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Objectives Women with germline BRCA1/2 mutations have a significantly elevated lifetime risk of ovarian cancer. Risk-reducing bilateral salpingo-oopherectomy (RRSO) is associated with an 80% reduction in the development of ovarian cancer. In January 2014 the Familial Ovarian Cancer Clinic (FOCC) was created as a centralized clinic to manage referrals of women with documented BRCA1/2 mutations. The objective of this study was to evaluate the choices that Canadian women with BRCA1/2 mutations made regarding ovarian cancer risk reduction within this highly specialized multidisciplinary clinic. Methods A retrospective chart review was performed on all women with confirmed BRCA1/2 mutations referred to the FOCC at Women's College Hospital, Toronto, Canada over a 45-month time period. Patient demographics, preoperative investigations, intraoperative findings and pathology were recorded. Results A total of 191 women were included in our cohort; 140(73.3%) underwent RRS and 51 (26.7%) deferred or declined surgery. In women who underwent RRS (median age 45 [30-72] years), 123 (87.9%) underwent RRSO and 17 (12.1%) chose a two-step risk-reducing bilateral salpingectomy with delayed oophorectomy (RRSDO). Of the women undergoing RRSO, 11 (8.9%) women chose concurrent hysterectomy. Prevalent themes affecting decision making included fears around premature surgical menopause, family planning, and concerns around development of endometrial cancer related to tamoxifen. Conclusions Women with BRCA1/2 mutations referred to our FOCC clinic face challenging decisions regarding risk reduction.

La présente opinion de comité énumère les recommandations pour la prise en charge gynécologique des femmes ayant reçu un diagnostic de syndrome du cancer du sein et de l'ovaire héréditaire (CSOH) en ce qui a trait au dépistage, à la contraception, à la chimioprophylaxie, aux facteurs à considérer pour la fertilité, à la chirurgie de réduction du risque et aux soins post-ovariectomie.La présente opinion de comité s'adresse aux gynécologues oncologues, aux gynécologues généralistes, aux médecins de famille, aux conseillers en génétique, aux infirmières autorisées, infirmières praticiennes, aux résidents et aux autres fournisseurs de soins.Les femmes adultes (18 ans et plus) présentant une mutation des gènes BRCA1 ou BRCA2 ou d'autres gènes associés au cancer de l'ovaire. DONNéES: Pour la revue de la littérature, les bases de données Medline, Cochrane et PubMed ont entre autres été interrogées. Les termes de recherche des Medical Subject Headings utilisés ont été BRCA ET gynaecology management [prise en charge gynécologique], hormone replacement therapy [hormonothérapie substitutive], risk reduction [réduction des risques], chemoprophylaxis [chimioprophylaxie] et fertility [fertilité], et les recherches ont ciblé les articles publiés entre janvier 2010 et octobre 2017. La recherche de publications s'est déroulée de juillet à octobre 2017. Au total, 183 études ont été sélectionnées, et 101 ont été utilisées.Le contenu et les recommandations ont été rédigés et acceptés par les auteurs principaux. Le Conseil d'administration de la Société des obstétriciens et gynécologues du Canada a approuvé la version finale avant publication. La qualité des données probantes a été évaluée au moyen des critères de l'approche GRADE (Grading of Recommendations Assessment, Development and Evaluation) [tableau 1]. L'interprétation des recommandations fortes et conditionnelles (faibles) est décrite dans le tableau 2. Le résumé des conclusions peut être fourni sur demande. AVANTAGES DéSAVANTAGES, ET COûTS: Nous pouvons nous attendre à une diminution des risques allant jusqu'à 90 % chez les femmes prédisposées au CSOH qui subissent une salpingo-ovariectomie bilatérale de réduction du risque. Les méfaits associés à la ménopause précoce iatrogène sont compensés par les avantages découlant de la réduction du risque. En réduisant l'occurrence de cancers des trompes, de l'ovaire et du péritoine, nous pouvons nous attendre à des économies dans le système de santé. MIS à JOUR: Une revue des données probantes sera menée cinq ans après la publication de la présente opinion afin de déterminer si une mise à jour complète ou partielle s'impose. Cependant, si de nouvelles données probantes importantes sont publiées avant la fin du cycle de cinq ans, le processus pourrait être accéléré afin que certaines recommandations soient mises à jour rapidement.Cette directive clinique a été élaborée à l'aide de ressources financées par la Société des obstétriciens et gynécologues du Canada.

Resume Objectif Passer en revue l'utilisation du morcellement tissulaire dans le cadre de la chirurgie gynecologique a effraction minimale. Issues Dans le cadre d'une chirurgie gynecologique, le morcellement peut etre utilise en vue de permettre le retrait de prelevements uterins de grandes dimensions, ce qui permet l'offre d'une option chirurgicale a effraction minimale aux patientes visees. Les issues oncologiques indesirables du morcellement tissulaire devraient etre attenuees par l'intermediaire d'une meilleure selection des patientes, d'explorations preoperatoires et de techniques novatrices qui minimisent la dispersion tissulaire. Resultats La litterature publiee a ete recuperee par l'intermediaire de recherches menees dans PubMed et Medline au printemps 2014 au moyen d'un vocabulaire controle (« leiomyomsarcoma », « uterine neoplasm », « uterine myomectomy », « hysterectomy ») et de mots cles (« leiomyoma », « endometrial cancer », « uterine sarcoma », « leiomyosarcoma », « morcellation » et « MRI ») appropries. Les resultats ont ete restreints aux analyses systematiques, aux essais comparatifs randomises / essais cliniques comparatifs et aux etudes observationnelles. Aucune restriction n'a ete imposee en matiere de date; toutefois, les resultats ont ete limites aux documents rediges en anglais ou en francais. Les recherches ont ete mises a jour de facon reguliere et ont ete integrees a la directive clinique jusqu'en aout 2014. La litterature grise (non publiee) a ete identifiee par l'intermediaire de recherches menees dans les sites Web d'organismes s'interessant a l'evaluation des technologies dans le domaine de la sante et d'organismes connexes, dans des collections de directives cliniques, dans des registres d'essais cliniques et aupres de societes de specialite medicale nationales et internationales. Valeurs La qualite des resultats est evaluee au moyen des criteres decrits dans le rapport du Groupe d'etude canadien sur les soins de sante preventifs (Tableau 1). Avantages, desavantages et couts Les gynecologues peuvent offrir l'option de la chirurgie a effraction minimale a leurs patientes, ce qui pourrait mettre en jeu le morcellement tissulaire et l'utilisation d'un morcellateur motorise a des fins de retrait de prelevements. Les femmes devraient etre avisees que, dans les cas ou l'on en vient a constater un sarcome uterin ou un cancer de l'endometre dont la presence etait insoupconnee, l'utilisation d'un morcellateur est associee a un risque accru de dissemination tumorale. Une formation adequate et des pratiques sures devraient etre mises en œuvre avant que l'on puisse offrir le recours au morcellement tissulaire. Declarations sommaires 1.Les sarcomes uterins peuvent etre difficiles a diagnostiquer de facon preoperatoire. Dans le cadre d'une chirurgie visant un leiomyome uterin supposement benin, le risque de constater un sarcome uterin dont la presence etait insoupconnee est d'environ 1 sur 350; dans le cas des leiomyosarcomes, ce risque est de 1 sur 500. (II-2) Un tel risque augmente avec l'âge. (II-2) 2.Dans les cas ou l'on constate un sarcome uterin dont la presence n'etait pas soupconnee, la tenue d'une chirurgie primaire donnant lieu a une rupture tumorale (y compris le morcellement de la tumeur) pourrait mener a la propagation intra-abdominale de la tumeur et a l'aggravation du pronostic. (II-2) 3.Les techniques chirurgicales permettant de preserver l'uterus demeurent une option sure pour les patientes presentant des leiomyomes symptomatiques qui souhaitent demeurer fertiles. (II-1) Recommandations 1.De nombreuses techniques peuvent etre utilisees aux fins du morcellement d'un prelevement uterin; les medecins devraient envisager l'utilisation de techniques qui minimisent la rupture des prelevements et leur propagation intra-abdominale. (III-C) 2.Toutes les patientes qui presentent un leiomyome uterin devraient faire l'objet d'une evaluation cherchant a determiner la presence possible d'une tumeur maligne, en fonction de leurs facteurs de risque et des resultats de l'imagerie preoperatoire, et ce, bien que la valeur de ces parametres soit limitee. (III-C) 3.La tenue preoperatoire d'une biopsie endometriale et d'une evaluation du col uterin en vue de chercher a eviter le morcellement de tumeurs malignes et premalignes potentiellement detectables est recommandee. (II-2A) 4.Les syndromes cancereux hereditaires donnant lieu a une hausse du risque de constater la presence d'une tumeur uterine maligne devraient etre consideres comme etant une contre-indication a la tenue d'un morcellement uterin non confine. (III-C) 5.Le morcellement de l'uterus est contre-indique pour ce qui est des femmes chez qui la presence d'un cancer est etablie ou soupconnee. (II-2A) Face a un fort indice de suspicion quant a la presence d'un sarcome uterin avant la chirurgie, les patientes devraient etre avisees de choisir de subir une hysterectomie abdominale totale, une salpingectomie bilaterale et peut-etre meme une ovariectomie. (II-2C) Une consultation en gyneco-oncologie devrait etre mise en œuvre. 6.La mise en œuvre de techniques de morcellement tissulaire necessite une formation et une experience adequates. Des initiatives visant a assurer la surete de la technique et du materiel de morcellement utilises devraient etre mises en œuvre au niveau local. (II-3B) 7.Le morcellement constitue une option acceptable pour le retrait de prelevements uterins benins et pourrait faciliter la mise en œuvre d'une approche chirurgicale a effraction minimale (laquelle est associee a des risques perioperatoires moindres). Des services de counseling devraient etre offerts a toutes les patientes au sujet des risques potentiellement associes a l'utilisation du morcellement (y compris les risques associes a la presence sous-jacente d'une tumeur maligne). (III-C)

With the widespread implementation of screening programs internationally, there will be an increase in early stage cervical cancer cases. In response to this, the Ministry of Health in each country will need to plan strategies to provide care such as radical surgery or radiation for this potentially curable group of women.The Gynaecologic Oncologists of Canada created a teaching module to intensively train a small number of locally identified gynecologists to perform radical hysterectomy and pelvic lymphadenectomy. The process was based on adult learning principles; it involved a Canadian gynecologic oncologist working in the low- or middle-resource country with the gynecologists and problem-solving local issues in health care delivery.The teaching process included a pretest and a posttest on the basis of the objectives of the module. There were 7 modules including preoperative evaluation of the patient, cone biopsy, radical hysterectomy, pelvic lymphadenectomy, ureteric injury, vascular injury, and follow-up after surgery. Each module was divided into background information, techniques, and complications. There were video clips imbedded in the modules. After the educational modules had been reviewed, the learners were walked through the surgical procedures repeatedly including a detailed assessment of performance after each case. Participants had the opportunity to provide feedback on the training program. The module was reviewed in Mongolia and implemented in Kenya.In low- and middle-resource countries where there is an urgent need to provide a curative surgical option for the management of early cervical cancer, a focused high-intensity curriculum delivered by a trained surgeon can translate into immediate change in clinical and surgical practice.

High-grade serous ovarian carcinoma (HG-SOC) is the most common subtype of ovarian cancer and has the worst prognosis. There is intense controversy on whether the temporal order of cytoreductive surgery and chemotherapy affects treatment outcome, with the main options being primary debulking surgery with adjuvant chemotherapy (PDS) versus neo-adjuvant chemotherapy with interval debulking surgery (NACT). Although some studies report that PDS-treated patients survive significantly longer than those receiving NACT, other reports showed no significant difference in patient outcome. To address this question in an unbiased way, we used computational modeling to simulate HG-SOC progression dynamics with different treatments. We adapted a mathematical framework to predict the evolution of chemotherapy resistance, and populated our model with survival data from >300 patients receiving PDS or NACT. After estimating the mutation rate of carcinoma cells and cancer cell number at diagnosis, we determined that most HG-SOC patients likely harbor chemotherapy-resistant cancer cells at diagnosis. Furthermore, we predicted the effects of PDS and NACT on the number of sensitive and resistant cells, as well as patient survival following treatment, and found that our model closely recapitulated clinical observations in both training and test sets. Based on our results, we predict that PDS with optimal debulking ( Finally, we evaluated the potential benefits of early diagnosis of naïve or relapsed HG-SOC. We recapitulated the clinical finding that CA125-based earlier diagnosis of relapsed cancer does not improve survival. We also predict that more sensitive detection methods (such as ctDNA-based diagnosis) are unlikely to improve survival post-relapse with current chemotherapy, because earlier diagnosis does not decrease the number of chemo-resistant cells, which are already enriched at recurrence. By contrast, our model predicts that with sufficiently sensitive assays, early detection could improve survival time and increase chances of cure. Note: This abstract was not presented at the meeting. Citation Format: Shengqing Gu, Liat Hogen, Stephanie Lheureux, Azin Sayad, Iryna Vyarvelska, Paulina Cybulska, Marcus Bernardini, Barry Rosen, Amit Oza, Benjamin G. Neel. Computational modeling of serous ovarian carcinoma dynamics: Implications for screening and therapy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-307. doi:10.1158/1538-7445.AM2015-LB-307

Carbohydrate-deficient glycoprotein syndromes (CDGS) are a family of multisystemic congenital diseases resulting in underglycosylated glycoproteins, suggesting defective N-glycan assembly. Fibroblast extracts from two patients with a recently described variant of this disease (CDGS type II) have previously been shown to have over 98% reduced activity of UDP-GlcNAc:alpha-6-D-mannoside beta-1,2-N-acetylglucosaminyltransferase II [GlcNAc-TII; Jaeken, J., Schachter, H., Carchon, H., De Cock, P., Coddeville, B.Spik, G. (1994) Arch. Dis. Childhood 71, 123-127]. We show in this paper that mononuclear cell extracts from one of these CDGS type-II patients have no detectable GlcNAc-TII activity and that similar extracts from 12 blood relatives of the patient, including his father, mother and brother, have GlcNAc-TII levels 32-67% that of normal levels (average 50.1% +/- 10.7% SD), consistent with an autosomal recessive disease. The poly(N-acetyllactosamine) content of erythrocyte membrane glycoproteins bands 3 and 4.5 of this CDGS patient were estimated, by tomato lectin blotting, to be reduced by 50% relative to samples obtained from blood relatives and normal controls. Similar to patients with hereditary erythroblastic multinuclearity with a positive acidified-serum lysis test (HEMPAS), erythrocyte membrane glycoproteins in the CDGS patient have increased reactivities with concanavalin A, demonstrating the presence of hybrid or oligomannose carbohydrate structures. However, bands 3 and 4.5 in HEMPAS erythrocytes have almost complete lack of poly(N-acetyllactosamine). Furthermore, CDGS type-II patients have a totally different clinical presentation and their erythrocytes do not show the serology typical of HEMPAS, suggesting that the genetic lesions responsible for these two diseases are possibly different.

Serous ovarian cancer (SOC) is the leading cause of morbidity/mortality from gynecologic malignancy. Current therapies increase survival significantly, yet the vast majority of SOC patients (70-90%) die of their disease. Patients almost always respond to initial courses of standard-of-care (platinum- and taxane-based) chemotherapy. Unfortunately, however, drug resistance almost always develops, resulting in the death of the patient. Two competing theories have been proposed to account for tumor initiation in SOC (and other malignancies); these theories also have important implications for therapy resistance. In the stochastic model, most, if not all, tumor cells can self-renew indefinitely; consequently, nearly all tumor cells provide a target population for the acquisition of drug resistance mutations. By contrast, the cancer stem cell (CSC) hypothesis holds that only a subset of tumor cells can initiate and maintain the tumor. Moreover, CSC might be intrinsically more resistant to some/many drugs that are effective against other (“bulk”) tumor cells. These two models differ fundamentally in their view of tumor-initiating cells (TIC). The essential feature of the CSC model is that tumors are organized hierarchically, such that TIC can be prospectively distinguished from non-TIC by phenotype. If the CSC model holds, it should be possible to identify and purify a stable cell population with the unique ability to generate serially transplantable tumors that recreate the heterogeneity of the initial malignancy. By contrast, the stochastic model predicts that TIC distribute into all cell fractions. Many studies of ovarian carcinogenesis and drug response have used immortalized cell lines grown for long periods of time in serum-containing culture. However, the extent to which these cells represent the biology of SOC is unclear. Many SOC lines do not reproduce serous histology when propagated as xenografts in immune-compromised mice; others cannot even give rise to xenografts. Even in culture, few of these lines show evidence of the cytologic and immunologic heterogeneity typically seen in primary tumors. Consequently, these lines might not be adequate for testing new therapies for SOC. Moreover, it is not clear that immortalized cell lines represent valid models for evaluating the CSC model or for studying TIC in SOC. Notably, studies of several other malignancies have shown that TIC as defined using immortalized cell lines do not have the same phenotype as those defined in xenografts using primary patient samples. Improving outcome for SOC patients will require better understanding of SOC pathogenesis and drug resistance, using assay systems that reflect the genetic and cellular diversity of human SOC more faithfully than conventional ovarian cancer cell lines. To this end, we have established a large collection of primary human SOC samples and developed a robust, quantitative assay for SOC tumor-initiating cells (TIC). Using this assay, we find that TICs are rare when assayed in either NOD/SCID or NOD/SCID/IL2Rγ−/− (NSG) mice. TIC frequency varies substantially between patients, although it is similar in primary ovarian masses and omental metastases, suggesting that TIC frequency is an intrinsic property of given ovarian tumor classes. For instance, CD133 marks all TICs from several primary SOC cases. However, in other cases, substantial TIC activity is found in both the CD133+ and CD133− fractions, whereas still other cases have exclusively CD133− TICs. Furthermore, the TIC phenotype can change in xenografts: primary tumors in which all TICs are CD133+ can give rise to xenografts that contain substantial numbers of CD133− TICs. Our results highlight the need for quantitative rigor in the evaluation of TICs and for caution when using passaged xenografts for such studies. Furthermore, although our data suggest that SOC conforms to the CSC hypothesis, the heterogeneity of the TIC phenotype may complicate its clinical application. To address whether instability in the TIC phenotype may be due to the acquisition of genetic alterations in the CD133- compared to the CD133+ fraction, we analyzed copy number alterations in CD133 positive and negative-derived xenografts. Preliminary analysis suggests that most genetic alterations are common in both fractions; however, in 3/6 cases, additional genetic alterations were observed in the CD133- fraction, suggesting the emergence of CD133- TIC might be, at least in part, genetically driven. The applicability of this observation to additional cases and primary sorted cells (i.e. those that were used to establish the xenografts), as well as the mechanism of genetic instability is currently under investigation. We used expression microarrays to examine differences between CD133+ and CD133- populations. We find that >1000 probes are differentially expressed in these two cell subsets, confirming that they are distinct cell populations. We have identified several putatively targetable pathways and transcription factor networks with altered expression in TIC-enriched fractions. The biological roles of these pathways in HG-SOC, specifically in the TIC compartment, are under investigation. Finally, we performed high-throughput flow cytometry: involving independent analysis of 365 cell surface markers to identify proteins expressed on all or subsets of HG-SOC cells. We have combined these analyses with mass cytometry (collaboration with Nolan's lab, Stanford University). Mass cytometry allows deep profiling of cell attributes and function using a novel multi-parametric approach combining flow cytometry with mass spectrometry that allows examination of up to 35 cell surface and/or intracellular markers on a single cell. Examination of 40 primary ovarian cancer samples has provided further supportive evidence for inter- and intra-patient heterogeneity in HG-SOC. Current analyses focus on biological validation of identified subpopulations marked by a series of cell surface and putative “stem cell” gene sets. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr SY35-02. doi:1538-7445.AM2012-SY35-02