent HPV ctDNA after CRT is independently associated with inferior PFS. HPV ctDNA testing can identify, as early as at the end of CRT, patients at high risk of recurrence for future treatment intensification trials.

Factors influencing surgeons' decision for diverting ileostomy and associated complications in ovarian cancer cytoreductive surgery.

This study aimed to identify factors influencing the decision to perform diverting ileostomy during cytoreductive surgery with colon resection for advanced ovarian cancer and investigate the associated complications and survival outcomes. This was a retrospective cohort study of patients with advanced ovarian cancer who underwent cytoreductive surgery with colon resection and re-anastomosis between January 2010 and July 2020. Multivariate analysis was performed on the factors contributing to diverting ileostomy identified in the univariate analysis. Of the 134 patients, 60 (44.8%) underwent diverting ileostomies. The median follow-up was 35.75 months (range; 0.03-145.05) and the median age was 57 (range; 26-86). The anastomotic leakage rate was 3.7% (n = 5). On the univariate analysis, longer operative time (10 vs 6.4 hours), multiple bowel resections (>1 vs 1 hour), total colon resection length, pre-operative paracentesis, intraoperative ascites, and transfusion were associated with diverting ileostomy. In the multivariate analysis, longer operative time (OR 1.61, p < .0001) and total colon resection length (OR 1.06, p = .027) remained significant. Diverting ileostomy was associated with higher rates of intensive care unit admission (14.3% vs 2.8%, p = .001), dehydration (40% vs 9.5%, p < .0001), and acute kidney injury (16.4% vs 1.4%, p = .002). The median progression-free survival was similar (23.87 vs 21.24 months in non-diverted vs diverted ileostomy, p = .82). Longer operative time and total length of colon resection influenced the selection of diverting ileostomy. The patients selected for diversion underwent multiple bowel resections more frequently, received more transfusions, and developed intraoperative ascites. These findings suggest that surgeons favor diversion for more extensive procedures. Patients who underwent diverted ileostomy experienced more short-term complications, likely reflecting the surgical complexity. Progression-free survival remained similar between the 2 groups, with diverse patients experiencing stoma-related morbidity over time, mainly dehydration and acute kidney injury. A prospective model to predict anastomotic leak risk may reduce diverting ileostomy rates.

FDG-PET and Circulating HPV in Patients With Cervical Cancer Treated With Definitive Chemoradiation (II)

Nearly all cervical cancers are caused by the human papilloma virus (HPV), which can be detected in cancer tissue by laboratory tests. There is evidence that the virus can also be detected from a blood sample to monitor the effects of treatment. Previous studies have shown that a special test called 18F-Fluorodeoxyglucose (FDG) Positron Emission Tomography/Computed Tomography (PET-CT) at 3 months after treatment may predict survival in cervical cancer. The purpose of this study is to see how well the FDG-PET Scan and blood tests for HPV can detect leftover cervical cancer cells after treatment. This study is not a particular form of treatment and patients will receive standard of care treatment.

Liquid Biopsy Evaluation and Repository Development at Princess Margaret

The objective of this protocol is to develop an institution-wide liquid biopsy protocol that will establish a common process for collecting blood and corresponding archived tumor specimens for future research studies at the University Health Network's Princess Margaret Cancer Centre. Circulating cell-free nucleic acids (cfNA), including cell-free DNA (cfDNA) and cell-free RNA (cfRNA), are non-invasive, real-time biomarkers that can provide diagnostic and prognostic information before cancer diagnosis, during cancer treatment, and at disease progression. Cancer research scientists and clinicians at the Princess Margaret are interested in incorporating the collection of peripheral blood samples ("liquid biopsies") into research protocols as a means of non-invasively assessing tumor progression and response to treatment at multiple time points during a patient's course of disease.

Radical Versus Simple Hysterectomy and Pelvic Node Dissection With Low-risk Early Stage Cervical Cancer

The reason this study is being done is to see if a simple hysterectomy is as good as a radical hysterectomy in preventing cancer of the cervix from returning, and whether, because less tissue surrounding the uterus is removed during surgery, there are fewer side-effects after the surgery and in the long-term.