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Background: The open-label, single-arm, multicenter ORZORA trial (NCT02476968) evaluated the efficacy and safety of maintenance olaparib in patients with platinum-sensitive relapsed ovarian cancer (PSR OC) who had tumor BRCA mutations (BRCAm) of germline (g) or somatic (s) origin or non-BRCA homologous recombination repair mutations (HRRm) and were in response to their most recent platinum-based chemotherapy after ≥2 lines of treatment. Methods: Patients received maintenance olaparib capsules (400mg twice daily) until disease progression. Prospective central testing at screening determined tumor BRCAm status and subsequent testing determined gBRCAm or sBRCAm status. Patients with predefined non-BRCA HRRm were assigned to an exploratory cohort. The co-primary endpoints were investigator-assessed progression-free survival (PFS; modified Response Evaluation Criteria in Solid Tumors v1.1) in BRCAm and sBRCAm cohorts. Secondary endpoints included health-related quality of life (HRQoL) and tolerability. Results: 177 patients received olaparib. At the primary data cut-off (17 April 2020), the median follow-up for PFS in the BRCAm cohort was 22.3months. The median PFS (95% CI) in BRCAm, sBRCAm, gBRCAm and non-BRCA HRRm cohorts was 18.0 (14.3-22.1), 16.6 (12.4-22.2), 19.3 (14.3-27.6) and 16.4 (10.9-19.3) months, respectively. Most patients with BRCAm reported improvements (21.8%) or no change (68.7%) in HRQoL and the safety profile was as expected. Conclusions: Maintenance olaparib had similar clinical activity in PSR OC patients with sBRCAm and those with any BRCAm. Activity was also observed in patients with a non-BRCA HRRm. ORZORA further supports use of maintenance olaparib in all patients with BRCA-mutated, including sBRCA-mutated, PSR OC.

Altres ajuts: Pla Estratègic de Recerca i Innovació en Salut (2016-2020 /SLT002/16/00200) Early detection of symptoms and prompt diagnosis of ovarian cancer are considered important avenues for improving patient experiences and outcomes. This qualitative study used a phenomenological approach to perform patient interviews, collecting individual accounts of the prediagnostic phase in women diagnosed and treated for ovarian cancer in 2016-2017. Purposive sampling was used to obtain a diverse sample of 24 participants, while thematic content analysis was used to extract themes and subthemes from interview data. Three themes and nine subthemes were identified. The first theme was women's delay in recognizing symptoms and seeking care, with subthemes on the lack of knowledge about early signs of ovarian cancer, gender-related barriers and false reassurance from negative test results. A second theme was missed opportunities during healthcare encounters, due to misattribution of women's symptoms by their physicians, underestimation of symptom severity and need for mediation and inadequate tests and/or false negative results. Finally, interviews highlighted the use of resources and alternative healthcare pathways, including complementary/alternative medicines, access to private health care and women's capacity for action and decision-making (agency) about their health. Delayed diagnosis of ovarian cancer is rooted in both individual factors (lack of health literacy, reluctance to seek care) and systemic issues (missed opportunities in healthcare encounters, access to timely specialist care). Further research is needed to investigate the extent to which traditional gender roles and socioeconomic inequalities condition women's ability to manage their own health and to interact with health professionals and the health system. In addition to the patient participation during the interviews, one author was a representative of a patient association.

[cat] INTRODUCCIÓ: L’endometriosi és una malaltia crònica, hormonodependent que pot arribar afectar fins a un 10% de les dones en edat fèrtil. Des que s’inicien els símptomes (dismenorrea, disquècia, disparèunia, dolor pelvià, disúria, entre altres) fins que s’estableix el diagnòstic poden arribar a passar fins a 10 anys. L’ecografia transvaginal és la prova complementària princeps pel diagnòstic de la malaltia. Quan l’endometriosi es localitza a la paret del recto-sigma, s’han descrit diferents procediments per millorar la precisió de l’ecografia en la detecció dels nòduls, incloent la preparació intestinal. A més, l’estatus inflamatori i d’estrès oxidatiu que suposa l’endometriosi augmenta el risc relatiu de presentar un càncer d’ovari. De nou, l’ecografia transvaginal té un paper clau en el diagnòstic diferencial entre benignitat i malignitat (aplicació de Simple Rules), però en un grup de pacients resultarà indeterminat. És per això que els biomarcadors juguen un paper clau en aquest grup de pacients amb resultats ecogràfics indeterminats. HIPÒTESI: El diagnòstic ecogràfic de l’endometriosi profunda a recto-sigma s’optimitza utilitzant la preparació intestinal prèvia a la realització de la prova per poder tenir un mapeig més precís en les pacients amb indicació de tractament quirúrgic. Les troballes ecogràfiques es poden confirmar durant la mateixa cirurgia (Estudi 1). En les pacients on no es requereix de tractament quirúrgic, la preparació intestinal permet fer un seguiment més detallat durant el tractament mèdic i/o de fertilitat (Estudi 2). El marcador tumoral HE4 a la circulació perifèrica pot ajudar a diferenciar l’endometriosi del càncer d’ovari en pacients amb troballes indeterminades durant l’ecografia transvaginal (Estudi 3.) OBJECTIUS: Objectiu principal: Comparar la precisió de l’ecografia transvaginal amb i sense preparació intestinal en el diagnòstic dels nòduls d’endometriosi a recto-sigma així com analitzar quin biomarcador (HE4 vs CA125) és més útil per diferenciar benignitat de malignitat en els pocs casos de troballes ecogràfiques indeterminades. Objectius secundaris: - Comparar la precisió de l’ecografia transvaginal amb i sense preparació intestinal en pacients que se sotmeten a cirurgia per endometriosi, comparant les troballes ecogràfiques amb les quirúrgiques. (Estudi 1) - Comparar la precisió de l’ecografia transvaginal amb i sense preparació intestinal en pacients que segueixen un tractament conservador (no quirúrgic) per endometriosi. (Estudi 2) - Valorar la tolerància de les pacients a la preparació intestinal. (Estudi 2) - Identificar si el biomarcador en circulació perifèrica HE4 és superior al CA125 en diferenciar l’endometriosi del càncer d’ovari quan els resultats de l’estudi ecogràfic són indeterminats. (Estudi 3) MÈTODES: Primer estudi: Es valora el recto-sigma amb ecografia transvaginal sense i amb preparació intestinal prèvia en pacients que s’han de sotmetre a tractament quirúrgic de l’endometriosi. Es comparen els resultats d’ambdues proves amb les troballes quirúrgiques. Segon estudi: Es valora el recto-sigma amb ecografia transvaginal sense i amb preparació intestinal prèvia en pacients que no tenen indicació quirúrgica. A més, es valora la tolerància a la preparació intestinal utilitzant una escala tipus Likert. Tercer estudi: En un grup de 208 pacients amb EAOC, endometrioma ovàric o carcinoma d’ovari (cèl·lules clares i endometroide), confirmats quirúrgicament, analitzem la relació entre les troballes ecogràfiques d’acord amb les Simple Rules, els nivells dels biomarcadors HE4 i CA125 en sang perifèrica i els resultats de l’estudi anatomopatològic. PRINCIPALS RESULTATS: Primer estudi: Es van incloure 40 pacients. Es van diagnosticar 4 nòduls més amb l’ecografia amb preparació intestinal, i 4 lesions valorades sense preparació com adherències, infiltraven la muscular pròpia intestinal, amb la preparació intestinal. Aquestes troballes es van confirmar amb les troballes quirúrgiques. Només un nòdul identificat amb la preparació intestinal no es va veure durant la cirurgia. Segon estudi: Es van incloure 110 pacients. Es van diagnosticar 2 nòduls més amb l’ecografia amb preparació intestinal, i el 55% de les lesions descrites com adherències sense preparació intestinal es van diagnosticar com a nòduls reals, de dimensions més reduïdes, amb la preparació intestinal. La preparació intestinal va ser ben tolerada per les pacients. Tercer estudi: Es van incloure 208 pacients amb lesions annexials (endometrioma, EAOC o càncer d’ovari) que es van sotmetre a cirurgia, 13 de les quals es van classificar com a indeterminades amb les troballes ecogràfiques. El biomarcador HE4, i no el CA125, va permetre diferenciar benignitat de malignitat, trobant diferències entre els tres grups. CONCLUSIONS: L’ecografia transvaginal amb preparació intestinal permet identificar més nòduls intestinals i descriure’ls amb més precisió que l’ecografia sense preparació prèvia, comparant-les amb les troballes quirúrgiques. Aquest augment en la precisió és útil tant per planificar la cirurgia com pel seguiment de les pacients sense indicació quirúrgica. La preparació intestinal és un procediment ben tolerat i acceptat entre les pacients amb endometriosi. El biomarcador HE4 és més sensible que el CA125 en les pacients amb endometriosi i sospita de malignitat amb ecografia indeterminada, convertint-se en el marcador d’elecció en aquest grup de pacients., [eng] INTRODUCTION: Endometriosis is a chronic, hormone-dependent disease that can affect up to 10% of women of childbearing age. There is a delay of up to 10 years from the onset of symptoms until the diagnosis. Transvaginal ultrasound is the main diagnosis tool. When endometriosis is located in the recto-sigma wall, different procedures have been described to improve the accuracy of ultrasound in the detection of the nodules, including bowel preparation. In addition, the inflammatory and oxidative stress status of endometriosis increases the relative risk of ovarian cancer. Again, transvaginal ultrasound plays a key role in the differential diagnosis between benignity and malignancy (application of Simple Rules), but in a group of patients it will be indeterminate. This is where biomarkers play a key role in this group of patients with indeterminate ultrasound results. The main objective of this thesis is to compare the accuracy of transvaginal ultrasound with and without bowel preparation in the diagnosis of rectosigmoid endometriosis nodules as well as to analyze which biomarker (HE4 vs CA125) is more useful to differentiate benignity from malignancy in the few cases where ultrasound findings are indeterminate. METHODS: We performed three studies. The first and second studies were related to transvaginal ultrasound findings with and without bowel preparation in patients with surgical indication and patients without. In this last group we also assessed the tolerance to the bowel preparation. In the third study, the ultrasound findings and tumoral biomarkers were assessed according the pathological findings in patients with ovarian cancer, endometriosis and ovarian cancer with endometriosis. RESULTS: The results of the first and second study showed that bowel preparation better assess the presence of rectosigmoid endometriosis nodules and it is a well-tolerated procedure. The results of the third study showed that the HE4 is a more useful biomarker to detect malignancy in patients with ovarian endometrioma when malignancy is suspected. CONCLUSIONS: Transvaginal ultrasound with bowel preparation allows the detection of more intestinal nodules and describes more precisely than ultrasound without previous preparation, comparing with surgical findings. This increase in accuracy is useful both for planning surgery and for monitoring patients without a surgical indication. Bowel preparation is a well-tolerated and accepted procedure among patients with endometriosis. The HE4 biomarker is more sensitive than CA125 in patients with endometriosis and suspected malignancy with indeterminate ultrasound, becoming the marker of choice in this group of patients.

Ovarian cancer is the most lethal gynaecological cancer in very-high-human-development-index regions. Ovarian cancer incidence and mortality rates are estimated to globally rise by 2035, although incidence and mortality rates depend on the region and prevalence of the associated risk factors. The aim of this study is to assess changes in incidence and mortality of ovarian cancer in Catalonia by 2030. Bayesian autoregressive age–period–cohort models were used to predict the burden of OC incidence and mortality rates for the 2015–2030 period. Incidence and mortality rates of ovarian cancer are expected to decline in Catalonia by 2030 in women ≥ 45 years of age. A decrease in ovarian-cancer risk was observed with increasing year of birth, with a rebound in women born in the 1980s. A decrease in mortality was observed for the period of diagnosis and period of death. Nevertheless, ovarian-cancer mortality remains higher among older women compared to other age groups. Our study summarizes the most plausible scenario for ovarian-cancer changes in terms of incidence and mortality in Catalonia by 2030, which may be of interest from a public health perspective for policy implementation.

(1) OBJECTIVE: To assess the performance of CA125, HE4, ROMA index and CPH-I index to preoperatively identify epithelial ovarian cancer (EOC) or metastatic cancer in the ovary (MCO). (2) METHODS: single center retrospective study, including women with a diagnosis of adnexal mass. We obtained the AUC, sensitivity, specificity and predictive values were of HE4, CA125, ROMA and CPH-I for the diagnosis of EOC and MCO. Subgroup analysis for women harboring adnexal masses with inconclusive diagnosis of malignancy by ultrasound features and Stage I EOC was performed. (3) RESULTS: 1071 patients were included, 852 (79.6%) presented benign/borderline tumors and 219 (20.4%) presented EOC/MCO. AUC for HE4 was higher than for CA125 (0.91 vs. 0.87). No differences were seen between AUC of ROMA and CPH-I, but they were both higher than HE4 AUC. None of the tumor markers alone achieved a sensitivity of 90%; HE4 was highly specific (93.5%). ROMA showed a sensitivity and specificity of 91.1% and 84.6% respectively, while CPH-I showed a sensitivity of 91.1% with 79.2% specificity. For patients with inconclusive diagnosis of malignancy by ultrasound features and with Stage I EOC, ROMA showed the best diagnostic performance (4) CONCLUSIONS: ROMA and CPH-I perform better than tumor markers alone to identify patients harboring EOC or MCO. They can be helpful to assess the risk of malignancy of adnexal masses, especially in cases where ultrasonographic diagnosis is challenging (stage I EOC, inconclusive diagnosis of malignancy by ultrasound features).

ObjectiveTo assess the impact of prehospital factors (diagnostic pathways, first presentation to healthcare services, intervals, participation in primary care) on 1-year and 5-year survival in people with epithelial ovarian cancer (EOC).DesignRetrospective quasi-population-based cohort study.SettingCatalan Integrated Public Healthcare System.ParticipantsPeople with EOC who underwent surgery with a curative intent in public Catalan hospitals between 1 January 2013 and 31 December 2014.Outcome measuresData from primary and secondary care clinical histories and care processes in the 18 months leading up to confirmation (signs and symptoms at presentation, diagnosis pathways, referrals, diagnosis interval) of the EOC diagnosis (stage, histology type, treatment). Diagnostic process intervals were based on the Aarhus statement. 1-year and 5-year survival analysis was undertaken.ResultsOf the 513 patients included in the cohort, 67.2% initially consulted their family physician, while 36.4% were diagnosed through emergency services. In the Cox models, survival was influenced by advanced stage at 1 year (HR 3.84, 95% CI 1.23 to 12.02) and 5 years (HR 5.36, 95% CI 3.07 to 9.36), as was the type of treatment received, although this association was attenuated over follow-up. Age became significant at 5 years of follow-up. After adjusting for age, adjusted morbidity groups, stage at diagnosis and treatment, 5-year survival was better in patients presenting with gynaecological bleeding (HR 0.35, 95% CI 0.16 to 0.79). Survival was not associated with a starting point involving primary care (HR 1.39, 95% CI 0.93 to 2.09), diagnostic pathways involving referral to elective gynaecological care from non-general practitioners (HR 0.80, 95% CI 0.51 to 1.26), or self-presentation to emergency services (HR 0.82, 95% CI 0.52 to 1.31).ConclusionsSurvival in EOC is not associated with diagnostic pathways or prehospital healthcare, but it is influenced by stage at diagnosis, administration of primary cytoreduction plus chemotherapy and patient age.

Simple Summary Since the irruption of PARPi in the therapeutic armamentarium for ovarian cancer, concerns regarding post-progression treatment outcomes have emerged, owing to known crossed-resistance mechanisms between PARPi and platinum. In this multicentric retrospective series of ovarian cancer patients, we evaluated chemotherapy results upon progression to maintenance with PARPi in the relapsed setting. We further selected the population of platinum-sensitive patients (according to the classical definition) retreated with platinum (n = 74). In this platinum-sensitive population, overall response rate and survival outcomes of platinum rechallenge after PARPi were similar to historical series of the prePARPi era. However, within this group, analysis according to BRCA status showed that BRCA mutant patients (n = 35) presented higher rates of progression and worse survival outcomes under subsequent platinum than BRCA wild type patients (n = 39), with statistically significant differences. This is the largest real-world data series of ovarian cancer patients treated with platinum rechallenge in the post-PARPi scenario. Background: Despite impressive progression-free survival (PFS) results from PARP inhibitors (PARPi) in ovarian cancer, concerns about their effect on post-progression treatment outcomes have recently arisen, particularly when administered in the relapsed setting. Overlapping mechanisms of resistance between PARPi and platinum have been described, and optimal therapies upon progression to PARPi are unknown. We communicate real-world data (RWD) on outcomes of subsequent chemotherapy upon progression to PARPi used as maintenance in ovarian cancer relapses, particularly focusing on platinum rechallenge, according to BRCA status. Methods: Data from high-grade serous or endometrioid ovarian cancer patients who received subsequent chemotherapy after progression to maintenance PARPi in the relapsed setting, in 16 Catalan hospitals between August 2016 and April 2021, and who were followed-up until July 2021, were included. Endpoints were overall response rate (ORR), and PFS and overall survival (OS) measured from the subsequent chemotherapy starting date. Results: 111 patients were included [46 (41.4%) presented pathological BRCA1/2 mutations, 8 (7.5%) in other homologous recombination-related genes]. Sixty-four patients (57.7%) had received two prior chemotherapy lines, including the one immediately prior to PARPi. PARPi were niraparib (n = 60, 54.1%), olaparib (n = 49, 44.1%), and rucaparib (n = 2, 1.8%). A total of 81 patients remained platinum-sensitive (PS population) after progression to PARPi (when progression-free interval [PFI] was >6 months after the last cycle of prior platinum) [median PFI 12.0 months (interquartile range, IQR, 8.8-17.1)]. Of those, 74 were treated with subsequent platinum regimens, with the following results: ORR of 41.9%, median PFS (mPFS) of 6.6 months (95% CI 6-9.2), and median OS (mOS) of 20.6 months (95% CI 13.6-28.9). Analysis of these 74 patients according to BRCA status showed that PFIs for BRCA mutant and non BRCA-mutant patients were 13.6 [IQR11.2-22.2] and 10.3 [IQR 7.4-14.9] months, respectively (p = 0.010); ORR were 40.0% versus 43.6%, respectively; Rates of progression (as best response) to subsequent platinum were 45.7% versus 17.9%, respectively (p = 0.004); mPFS and mOS were 3.5 (95% CI 2.5-8.6) versus 7.5 months (95% CI 6.5-10.1, p = 0.03), and 16.4 (95% CI 9.3-27.5) versus 24.2 months (95% CI 17.2-NR, p = 0.036), respectively. Conclusion: This is the largest series of real-world data on ovarian cancer patients retreated with platinum in the post-PARPi scenario, separately analyzing BRCA mutant and non-mutant patients, to our knowledge. In our platinum-sensitive population, rechallenge with platinum after progression upon PARPi in the 3rd or later lines for ovarian cancer relapses shows relevant ORR and similar PFS outcomes to historical series of the prePARPi era. However, BRCA mutant patients presented significantly higher rates of progression under subsequent platinum and worse survival outcomes associated with subsequent platinum than non-BRCA-mutant patients.

Case–control studies have shown an association of BARD1 with hereditary breast and/or ovarian cancer (HBOC) predisposition. BARD1 alternatively spliced isoforms are abundant and some are highly expressed in different cancer types. In addition, a number of BARD1 germline pathogenic variants have been reported among HBOC patients. In previous reports, BARD1 c.1977A>G variant has been classified as pathogenic since it produces a frameshift transcript lacking exons 2 to 9. In the present study, we sought to validate the mRNA splicing results previously published and to contribute with new evidence to refine the classification of this substitution according to ACMG/AMP guidelines. The presence of the variant was screened in patients and controls. RT-PCR was performed in order to compare the transcriptional profiles of two variant carriers and ten non-carrier controls. In addition, allele-specific expression was assessed. No differences in variant frequency were detected between patients and controls. The RNA assay confirmed the presence of the shorter transcript lacking exons 2–9, but it was detected both in carriers and non-carriers. Furthermore, allelic imbalance was discarded and no significant differences in the proportion of full-length and shorter transcript were detected between carriers and controls. The shorter transcript detected corresponds to BARD1 isoform η, constituted by exons 1, 10 and 11. Our results support that this transcript is a constitutive splicing product rather than an aberrant transcript caused by BARD1 c.1977A>G variant, and for this reason this variant should be considered as likely benign following ACMG/AMP guidelines.

Purpose: This study aimed to report the uptake of hysterectomy and/or bilateral salpingo-oophorectomy (BSO) to prevent gynaecological cancers (risk-reducing surgery [RRS]) in carriers of pathogenic MMR (path_MMR) variants.Methods: The Prospective Lynch Syndrome Database (PLSD) was used to investigate RRS by a cross-sectional study in 2292 female path_MMR carriers aged 30-69 years.Results: Overall, 144, 79, and 517 carriers underwent risk-reducing hysterectomy, BSO, or both combined, respectively. Two-thirds of procedures before 50 years of age were combined hysterectomy and BSO, and 81% of all procedures included BSO. Risk-reducing hysterectomy was performed before age 50 years in 28%, 25%, 15%, and 9%, and BSO in 26%, 25%, 14% and 13% of path_MLH1, path_MSH2, path_MSH6, and path_PMS2 carriers, respectively. Before 50 years of age, 107 of 188 (57%) BSO and 126 of 204 (62%) hysterectomies were performed in women without any prior cancer, and only 5% (20/392) were performed simultaneously with colorectal cancer (CRC) surgery.Conclusion: Uptake of RRS before 50 years of age was low, and RRS was rarely undertaken in association with surgical treatment of CRC. Uptake of RRS aligned poorly with gene-and age-associated risk estimates for endometrial or ovarian cancer that were published recently from PLSD and did not correspond well with current clinical guidelines. The reasons should be clarified. Decision-making on opting for or against RRS and its timing should be better aligned with predicted risk and mortality for endometrial and ovarian cancer in Lynch syn-drome to improve outcomes. (C) 2021 The Author(s). Published by Elsevier Ltd.

The nuclease MRE11A is often included in genetic test panels for hereditary breast and ovarian cancer (HBOC) due to its BRCA1-related molecular function in the DNA repair pathway. However, whether MRE11A is a true predisposition gene for HBOC is still questionable. We determined to investigate this notion by dissecting the molecular genetics of the c.1516G > T;p.E506* truncating MRE11A variant, that we pinpointed in two unrelated French-Canadian (FC) HBOC patients. We performed a case–control study for the variant in ~ 2500 breast, ovarian, and endometrial cancer patients from the founder FC population of Quebec. Furthermore, we looked for the presence of second somatic alterations in the MRE11A gene in the tumors of the carriers. In summary, these investigations suggested that the identified variant is not associated with an increased risk of developing breast or ovarian cancer. We finally performed a systematic review for all the previously reported MRE11A variants in breast and ovarian cancer. We found that MRE11A germline variants annotated as pathogenic on ClinVar often lacked evidence for such classification, hence misleading the clinical management for affected patients. In summary, our report suggests the lack of clinical utility of MRE11A testing in HBOC, at least in the White/Caucasian populations.

Colorectal (CRC) and endometrial cancer (EC) are the most common types of cancer in Lynch syndrome (LS). Risk reducing surgeries (RRS) might impact cancer incidence and mortality. Our objectives were to evaluate cumulative incidences of CRC, gynecological cancer and all-cause mortality after RRS in LS individuals.Retrospective analysis of 976 LS carriers from a single-institution registry. Primary endpoints were cumulative incidence at 75 years of cancer (metachronous CRC in 425 individuals; EC and ovarian cancer (OC) in 531 individuals) and all-cause mortality cumulative incidence, comparing extended (ES) vs. segmental surgery (SS) in the CRC cohort and risk reducing gynecological surgery (RRGS) vs. surveillance in the gynecological cohort.Cumulative incidence at 75 years of metachronous CRC was 12.5% vs. 44.7% (RRS in LS reduces the incidence of metachronous CRC and gynecological neoplasms, also indicating a reduction in all-cause mortality cumulative incidence in females undergoing RRGS.

Only a small fraction of hereditary breast and/or ovarian cancer (HBOC) cases are caused by germline variants in the high-penetrance breast cancer 1 and 2 genes (BRCA1 and BRCA2). BRCA1-associated ring domain 1 (BARD1), nuclear partner of BRCA1, has been suggested as a potential HBOC risk gene, although its prevalence and penetrance are variable according to populations and type of tumor. We aimed to investigate the prevalence of BARD1 truncating variants in a cohort of patients with clinical suspicion of HBOC. A comprehensive BARD1 screening by multigene panel analysis was performed in 4015 unrelated patients according to our regional guidelines for genetic testing in hereditary cancer. In addition, 51,202 Genome Aggregation Database (gnomAD) non-Finnish, non-cancer European individuals were used as a control population. In our patient cohort, we identified 19 patients with heterozygous BARD1 truncating variants (0.47%), whereas the frequency observed in the gnomAD controls was 0.12%. We found a statistically significant association of truncating BARD1 variants with overall risk (odds ratio (OR) = 3.78, CI = 2.10&ndash, 6.48, p = 1.16 &times, 10&minus, 5). This association remained significant in the hereditary breast cancer (HBC) group (OR = 4.18, 7.70, p = 5.45 &times, 5). Furthermore, deleterious BARD1 variants were enriched among triple-negative BC patients (OR = 5.40, CI = 1.77&ndash, 18.15, p = 0.001) compared to other BC subtypes. Our results support the role of BARD1 as a moderate penetrance BC predisposing gene and highlight a stronger association with triple-negative tumors.

Background: Approximately 25% of women diagnosed with tubo-ovarian high-grade serous carcinoma have germline deleterious mutations in BRCA1 or BRCA2, characteristic of hereditary breast and ovarian cancer syndrome, while somatic mutations have been detected in 3&ndash, 7%. We set out to determine the BRCA mutation rates and optimal tissue requirements for tumor BRCA testing in patients diagnosed with tubo-ovarian high-grade serous carcinoma. Methods: Sequencing was performed using a multiplexed polymerase chain reaction-based approach on 291 tissue samples, with a minimum sequencing depth of 500X and an allele frequency of &gt, 5%. Results: There were 253 surgical samples (87%), 35 biopsies (12%) and 3 cytology cell blocks (1%). The initial failure rate was 9% (25/291), including 9 cases (3%) with insufficient tumor, and 16 (6%) with non-amplifiable DNA. Sequencing was successful in 78% (228/291) and deemed indeterminate due to failed exons or variants below the limit of detection in 13% (38/291). Repeat testing was successful in 67% (28/42) of retested samples, with an overall success rate of 86% (251/291). Clinically significant (pathogenic, likely pathogenic) variants were identified in 17% (48/276) of complete and indeterminate cases. Successful sequencing was dependent on sample type, tumor cellularity and size (p &le, 0.001) but not on neoadjuvant chemotherapy or age of blocks (p &gt, 0.05). Conclusions: Our study shows a 17% tumor BRCA mutation rate, with an overall success rate of 86%. Biopsy and cytology samples and post-chemotherapy specimens can be used for tumor BRCA testing, and optimal tumors measure &ge, 5 mm in size with at least 20% cellularity.

© The Author(s)., [Background]: The BRCA1 c.3331_3334delCAAG founder mutation has been reported in hereditary breast and ovarian cancer families from multiple Hispanic groups. We aimed to evaluate BRCA1 c.3331_3334delCAAG haplotype diversity in cases of European, African, and Latin American ancestry. [Methods]: BC mutation carrier cases from Colombia (n = 32), Spain (n = 13), Portugal (n = 2), Chile (n = 10), Africa (n = 1), and Brazil (n = 2) were genotyped with the genome-wide single nucleotide polymorphism (SNP) arrays to evaluate haplotype diversity around BRCA1 c.3331_3334delCAAG. Additional Portuguese (n = 13) and Brazilian (n = 18) BC mutation carriers were genotyped for 15 informative SNPs surrounding BRCA1. Data were phased using SHAPEIT2, and identical by descent regions were determined using BEAGLE and GERMLINE. DMLE+ was used to date the mutation in Colombia and Iberia., [Results]: The haplotype reconstruction revealed a shared 264.4-kb region among carriers from all six countries. The estimated mutation age was ~ 100 generations in Iberia and that it was introduced to South America early during the European colonization period., [Conclusions]: Our results suggest that this mutation originated in Iberia and later introduced to Colombia and South America at the time of Spanish colonization during the early 1500s. We also found that the Colombian mutation carriers had higher European ancestry, at the BRCA1 gene harboring chromosome 17, than controls, which further supported the European origin of the mutation. Understanding founder mutations in diverse populations has implications in implementing cost-effective, ancestry-informed screening., AMDEA was supported with graduate Fellowships from UC Davis T32 Biotechnology Program. MB, ME, and LGC-C received funding from GSK Oncology and from “Oficina de Desarrollo a la Docencia de la Universidad del Tolima, Convocatoria 2010”. AC and AEF received funding from the Colciencias program “Becas Doctorales Nacionales, Convocatorias 528-2011 and 647-2015”. JB received funding from the Colciencias program “Formación de Capital Humano de Alto Nivel para el Departamento de Tolima- 2016, convocatoria 755”. BRCA1/2 genotyping of the Brazilian patients was performed in part with grants from CNPq (408313/2016-1), FAPERGS and Fundo de Incentivo a Pesquisa (FIPE) do Hospital de Clínicas de Porto Alegre, Brazil. AV received funding from CIBERER (grant ER17P1AC7112/2017). PC received funding from FONDEF grant #CA12I10152. CL was Supported by the Carlos III National Health Institute funded by FEDER funds—a way to build Europe—[PI19/00553; PI16/00563; PI16/01898; SAF2015-68016-R and CIBERONC]; the Government of Catalonia [Pla estratègic de recerca i innovació en salut (PERIS_MedPerCan and URDCat projects), 2017SGR1282 and 2017SGR496]. BR received funding from the National Institutes of Health (R01GM123306).

Contains fulltext : 229292.pdf (Publisher’s version ) (Open Access) PURPOSE: We assessed the associations between population-based polygenic risk scores (PRS) for breast (BC) or epithelial ovarian cancer (EOC) with cancer risks for BRCA1 and BRCA2 pathogenic variant carriers. METHODS: Retrospective cohort data on 18,935 BRCA1 and 12,339 BRCA2 female pathogenic variant carriers of European ancestry were available. Three versions of a 313 single-nucleotide polymorphism (SNP) BC PRS were evaluated based on whether they predict overall, estrogen receptor (ER)-negative, or ER-positive BC, and two PRS for overall or high-grade serous EOC. Associations were validated in a prospective cohort. RESULTS: The ER-negative PRS showed the strongest association with BC risk for BRCA1 carriers (hazard ratio [HR] per standard deviation = 1.29 [95% CI 1.25-1.33], P = 3×10(-72)). For BRCA2, the strongest association was with overall BC PRS (HR = 1.31 [95% CI 1.27-1.36], P = 7×10(-50)). HR estimates decreased significantly with age and there was evidence for differences in associations by predicted variant effects on protein expression. The HR estimates were smaller than general population estimates. The high-grade serous PRS yielded the strongest associations with EOC risk for BRCA1 (HR = 1.32 [95% CI 1.25-1.40], P = 3×10(-22)) and BRCA2 (HR = 1.44 [95% CI 1.30-1.60], P = 4×10(-12)) carriers. The associations in the prospective cohort were similar. CONCLUSION: Population-based PRS are strongly associated with BC and EOC risks for BRCA1/2 carriers and predict substantial absolute risk differences for women at PRS distribution extremes.

Adult-type granulosa cell tumor (aGCT) is a rare malignant ovarian sex cord-stromal tumor, harboring recurrent FOXL2 c.C402G/p.C134W hotspot mutations in 97% of cases. These tumors are considered to have a favorable prognosis, however aGCTs have a tendency for local spread and late recurrences, which are associated with poor survival rates. We sought to determine the genetic alterations associated with aGCT disease progression. We subjected primary non-recurrent aGCTs (n=7), primary aGCTs that subsequently recurred (n=9) and their matched recurrences (n=9), and aGCT recurrences without matched primary tumors (n=10) to targeted massively parallel sequencing of ≥410 cancer-related genes. In addition, 3 primary non-recurrent aGCTs and 9 aGCT recurrences were subjected to FOXL2 and TERT promoter Sanger sequencing analysis. All aGCTs harbored the FOXL2 C134W hotspot mutation. TERT promoter mutations were found to be significantly more frequent in recurrent (18/28, 64%) than primary aGCTs (5/19, 26%, p=0.017). In addition, mutations affecting TP53, MED12 and TET2 were restricted to aGCT recurrences. Pathway annotation of altered genes demonstrated that aGCT recurrences displayed an enrichment for genetic alterations affecting cell cycle pathway-related genes. Analysis of paired primary and recurrent aGCTs revealed that TERT promoter mutations were either present in both primary tumors and matched recurrences or were restricted to the recurrence and absent in the respective primary aGCT. Clonal composition analysis of these paired samples further revealed that aGCTs display intra-tumor genetic heterogeneity and harbor multiple clones at diagnosis and relapse. We observed that in a subset of cases, recurrences acquired additional genetic alterations not present in primary aGCTs, including TERT, MED12 and TP53 mutations and CDKN2A/B homozygous deletions. Albeit harboring relatively simple genomes, our data provide evidence to suggest that aGCTs are genetically heterogeneous tumors and that TERT promoter mutations and/or genetic alterations affecting other cell cycle-related genes may be associated with disease progression and recurrences.

Fanconi anemia (FA) is caused by biallelic mutations in FA genes. Monoallelic mutations in five of these genes (BRCA1, BRCA2, PALB2, BRIP1 and RAD51C) increase the susceptibility to breast/ovarian cancer and are used in clinical diagnostics as bona-fide hereditary cancer genes. Increasing evidence suggests that monoallelic mutations in other FA genes could predispose to tumor development, especially breast cancer. The objective of this study is to assess the mutational spectrum of 14 additional FA genes (FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, FANCM, FANCP, FANCQ, FANCR and FANCU) in a cohort of hereditary cancer patients, to compare with local cancer-free controls as well as GnomAD. A total of 1021 hereditary cancer patients and 194 controls were analyzed using our next generation custom sequencing panel. We identified 35 pathogenic variants in eight genes. A significant association with the risk of breast cancer/breast and ovarian cancer was found for carriers of FANCA mutations (odds ratio (OR) = 3.14 95% confidence interval (CI) 1.4&ndash, 6.17, p = 0.003). Two patients with early-onset cancer showed a pathogenic FA variant in addition to another germline mutation, suggesting a modifier role for FA variants. Our results encourage a comprehensive analysis of FA genes in larger studies to better assess their role in cancer risk.

Els programes de recuperació multimodal o en la seva definició anglesa Enhanced Recovery After Surgery (ERAS), inclouen múltiples elements perioperatoris dissenyats per aconseguir una recuperació rápida després de la cirurgia, reduir la morbiditat perioperatòria i aconseguir una estada hospitalària més curta. No obstant això, la evidència sobre la seva eficàcia quan s'aplica a pacients amb càncer ginecològic avançat es escassa. En aquest assaig clínic aleatoritzat prospectiu i intervencionista, les dones sotmeses a una cirurgia laparotòmica per sospita de càncer d'ovari avançat (estadis FIGO IIb-IV) des de juny de 2014 fins a març de 2018 en un hospital de referència en oncologia ginecològica a Barcelona (Espanya ) van ser tractades seguint un protocol ERAS específic o maneig convencional (MC). L'Objectiu primari va ser la reducció de l'estada hospitalaria, i els objectius secundaris van ser la incidència i el tipus de complicacions intraoperatòries i postoperatòries, la taxa de reingrés i la mortalitat dins el període de seguiment de 30 dies. Es va realitzar una anàlisi de costos comparant les dues estratègies. Es van reclutar un total de 110 pacients, de les quals es van incloure en l'anàlisi final 99, 50 pacients en grup ERAS, i 49 a MC. Tots dos grups van ser comparables pel que fa a les característiques basals i la complexitat de la cirurgia citoreductora, amb una puntuació general de complexitat quirúrgica d'Aletti o Surgery Complexity Score (SCS) de 7,4. El compliment general de l'protocol ERES va ser de l'93%. En comparació amb el grup MC, els pacients en el grup ERAS van tenir una reducció en la estada hospitalaria mitjana de dos dies (7 vs. 9 dies; p = 0,0099) i una taxa disminuïda de reingrés (6% vs 20%, p = 0,0334). No es van detectar diferències significatives addicionals pel que fa a la incidència de complicacions intraoperatòries o postoperatòries, complicacions greus (Dindo grau IIIB-IV), Complication comprehensive index (CCI), necessitat de reintervenció durant l'estada hospitalària o mortalitat. L'anàlisi de cost per pacient va revelar una reducció de 849 ? per pacient inclòs en el protocol ERAS en comparació amb el protocol MC. Los programas de recuperación multimodal o en su definición inglesa Enhanced Recovery After Surgery (ERAS), incluyen múltiples elementos perioperatorios diseñados para lograr una recuperación temprana después de la cirugía, reducir la morbilidad perioperatoria y conseguir una estancia hospitalaria más corta. Sin embargo, los datos sólidos sobre su eficacia cuando se aplica a pacientes con cáncer ginecológico avanzado son escasos. En este ensayo clínico aleatorizado prospectivo e intervencionista, las mujeres sometidas a una cirugía laparotómica por sospecha de cáncer de ovario avanzado (estadios FIGO IIb-IV) desde junio de 2014 hasta marzo de 2018 en un hospital de referencia en oncología ginecológica en Barcelona (España) fueron tratadas siguiendo un protocolo ERAS específico o manejo convencional (MC). El Objetivo primario fue la reducción de la LOS, y los objetivos secundarios fueron la incidencia y el tipo de complicaciones intraoperatorias y postoperatorias, la tasa de reingreso y la mortalidad dentro del período de seguimiento de 30 días. Se realizó un análisis de costes comparando ambas estrategias. Se reclutaron un total de 110 pacientes, de las cuales se incluyeron en el análisis final 99, 50 pacientes en grupo ERAS, y 49 en MC. Ambos grupos fueron comparables con respecto a las características basales y la complejidad de la cirugía citorreductora, con una puntuación general de complejidad quirúrgica de Aletti o Surgery Complexity Score (SCS) de 7,4. El cumplimiento general del protocolo ERAS fue del 93%. En comparación con el grupo MC, los pacientes en el grupo ERAS tuvieron una reducción en la LOS mediana de dos días (7 vs. 9 días; p = 0.0099) y una tasa disminuida de reingreso (6% vs. 20%, p = 0.0334). No se detectaron diferencias significativas adicionales con respecto a la incidencia de complicaciones intraoperatorias o postoperatorias, complicaciones graves (DINDO grado IIIB-IV), Complication comprehensive index (CCI), necesidad de reintervención durante la estancia hospitalaria o mortalidad. El análisis de costo por paciente reveló una reducción de 849? por paciente incluido en el protocolo ERAS en comparación con el protocolo MC. Enhanced recovery after surgery (ERAS) programs include multiple perioperative elements designed to achieve early recovery after surgery, reduce perioperative morbidity and a shorter length of stay (LOS). However solid data regarding its efficacy when applied to Advanced Gynecological cancer patients is sparse. Methods In this prospective, interventional randomized clinical trial, women undergoing lapartomic surgery for suspected advanced ovarian cancer (FIGO stages IIb–IV) from June 2014 to March 2018 at a reference hospital in gynecologic oncology in Barcelona (Spain) were treated following either an ERAS protocol or conventional management (MC). The primary outcome was reduction in LOS, and secondary outcomes were incidence and type of intra and postoperative complications, rate of readmission and mortality within the 30-day follow-up period. A cost analysis was performed comparing both strategies Results The ERAS group comprised 50 patients, and the MC group, 49 patients. Both groups were comparable with respect to baseline characteristics and complexity of the cytoreductive surgery, with an overall medium/high Aletti surgical complexity score (SCS) of 7.4. Overall compliance to the ERAS protocol was 93%. As compared to the MC group, patients in the ERAS group had a decreased median of LOS of two days (7 vs. 9 days; p = 0.0099) and a decreased rate of readmission (6% vs. 20%, p = 0.0334). No further significant differences were detected with respect to incidence of intraoperative or postoperative complications, severe (grade IIIB–IV) complications, Complication comprehensive index (CCI), reoperation during primary stay, or mortality. The cost per patient analysis revealed a reduction of 849 ? per patient included in ERAs protocol compared with MC protocol. Universitat Autònoma de Barcelona. Programa de Doctorat en Pediatria, Obstetrícia i Ginecologia

High-grade serous carcinoma (HGSC) is the most common and deadly subtype of ovarian cancer. It is characterised by presenting defects in the homologous recombination repair, most frequently associated to BRCA1 mutations. Although most patients will initially respond to first-line chemotherapy with platinum-based agents, up to a quarter will be resistant to treatment. In this thesis we have aimed, firstly, to advance in the understanding of HGSC tumour physiology and its dependence on BRCA1 and, secondly, to identify a protein signature able to discriminate between chemotherapy resistant and sensitive patients. To this intent, in the first part of the thesis, we have performed a multi-layered proteomic characterization of patient-derived ovarian tissues, which has revealed the importance of both ubiquitination and phosphorylation layers of regulation in modulating key cellular processes in HGSC, their dependency on BRCA1 and the identification of BRCA1 substrates responsible for driving ubiquitination signalling. In the second part of the thesis, using discovery and targeted proteomics in HGSC tissues, we have identified a protein signature able to discriminate between chemotherapy resistant and sensitive patients at the time of cancer diagnosis. Collectively, we have performed a comprehensive molecular characterization of HGSC that provides a groundwork for future mechanistic-based studies and the development of new targeted therapies in ovarian cancer. In addition, we advance in the optimization of therapeutic decision making through the identification of a promising protein signature able to predict response to chemotherapy. El carcinoma serós d’alt grau (HGSC) és el tipus de càncer d’ovari més freqüent i el que s’associa a una més alta mortalitat. Es caracteritza per presentar defectes en la recombinació homòloga, sobretot associats a mutacions en el gen BRCA1. Tot i que inicialment la majoria de pacients respondran a tractaments amb quimioteràpia basats en platí, fins a un quart dels pacients seran resistents a aquest tractament. En aquesta tesi hem volgut, primerament, avançar en l’enteniment de la fisiologia tumoral del HGSC i la seva dependència en BRCA1 i, en segon lloc, identificar una signatura de proteïnes capaç de discriminar entre pacients resistents i sensibles a la quimioteràpia. Basant-nos en aquests objectius, en la primera part de la tesi hem realitzat una caracterització proteòmica de teixits derivats de pacients, que ha demostrat la importància dels nivells de regulació per ubiquitinació i fosforilació en la modulació de processos cel·lulars en el HGSC, la seva dependència en BRCA1 i la identificació de substrats de BRCA1 responsables de la modulació dels processos d’ubiquitinació. En la segona part de la tesi, utilitzant proteòmica de cribratge i dirigida, hem identificat una signatura de proteïnes en teixit capaç de discriminar entre pacients resistents i sensibles a la quimioteràpia en el moment del diagnòstic del càncer. En conjunt, hem realitzat una caracterització molecular integral del HGSC que serveix com a base per a futurs estudis mecanístics i el desenvolupament de noves teràpies. A més, avancem en la optimització de la presa de decisions terapèutiques amb la identificació d’una signatura de proteïnes prometedora capaç de predir la resposta al tractament amb quimioteràpia.

Hipótesis: ¿El daño crónico en el ADN o bloqueo de la HR crónico produce un shift o una selección de células que han cambiado su metabolismo para poder sobrevivir a la situación? Objetivos: El principal objetivo de esta tesis doctoral ha sido estudiar la correlación entre los defectos de reparación en la recombinación homóloga o daño crónico en el ADN y la adaptación metabólica que se lleva a cabo para poder sobrevivir en esa situación en el cáncer de ovario seroso de alto grado. Como objetivos concretos de la tesis tenemos: A) Generación y caracterización de modelos que padezcan daño crónico en el ADN o sufran defectos en la reparación por recombinación homóloga. B) Estudiar los mecanismos de adaptación metabólica de estos modelos celulares al daño crónico y los fallos en la recombinación homologa C) Ver el papel que pueden jugar inhibidores de la cadena respiratoria como posibles tratamientos a tumores de estas características y las interacciones con otros tratamientos que se utilizan actualmente.

International audience; A substantial proportion of epithelial ovarian cancer (EOC) arises in the fallopian tube and other epithelia of the upper genital tract; these epithelia may incur damage and neoplastic transformation after sexually transmitted infections (STI) and pelvic inflammatory disease. We investigated the hypothesis that past STI infection, particularly Chlamydia trachomatis, is associated with higher EOC risk in a nested case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort including 791 cases and 1669 matched controls. Serum antibodies against C. trachomatis, Mycoplasma genitalium, herpes simplex virus type 2 (HSV-2) and human papillomavirus (HPV) 16, 18 and 45 were assessed using multiplex fluorescent bead-based serology. Conditional logistic regression was used to estimate relative risks (RR) and 95% confidence intervals (CI) comparing women with positive vs. negative serology. A total of 40% of the study population was seropositive to at least one STI. Positive serology to C. trachomatis Pgp3 antibodies was not associated with EOC risk overall, but with higher risk of the mucinous histotype (RR = 2.30 [95% CI = 1.22-4.32]). Positive serology for chlamydia heat shock protein 60 (cHSP60-1) was associated with higher risk of EOC overall (1.36 [1.13-1.64]) and with the serous subtype (1.44 [1.12-1.85]). None of the other evaluated STIs were associated with EOC risk overall; however, HSV-2 was associated with higher risk of endometrioid EOC (2.35 [1.24-4.43]). The findings of our study suggest a potential role of C. trachomatis in the carcinogenesis of serous and mucinous EOC, while HSV-2 might promote the development of endometrioid disease.

Germline/somatic BRCA-mutated ovarian carcinomas (OC) are associated to have better response with platinum-based chemotherapy and long-term prognosis than non-BRCA-associated OCs. In addition, these mutations are predictive factors to response to Poly(ADP-ribose) polymerase (PARP) inhibitors. Different positioning papers have addressed the clinical recommendations for BRCA testing in OC. This consensus guide represents a collection of technical recommendations to address the detection of BRCA1/2 mutations in the molecular diagnostic testing strategy for OC. Under the coordination of Spanish Society of Pathology (SEAP-IAP) and the Spanish Society of Human Genetics (AEGH), these recommendations have been developed by pathologists and geneticists taking into account previously published recommendations and their experience in the molecular characterization of these genes. Since the implementation of BRCA testing as a predictive factor can initiate the workflow by testing germline mutations in the blood or by testing both germline and somatic mutations in tumor tissue, distinctive features of both strategies are discussed. Additionally, the recommendations included in this paper provide some references, quality parameters, and genomic tools aimed to standardize and facilitate the clinical genomic diagnosis of OC.

PURPOSE In the ENGOT-OV16/NOVA trial (ClinicalTrials.gov identifier: NCT01847274 ), maintenance therapy with niraparib, a poly(ADP-ribose) polymerase inhibitor, prolonged progression-free survival in patients with platinum-sensitive, recurrent ovarian cancer who had a response to their last platinum-based chemotherapy. The objective of the study was to assess the clinical benefit and patient-reported outcomes in patients who had a partial response (PR) and complete response (CR) to their last platinum-based therapy. PATIENTS AND METHODS A total of 553 patients were enrolled in the trial. Of 203 patients with a germline BRCA mutation (g BRCAmut), 99 had a PR and 104 had a CR to their last platinum-based therapy; of 350 patients without a confirmed g BRCAmut (non–g BRCAmut), 173 had a PR and 177 had a CR. Post hoc analyses were carried out to evaluate safety and the risk of progression in these patients according to g BRCAmut status and response to their last platinum-based therapy. Ovarian cancer–specific symptoms and quality of life were assessed using the Functional Assessment of Cancer Therapy–Ovarian Symptom Index. RESULTS Progression-free survival was improved in patients treated with niraparib compared with placebo in both the g BRCAmut cohort (PR: hazard ratio [HR], 0.24; 95% CI, 0.131 to 0.441; P < .0001; CR: HR, 0.30; 95% CI, 0.160 to 0.546; P < .0001) and the non–g BRCAmut cohort (PR: HR, 0.35; 95% CI, 0.230 to 0.532; P < .0001; CR: HR, 0.58; 95% CI, 0.383 to 0.868; P = .0082). The incidence of any-grade and grade 3 or greater adverse events was manageable. No meaningful differences were observed between niraparib and placebo in PR and CR subgroups with respect to patient-reported outcomes. CONCLUSION Patients achieved clinical benefit from maintenance treatment with niraparib regardless of response to the last platinum-based therapy.

Background: Cancer antigen 125 (CA125) is the most promising ovarian cancer screening biomarker to date. Multiple studies reported CA125 levels vary by personal characteristics, which could inform personalized CA125 thresholds. However, this has not been well described in premenopausal women. Methods: We evaluated predictors of CA125 levels among 815 premenopausal women from the New England Case Control Study (NEC). We developed linear and dichotomous (≥35 U/mL) CA125 prediction models and externally validated an abridged model restricting to available predictors among 473 premenopausal women in the European Prospective Investigation into Cancer and Nutrition Study (EPIC). Results: The final linear CA125 prediction model included age, race, tubal ligation, endometriosis, menstrual phase at blood draw, and fibroids, which explained 7% of the total variance of CA125. The correlation between observed and predicted CA125 levels based on the abridged model (including age, race, and menstrual phase at blood draw) had similar correlation coefficients in NEC (r = 0.22) and in EPIC (r = 0.22). The dichotomous CA125 prediction model included age, tubal ligation, endometriosis, prior personal cancer diagnosis, family history of ovarian cancer, number of miscarriages, menstrual phase at blood draw, and smoking status with AUC of 0.83. The abridged dichotomous model (including age, number of miscarriages, menstrual phase at blood draw, and smoking status) showed similar AUCs in NEC (0.73) and in EPIC (0.78). Conclusions: We identified a combination of factors associated with CA125 levels in premenopausal women. Impact: Our model could be valuable in identifying healthy women likely to have elevated CA125 and consequently improve its specificity for ovarian cancer screening.

Ovarian cancer is the most lethal gynecological malignancy due to the silent nature on its early onset and the rapid acquisition of drug resistance. Histologically heterogeneous, it includes several subtypes with different mutational landscapes, hampering the development of effective targeted therapies. Non-coding RNAs are emerging as potential new therapeutic targets in cancer. To search for a microRNA signature related to ovarian carcinomas and study its potential as effective targeted therapy, we examined the expression of 768 miRNA in a large collection of tumor samples and found miR-654-5p to be infraexpressed in ovarian serous carcinomas, the most common and aggressive type. Restoration of miR-654-5p levels reduced tumor cell viability in vitro and in vivo and impaired sphere formation capacity and viability of ovarian cancer patient-derived ascitic cells ex vivo. CDCP1 and PLAGL2 oncogenes were found to be the most relevant direct miR-654-5p targets and both genes convey in a molecular signature associated with key cancer pathways relevant to ovarian tumorigenesis, such as MYC, WNT and AKT pathways. Together, we unveiled the tumor suppressor function of miR-654-5p, suggesting that its restoration or co-targeting of CDCP1 and PLAGL2 may be an effective therapeutic approach for ovarian cancer., This work was supported in part by grants from Instituto de la Mujer Dexeus (DEXEUS-B29/012), CIBER (CB16/12/00328), SGR (2017 SGR 1661), the Ministerio de Economia y Competitividad and Fondos FEDER (RTC-2015-3821-1), Instituto Carlos III (PI15/00238 to A.S. and PI17/00564 to M.F.S) and the Miguel Servet Program (CP13/00158 and CPII18/00027 to AS. and CPII16/00006 to MFS). AP and LS were supported by predoctoral VHIR fellowships and CJ by an AGAUR predoctoral fellowship (VHIR: PRED-VHIR-2014-11 and PRED-VHIR-2017; AGAUR: 2017FI_B_00095, respectively).

El càncer d'ovari és la neoplàsia maligna ginecològica més letal, freqüentment diagnosticada en estadis avançats quan la malaltia es troba disseminada. L'heterogeneïtat genòmica i genètica descrita en càncer d'ovari contribueix al desenvolupament de resistència tumoral, dificulta tractaments efectius i finalment causa la recurrència de la malaltia. Tot i això, també ofereix noves vulnerabilitats específiques de les cèl·lules canceroses que poden millorar l'efectivitat de les teràpies existents. En aquest sentit, com el fus mitòtic és una diana clàssica en el desenvolupament de teràpies contra el càncer, l'ús d'agents que incrementen la inestabilitat cromosòmica està emergint com a nova eina terapèutica augmentant el benefici clínic dels pacients. En la present tesi hem identificat una sèrie de gens mitòtics que es troben sobreexpressats en càncer d'ovari associats a una pitjor supervivència. En concret, s'ha caracteritzat el paper d'Aurora Borealis (BORA), prèviament descrita com una proteïna mitòtica que juga un paper clau en l'activació de la quinasa mitòtica, PLK1. Els assajos de guany i pèrdua de funció de BORA en models de ratolí i en cultius de cèl·lules d'ascites provinents de pacients crescuts en 3D, juntament amb una anàlisi transcriptòmica en línies cel·lulars clínicament representatives de càncer d'ovari, van revelar un paper oncogènic de BORA en el desenvolupament del tumor que modula la supervivència cel·lular, la disseminació i les vies inflamatòries. Tractaments combinats usant inhibidors aprovats a la clínica contra els efectors oncogènics de BORA, com BCL-2 i CDK6, van oferir resultats prometedors en els nostres models de càncer d'ovari. En resum, les dades que es mostren en aquesta tesi mostren noves evidències sobre el paper de BORA a la tumorigènesi i proporcionen noves eines terapèutiques per al tractament del càncer d'ovari. El cáncer de ovario es la neoplasia maligna ginecológica más letal, frecuentemente diagnosticada en estadios avanzados cuando la enfermedad se encuentra diseminada. La heterogeneidad molecular, tanto genómica como genética, descrita en cáncer de ovario contribuye al desarrollo de resistencia tumoral, dificulta tratamientos efectivos y finalmente causa la recurrencia de la enfermedad. Sin embargo, también ofrece nuevas vulnerabilidades específicas de las células cancerosas que pueden mejorar la efectividad de las terapias existentes. En este sentido, como el huso mitótico es una diana clásica en el desarrollo de terapias contra el cáncer, el uso de agentes que incrementan la inestabilidad cromosómica está emergiendo como nueva herramienta terapéutica aumentando el beneficio clínico de los pacientes. En la presente tesis hemos identificado una serie de genes mitóticos que se encuentran sobre-expresados en cáncer de ovario asociados a una peor supervivencia. En concreto, se ha caracterizado el papel de Aurora Borealis (BORA), previamente descrita como una proteína mitótica que juega un papel clave en la activación de la quinasa mitótica, PLK1. Los ensayos de ganancia y pérdida de función de BORA en modelos de ratón y en cultivos de células de ascitis provenientes de pacientes crecidos en 3D, junto con un análisis transcriptómico en líneas celulares clínicamente representativas de cáncer de ovario, revelaron un papel oncogénico de BORA en el desarrollo del tumor que modula la supervivencia celular, la diseminación y las vías inflamatorias. Tratamientos combinados usando inhibidores aprobados en la clínica contra los efectores oncogénicos de BORA, como BCL-2 y CDK6, ofrecieron resultados prometedores en nuestros modelos de cáncer de ovario. En resumen, los datos que se muestran en esta tesis muestran nuevas evidencias sobre el papel de BORA en la tumorigénesis y proporcionan nuevas herramientas terapéuticas para el tratamiento del cáncer de ovario. Ovarian cancer is the most lethal gynecology malignancy, frequently diagnosed at advanced stages with disseminated disease. The genomic and genetic molecular heterogeneity described in ovarian cancer contributes to the development of tumor resistance, hampers effective treatments and ultimately causes disease recurrence. However, it also offers novel potential vulnerabilities that can enhance the effectiveness of existing therapies. In this regard, as the mitotic spindle is a classical target for treating cancer, chromosomal instability-exploiting therapies are emerging in the landscape of anti-cancer therapeutic tools yielding better clinical outcomes. In the present thesis we have identified a number of mitotic-enriched genes overexpressed in ovarian cancer associated with poor overall survival. We further characterized the role of Aurora Borealis (BORA), previously described as a mitotic protein which plays a key role in activating the master mitotic kinase, PLK1. Gain and loss of function assays in mouse models and ex vivo patient-derived ascites cultures, together with a whole genome transcriptome analysis in clinically representative cells lines, revealed an oncogenic role of BORA in tumor development modulating survival, dissemination and inflammatory related-pathways. Importantly, combinatory treatments of FDA-approved inhibitors against oncogenic downstream effectors of BORA, such BCL-2 and CDK6, offered promising results in ovarian cancer models. Collectively, the data shown in this thesis depict novel evidence regarding the role of BORA in tumorigenesis and provide novel potential therapeutic opportunities for ovarian cancer management.

PURPOSE This study estimated time without symptoms or toxicity (TWiST) with niraparib compared with routine surveillance (RS) in the maintenance treatment of patients with recurrent ovarian cancer. PATIENTS AND METHODS Mean progression-free survival (PFS) was estimated for niraparib and RS by fitting parametric survival distributions to Kaplan-Meier data for 553 patients with recurrent ovarian cancer who were enrolled in the phase III ENGOT-OV16/NOVA trial. Patients were categorized according to the presence or absence of a germline BRCA mutation—g BRCAmut and non-g BRCAmut cohorts. Mean time with toxicity was estimated based on the area under the Kaplan-Meier curve for symptomatic grade 2 or greater fatigue, nausea, and vomiting adverse events (AEs). Time with toxicity was the number of days a patient experienced an AE post–random assignment and before disease progression. TWiST was estimated as the difference between mean PFS and time with toxicity. Uncertainty was explored using alternative PFS estimates and considering all symptomatic grade 2 or greater AEs. RESULTS In the g BRCAmut and non-g BRCAmut cohorts, niraparib treatment resulted in a mean PFS benefit of 3.23 years and 1.44 years, respectively, and a mean time with toxicity of 0.28 years and 0.10 years, respectively, compared with RS. Hence, niraparib treatment resulted in a mean TWiST benefit of 2.95 years and 1.34 years, respectively, compared with RS, which is equivalent to more than four-fold and two-fold increases in mean TWiST between niraparib and RS in the g BRCAmut and non-g BRCAmut cohorts, respectively. This TWiST benefit was consistent across all sensitivity analyses, including modeling PFS over 5-, 10-, and 15-year time horizons. CONCLUSION Patients who were treated with niraparib compared with RS experienced increased mean TWiST. Thus, patients who were treated with niraparib in the ENGOT-OV16/NOVA trial experienced more time without symptoms or symptomatic toxicities compared with control.

Background Cancer Antigen 125 (CA125) is currently the best available ovarian cancer screening biomarker. However, CA125 has been limited by low sensitivity and specificity in part due to normal variation between individuals. Personal characteristics that influence CA125 could be used to improve its performance as screening biomarker. Methods We developed and validated linear and dichotomous (≥35 U/mL) circulating CA125 prediction models in postmenopausal women without ovarian cancer who participated in one of five large population-based studies: Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO, n = 26,981), European Prospective Investigation into Cancer and Nutrition (EPIC, n = 861), the Nurses’ Health Studies (NHS/NHSII, n = 81), and the New England Case Control Study (NEC, n = 923). The prediction models were developed using stepwise regression in PLCO and validated in EPIC, NHS/NHSII and NEC. Result The linear CA125 prediction model, which included age, race, body mass index (BMI), smoking status and duration, parity, hysterectomy, age at menopause, and duration of hormone therapy (HT), explained 5% of the total variance of CA125. The correlation between measured and predicted CA125 was comparable in PLCO testing dataset (r = 0.18) and external validation datasets (r = 0.14). The dichotomous CA125 prediction model included age, race, BMI, smoking status and duration, hysterectomy, time since menopause, and duration of HT with AUC of 0.64 in PLCO and 0.80 in validation dataset. Conclusions The linear prediction model explained a small portion of the total variability of CA125, suggesting the need to identify novel predictors of CA125. The dichotomous prediction model showed moderate discriminatory performance which validated well in independent dataset. Our dichotomous model could be valuable in identifying healthy women who may have elevated CA125 levels, which may contribute to reducing false positive tests using CA125 as screening biomarker.

Background: Colorectal (CRC) and endometrial cancer (EC) are the most common types of cancer in Lynch syndrome (LS). Risk reducing surgeries (RRS) might impact cancer incidence and mortality. Our objectives were to evaluate cumulative incidences of CRC, gynecological cancer and all-cause mortality after RRS in LS individuals. Methods: Retrospective analysis of 976 LS carriers from a single-institution registry. Primary endpoints were cumulative incidence at 75 years of cancer (metachronous CRC in 425 individuals, EC and ovarian cancer (OC) in 531 individuals) and all-cause mortality cumulative incidence, comparing extended (ES) vs. segmental surgery (SS) in the CRC cohort and risk reducing gynecological surgery (RRGS) vs. surveillance in the gynecological cohort. Results: Cumulative incidence at 75 years of metachronous CRC was 12.5% vs. 44.7% (p = 0.04) and all-cause mortality cumulative incidence was 38.6% vs. 55.3% (p = 0.31), for ES and SS, respectively. Cumulative, incidence at 75 years was 11.2% vs. 46.3% for EC (p = 0.001) and 0% vs. 12.7% for OC (p N/A) and all-cause mortality cumulative incidence was 0% vs. 52.7% (p N/A), for RRGS vs. surveillance, respectively. Conclusions: RRS in LS reduces the incidence of metachronous CRC and gynecological neoplasms, also indicating a reduction in all-cause mortality cumulative incidence in females undergoing RRGS.

Kruckenberg tumor is a metastatic lesion of the ovary, the source of which is the primary cancerous focus in other organs (generally in the digestive system); it often causes difficulties in differential diagnosis with primary ovarian cancer. We report a case of a 67 year-old woman who presented bilateral, 3 cm in diameter, pure solid, encapsulated and hyperechoic smooth masses, surrounded by an hypoechoic ring with a clear tumour margins. Doppler ultrasonography revealed abundant vascularisation, with a characteristic tree-shaped structure penetrating from the periphery into the central part of the lesion with low impedance and diminished vascular resistance. Approximately 5% to 10% of all ovarian malignancies are metastatic carcinomas. Asymmetrically enlarged bilateral encapsulated masses, with variable intratumoural echogenic density, and ascites are the main characteristics on sonography of Krukenberg tumours. The structure of these tumours is usually hyperechoic with abundant vascularisation. Several sonographic markers have been used to show the low impedance of intratumoural circulation in ovarian malignancy, attributing this to active angiogenesis of these tumours. Krukenberg tumours have a poor prognosis, with an overall 5 year survival rate of 12%. Hence prophylactic bilateral ooforectomy is recommended for women with stomach cancer.

Objective To assess the economic burden of epithelial ovarian cancer (EOC) in incident patients and the burden by disease stage in Spain. Methods We developed a Markov model from a social perspective simulating the natural history of EOC and its four stages, with a 10-year time horizon, 3-week cycles, 3% discount rate, and 2016 euros. Healthcare resource utilization and costs were estimated by disease stage. Direct healthcare costs (DHC) included early screening, genetic counselling, medical visits, diagnostic tests, surgery, chemotherapy, hospitalizations, emergency services, and palliative care. Direct non-healthcare costs (DNHC) included formal and informal care. Indirect costs (IC) included labour productivity losses due to temporary and permanent leaves, and premature death. Epidemiology data and resource use were taken from the literature and validated for Spain by the OvarCost group using a Delphi method. Results The total burden of EOC over 10 years was 3102 mill euros: 15.1% in stage I, 3.9% in stage II, 41.0% in stage III, and 40.2% in stage IV. Annual average cost/patient was €24,111 and it was €8,641; €14,184; €33,858, and €42,547 in stages I–IV, respectively. Of total costs, 71.2% were due to DHC, 24.7% to DNHC, and 4.1% to IC. Conclusions EOC imposes a significant economic burden on the national healthcare system and society in Spain. Investment in better early diagnosis techniques might increase survival and patients’ quality of life. This would likely reduce costs derived from late stages, consequently leading to a substantial reduction of the economic burden associated with EOC. Electronic supplementary material The online version of this article (10.1007/s10198-018-0986-y) contains supplementary material, which is available to authorized users.

The prevalence and spectrum of germline mutations in BRCA1 and BRCA2 have been reported in single populations, with the majority of reports focused on White in Europe and North America. The Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) has assembled data on 18,435 families with BRCA1 mutations and 11,351 families with BRCA2 mutations ascertained from 69 centers in 49 countries on six continents. This study comprehensively describes the characteristics of the 1,650 unique BRCA1 and 1,731 unique BRCA2 deleterious (disease-associated) mutations identified in the CIMBA database. We observed substantial variation in mutation type and frequency by geographical region and race/ethnicity. In addition to known founder mutations, mutations of relatively high frequency were identified in specific racial/ethnic or geographic groups that may reflect founder mutations and which could be used in targeted (panel) first pass genotyping for specific populations. Knowledge of the population-specific mutational spectrum in BRCA1 and BRCA2 could inform efficient strategies for genetic testing and may justify a more broad-based oncogenetic testing in some populations.

Epithelial ovarian cancer is characterized by a low recovery rate because the disease is typically diagnosed at an advanced stage, by which time most patients (80%) already exhibit disseminated neoplasia. The cytokine receptor CXCR4 has been implicated in the development of metastasis in various tumor types. Using a patient-derived tissue macroarray and mRNA expression analysis, we observed high CXCR4 levels in high-grade serous epithelial ovarian carcinomas, the most metastatic tumor, compared with those in endometrioid carcinomas. CXCR4 inhibition by treatment with the CXCR4 antagonist AMD3100 or by expression of shRNA anti-CXCR4 similarly inhibited angiogenesis in several models of ovarian carcinomas orthotopically grown in nude mice, but the effect on tumor growth was correlated with the levels of CXCR4 expression. Moreover, CXCR4 inhibition completely blocked dissemination and metastasis. This effect was associated with reduced levels of active Src, active ERKs, the inhibition of EMT transition, and block of hematogenous ovarian cancer dissemination decreasing circulating human tumoral cells (CTC). In tumors, CXCR4-expressing cells also had more mesenchymal characteristics. In conclusion, our results indicate that CXCR4 expression confers a proinvasive phenotype to ovarian carcinoma cells. Thus, anti-CXCR4 therapy is a possible agent for a complementary treatment of advanced disseminated epithelial high-grade serous ovarian cancer patients., This study was supported by research grants from the Spanish Ministerio de Economía y Competitividad (SAF2013-46063R), The Spanish Institute of Health Carlos III (ISCIII) and the European Regional Development Fund (ERDF) under the Integrated Project of Excellence no. PIE13/00022 (ONCOPROFILE), and the Generalitat de Catalunya (2014SGR364) to F. Vinals. Work supported by the Xarxa de Bancs de Tumors de Catalunya sponsored by Pla Director d'Oncología de Catalunya (XBTC), IDIBELL and PLATAFORMA BIOBANCOSPT13/0010/0013 and for the MD Anderson Foundation Biobank (B.0000745, ISCIII National Biobank Record). Grants from the AECC (Grupos Estables de Investigacion 2011-AECC-GCB 110333 REVE), the Instituto de Salud Carlos III (ISCIII), FEDER (PI16/00134), and CIBERONC (CB16/12/00295) to G. Moreno-Bueno. E. Alsina-Sanchís is a recipient of a predoctoral fellowship from the Ministerio de Economía y Competitividad.

PLoS One. 2017 Sep 21;12(9):e0184439. doi: 10.1371/journal.pone.0184439. eCollection 2017.E-cadherin: A determinant molecule associated with ovarian cancer progression, dissemination and aggressiveness.Rosso M1, Majem B2, Devis L2, Lapyckyj L1, Besso MJ1, Llauradó M2, Abascal MF1, Matos ML1, Lanau L2, Castellví J3, Sánchez JL4, Pérez Benavente A4, Gil-Moreno A2,4, Reventós J2, Santamaria Margalef A2, Rigau M2, Vazquez-Levin MH1.Author informationAbstractOvarian cancer (OC) is the fifth cancer death cause in women worldwide. The malignant nature of this disease stems from its unique dissemination pattern. Epithelial-to-mesenchymal transition (EMT) has been reported in OC and downregulation of Epithelial cadherin (E-cadherin) is a hallmark of this process. However, findings on the relationship between E-cadherin levels and OC progression, dissemination and aggressiveness are controversial. In this study, the evaluation of E-cadherin expression in an OC tissue microarray revealed its prognostic value to discriminate between advanced- and early-stage tumors, as well as serous tumors from other histologies. Moreover, E-cadherin, Neural cadherin (N-cadherin), cytokeratins and vimentin expression was assessed in TOV-112, SKOV-3, OAW-42 and OV-90 OC cell lines grown in monolayers and under anchorage-independent conditions to mimic ovarian tumor cell dissemination, and results were associated with cell aggressiveness. According to these EMT-related markers, cell lines were classified as mesenchymal (M; TOV-112), intermediate mesenchymal (IM; SKOV-3), intermediate epithelial (IE; OAW-42) and epithelial (E; OV-90). M- and IM-cells depicted the highest migration capacity when grown in monolayers, and aggregates derived from M- and IM-cell lines showed lower cell death, higher adhesion to extracellular matrices and higher invasion capacity than E- and IE-aggregates. The analysis of E-cadherin, N-cadherin, cytokeratin 19 and vimentin mRNA levels in 20 advanced-stage high-grade serous human OC ascites showed an IM phenotype in all cases, characterized by higher proportions of N- to E-cadherin and vimentin to cytokeratin 19. In particular, higher E-cadherin mRNA levels were associated with cancer antigen 125 levels more than 500 U/mL and platinum-free intervals less than 6 months. Altogether, E-cadherin expression levels were found relevant for the assessment of OC progression and aggressiveness. Fil: Rosso, Marina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Majem, Blanca. Universidad Autonoma de Barcelona. Hospital Vall D' Hebron. Instituto de Investigación Vall D'hebron; España Fil: Devis, Laura. Universidad Autonoma de Barcelona. Hospital Vall D' Hebron. Instituto de Investigación Vall D'hebron; España Fil: Lapyckyj, Lara. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Besso, María José. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Llauradó, Marta. University of British Columbia; Canadá Fil: Abascal, Maria Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Matos, María Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Lanau, Lucia. Universidad Autonoma de Barcelona. Hospital Vall D' Hebron. Instituto de Investigación Vall D'hebron; España Fil: Castellví, Josep. Universidad Autonoma de Barcelona. Hospital Vall D' Hebron. Instituto de Investigación Vall D'hebron; España Fil: Sanchez, José Luis. Universidad Autonoma de Barcelona. Hospital Vall D' Hebron. Instituto de Investigación Vall D'hebron; España Fil: Perez Benavente, Asunción. Universidad Autonoma de Barcelona. Hospital Vall D' Hebron. Instituto de Investigación Vall D'hebron; España Fil: Gil Moreno, Antonio. Universidad Autonoma de Barcelona. Hospital Vall D' Hebron. Instituto de Investigación Vall D'hebron; España Fil: Reventós, Jaumé. Universidad Autonoma de Barcelona. Hospital Vall D' Hebron. Instituto de Investigación Vall D'hebron; España Fil: Santamaria Margalef, Anna. Universidad Autonoma de Barcelona. Hospital Vall D' Hebron. Instituto de Investigación Vall D'hebron; España Fil: Rigau, Marina. Universidad Autonoma de Barcelona. Hospital Vall D' Hebron. Instituto de Investigación Vall D'hebron; España Fil: Vazquez, Monica Hebe. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina

There have been no major improvements in the overall survival of ovarian cancer patients in recent decades. Even though more accurate surgery and more effective treatments are available, the mortality rate remains high. Given the differences in origin and the heterogeneity of these tumors, research to elucidate the signaling pathways involved is required. The Transforming Growth Factor (TGFβ) family controls different cellular responses in development and cell homeostasis. Disruption of TGFβ signaling has been implicated in many cancers, including ovarian cancer. This article considers the involvement of TGFβ in ovarian cancer progression, and reviews the various mechanisms that enable the TGFβ signaling pathway to control ovarian cancer cell proliferation. These mechanistic explanations support the therapeutic use of TGFβ inhibitors in ovarian cancer, which are currently in the early phases of development.

The OCAC OncoArray genotyping project: et al., To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3 and 9q31.1) and one for endometrioid EOC (5q12.3). We then performed meta-analysis on the results for high-grade serous ovarian cancer with the results from analysis of 31,448 BRCA1 and BRCA2 mutation carriers, including 3,887 mutation carriers with EOC. This identified three additional susceptibility loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC., The OCAC OncoArray genotyping project was funded through grants from the US National Institutes of Health (CA1X01HG007491-01 (C.I.A.), U19-CA148112 (T.A.S.), R01-CA149429 (C.M.P.) and R01-CA058598 (M.T.G.)); Canadian Institutes of Health Research (MOP-86727 (L.E.K.)); and the Ovarian Cancer Research Fund (A.B.). Funding for the CIMBA OncoArray genotyping was provided by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research, the Ministère de l’Économie, de la Science et de l’Innovation du Québec through Génome Québec, the Quebec Breast Cancer Foundation for the PERSPECTIVE project, the US National Institutes of Health (CA1X01HG007491-01 (C.I.A.)), the Odense University Hospital Research Foundation (M.T.), the National R&D Program for Cancer Control, Ministry of Health and Welfare, Republic of Korea (1420190 (S.K.P.)), the Italian Association for Cancer Research (IG16933 (L.O.)) and German Cancer Aid (110837 (R.K.S.).

Accepted manuscript version. Published version available at https://doi.org/10.1158/0008-5472.CAN-16-3322. Invasive epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy. The etiology of EOC remains elusive; however, experimental and epidemiologic data suggest a role for hormone-related exposures in ovarian carcinogenesis and risk factor differences by histologic phenotypes and developmental pathways. Research on pre-diagnosis androgen concentrations and EOC risk has yielded inconclusive results, and analyses incorporating EOC subtypes are sparse. We conducted a pooled analysis of 7 nested case-control studies in the Ovarian Cancer Cohort Consortium to investigate the association between pre-diagnosis circulating androgens (testosterone, free testosterone, androstenedione, dehydroepiandrosterone sulfate (DHEAS)), sex hormone binding globulin (SHBG), and EOC risk by tumor characteristics (i.e. histology, grade, and stage). The final study population included 1,331 EOC cases and 3,017 matched controls. Multivariable conditional logistic regression was used to assess risk associations in pooled individual data. Testosterone was positively associated with EOC risk (all subtypes combined, Odds Ratio (OR)log2=1.12 [95% Confidence Interval (CI) 1.02-1.24]); other endogenous androgens and SHBG were not associated with overall risk. Higher concentrations of testosterone and androstenedione associated with an increased risk in endometrioid and mucinous tumors (e.g., testosterone, endometrioid tumors, ORlog2=1.40 [1.03-1.91]), but not serous or clear cell. An inverse association was observed between androstenedione and high grade serous tumors (ORlog2=0.76 [0.60-0.96]). Our analyses provide further evidence for a role of hormone-related pathways in EOC risk, with differences in associations between androgens and histologic subtypes of EOC.

Genome-wide studies of patients carrying pathogenic variants (mutations) in BRCA1 or BRCA2 have reported strong associations between single-nucleotide polymorphisms (SNPs) and cancer risk. To conduct the first genome-wide association analysis of copy-number variants (CNVs) with breast or ovarian cancer risk in a cohort of 2500 BRCA1 pathogenic variant carriers, CNV discovery was performed using multiple calling algorithms and Illumina 610k SNP array data from a previously published genome-wide association study. Our analysis, which focused on functionally disruptive genomic deletions overlapping gene regions, identified a number of loci associated with risk of breast or ovarian cancer for BRCA1 pathogenic variant carriers. Despite only including putative deletions called by at least two or more algorithms, detection of selected CNVs by ancillary molecular technologies only confirmed 40% of predicted common (>1% allele frequency) variants. These include four loci that were associated (unadjusted P

El càncer d'ovari (CO) és la cinquena causa del càncer en dones i la principal causa de mort entre les malalties ginecològiques. Els símptomes inespecífics i les eines diagnòstiques actualment insuficients no detecten la malaltia en estadis inicials, quan la supervivència és del 90%. Així, al voltant del 70% dels pacients es diagnostiquen en estadis avançats, quan la supervivència és, Ovarian cancer (OC) is the fifth cause of cancer in women and the leading cause of death among gynecological malignancies in developed countries. The unspecific symptoms and currently insufficient diagnostic tools fail to detect the disease at an early stage, when the 5-years survival is 90%. Thus, around 70% of the patients are diagnosed at late stage, when the 5-years survival is

El cáncer de ovario es una neoplasia de mal pronóstico, dado que habitualmente se diagnostica localmente avanzada. La PET/TC es una técnica de imagen híbrida ampliamente utilizada en oncología, pero que en el cáncer de ovario, únicamente está claramente recomendada por las principales guías de actuación internacional (National Comprehensive Cancer Network, European Society of medical oncology, Sociedad española de ginecología y obstetricia) en el caso de recidiva de la enfermedad. Recientemente la Society of Gynecologic Oncology y la National Comprehensive Cancer Network, abren la posibilidad a utilizar la PET/TC de forma opcional en la estadificación inicial de pacientes con cáncer de ovario localmente avanzado. En este estudio se ha comparado la PET/TC con la TC (técnica convencional) en la estadificación inicial de la neoplasia de ovario. Se ha demostrado que la PET/TC es capaz de detectar mayor porcentaje de pacientes con metástasis respecto a la TC (40.74% respecto a 11.11%). La localización más frecuente de las metástasis a distancia por PET/TC son las adenopatías supradiafragmáticas, seguido de la afectación pleural. La PET/TC cambia el estadio FIGO respecto al TC inicial en un 59.25%% de pacientes a expensas fundamentalmente de encontrar más enfermedad peritoneal o a distancia. Globalmente, la implementación de la FDG-PET/TC en nuestro estudio modificó la intención terapéutica respecto a la intención inicial en el 25.9% de los casos. También se ha valorado la resecabilidad primaria de pacientes con cáncer de ovario con la PET/TC abdominal y la TC abdominal, ambas respecto a la laparoscopia diagnóstica. Se ha comprobado que los hallazgos abdominales de la PET/TC se correlacionan mejor con la laparoscopia diagnóstica que la TC (K = 0.684 para la PET/TC comparado con K=0.419 para la TC). La PET/TC fue concordante con la laparoscopia en el 85.18% de los pacientes mientras que la TC en un 70.4% de los pacientes. Los casos discordantes entre la PET/TC y la laparoscopia en términos de resecabilidad eran pacientes con enfermedad diseminada extraabdominal detectada por PET/TC o por carcinomatosis miliar detectada por laparoscopia e infravalorada por la PET/TC. En un grupo de pacientes con neoplasia de ovario localmente avanzada (no resecables de forma primaria, FIGO III o IV) se ha estudiado la respuesta a la QTNA mediante PET/TC y se ha comparado con el método del Gynecologic Cancer InterGroup. La disminución del SUVmáx del global del estudio (∆SUVGlobal) y del tumor primario (∆SUVprimario), son variables predictoras de la sensibilidad al platino, pero no de la resecabilidad en el intervalo ni de la respuesta histopatológica. Con una disminución del 69.78% del SUVGlobal y del 61.87% del SUVprimario se consigue clasificar correctamente las pacientes en respondedoras/no respondedoras al platino, con eficiencias diagnósticas del 76.62% para el ∆SUVGlobal y del 73.07% para ∆SUVprimario, superiores a las obtenidas con el método Gynecologic Cancer InterGroup (50%)., Ovarian cancer has a poor prognosis, because the majority of patients have advanced disease at the time of diagnosis. Although 18F-FDG PET/CT is widely used in oncology, the guidelines for ovarian cancer (National Comprehensive Cancer Network, European Society of Medical Oncology and Sociedad Española de Ginecología y Obstetricia) clearly indicating 18F-FDG PET/CT in recurrence. The Society of Gynecologic Oncology and the National Comprehensive Cancer Network recently included PET/CT as an option for the initial staging of locally advanced disease. We compared PET/CT and CT in the initial staging of ovarian cancer. PET/CT detected distant metastases in more patients than CT (40.74% vs. 11.11%). The most frequent locations of distant metastases detected by PET/CT were the supradiaphragmatic lymph nodes and pleura. PET/CT changed FIGO staging compared with CT in 59.25% of cases, especially due to unsuspected peritoneal metastasis or distant metastases. However, PET/CT changed treatment management in only 25.9% patients. We also compared abdominal PET/CT and abdominal CT in the assessment of resectability, with respect to laparoscopic valuation (gold standard). Abdominal PET/CT correlated better than abdominal CT with diagnostic laparoscopy findings in terms of resectability (K=0.684 for PET/CT compared to K=0.419 for CT alone). Abdominal PET/CT findings were concordant with surgical stage in 85.18% of patients and abdominal CT was concordant in 70.4% of patients. Discrepancies between PET/CT and laparoscopic findings were explained by extra-abdominal disease detected by PET/CT or miliary peritoneal metastases detected by laparoscopy and seen less clearly by PET/CT. In a group of patients with locally advanced ovarian cancer (FIGO IIIC or IV). We compared PET/CT and Gynecologic Cancer InterGroup method in evaluation response of neoadjuvant chemotherapy in patients with primary unresectable locally advanced ovarian cancer. The change in the SUVmax of the primary tumor (∆SUVprimary) and the overall change in SUVmax in the study (∆SUVGlobal) predicted platinum sensitivity but not interval resectability or histopathological response. Decreases in SUVmax (∆SUVGlobal ≥69.78% (accuracy=76.62%) or ∆SUVprimary ≥61.87% (accuracy=73.07%)) identified platinum responders or non-responders better than the Gynecologic Cancer InterGroup method (accuracy=50%).

C75 is a synthetic anticancer drug that inhibits fatty acid synthase (FAS) and shows a potent anorexigenic side effect. In order to find new cytotoxic compounds that do not impact food intake, we synthesized a new family of C75 derivatives. The most promising anticancer compound among them was UB006 ((4SR,5SR)-4-(hydroxymethyl)-3-methylene-5-octyldihydrofuran-2(3H)-one). The effects of this compound on cytotoxicity, food intake and body weight were studied in UB006 racemic mixture and in both its enantiomers separately. The results showed that both enantiomers inhibit FAS activity and have potent cytotoxic effects in several tumour cell lines, such as the ovarian cell cancer line OVCAR-3. The (−)-UB006 enantiomer's cytotoxic effect on OVCAR-3 was 40-fold higher than that of racemic C75, and 2- and 38-fold higher than that of the racemic mixture and its opposite enantiomer, respectively. This cytotoxic effect on the OVCAR-3 cell line involves mechanisms that reduce mitochondrial respiratory capacity and ATP production, DDIT4/REDD1 upregulation, mTOR activity inhibition, and caspase-3 activation, resulting in apoptosis. In addition, central and peripheral administration of (+)-UB006 or (−)-UB006 into rats and mice did not affect food intake or body weight. Altogether, our data support the discovery of a new potential anticancer compound (−)-UB006 that has no anorexigenic side effects.

Acrylamide is an organic chemical that has several important uses in industry, such as a flocculant in public water supplies, and in biomedical research. In 1994, acrylamide was classified by the International Agency for Research on Cancer as ‘probably carcinogenic’ to humans. In 2002, acrylamide was discovered in some starchy foods that are cooked at high temperature (e.g., potato crisps and chips). Acrylamide also is a common component of cigarette smoke. From 2006-2010, epidemiologic studies began to examine and report on the possible association between dietary acrylamide intake and risk of human cancer, including ovarian and endometrial cancers (two of which suggested possible associations). Endometrial and ovarian are the fourth and fifth most common cancers diagnosed in European women. The general aim of this thesis was to assess the risk of endometrial cancer (EC) and epithelial ovarian (EOC) cancer in relation to dietary acrylamide exposure based on questionnaire information and biomarkers of internal exposure. The study population for this project was 368,010 women from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Dietary acrylamide intake in the full EPIC cohort was estimated using the most recent European acrylamide-content food databases, country-specific food intake questionnaires, and 24-hour dietary recalls at baseline. Multivariate Cox Proportional hazard models were used to estimate hazard ratios (HR) and 95% confidence intervals (95% CI) for questionnaire-based acrylamide intake and EC or EOC risk. Cohort analyses were conducted in all women and in subgroups. Two nested case-control studies of acrylamide biomarkers and EC or EOC risk were conducted in non-smoking postmenopausal women. Pre-diagnostic biomarkers of acrylamide and its epoxide metabolite, glycidamide, were measured as hemoglobin adducts (HbAA and HbGA, respectively) using HPLC/MS/MS in red blood cells collected at baseline 5-10 years before diagnosis. Unconditional logistic regression models were used to estimate odds ratios (OR) and 95% CI for the relation between acrylamide biomarkers (HbAA, HbGA, HbAA+HbGA, and HbGA/HbAA) and EC or EOC risk. The relation between dietary and demographic determinants of biomarker levels of acrylamide and glycidamide were also examined using simple and multiple linear regression analyses in 801 control women. After a mean follow-up of 11 years, there were 1,382 cases of EC and 1,191 cases of EOC in the EPIC cohort. In general, the results of the dietary acrylamide intake analyses showed no associations with EOC and EC, except for a possible association between higher acrylamide intake and type-I EC in women who were non-smokers and non-users of oral contraceptives (HRQ5vsQ1: 1.97, 95% CI: 1.08-3.62). The main food group determinants of acrylamide and glycidamide biomarker levels were biscuits, crackers and cakes; and alcohol intake and body mass index were important determinants of the ratio of glycidamide to acrylamide. The nested case-control study of acrylamide and glycidamide biomarker levels and EC (383 cases, 171 type-I, and 385 controls) did not find any support for associations between acrylamide or glycidamide and EC risk. The nested case-control study of acrylamide and glycidamide biomarkers and EOC risk (334 cases and 417 controls) found some evidence for associations with the third quintile of HbGA, and the second and third quintiles of HbAA+HbGA. Participants classified in the fifth quintile of HbGA or HbAA+HbGA showed statistically non-significant higher risks of EOC (ORHbGA.Q5vsQ1: 1.63, 95% CI: 0.92-2.86; P-trend: 0.04, and ORHbAA+HbGGA.Q5vsQ1: 1.60, 95% CI: 0.89-2.87; P-trend: 0.14). In conclusion, results in women from the EPIC cohort did not provide convincing support for the hypothesis that higher acrylamide and glycidamide exposures are associated with higher risk for EC. For EOC, inconsistent results were observed in our study. Additional nested case- control studies with larger sample size in different populations, and pooled analysis of existing studies of the relation between acrylamide and glycidamide biomarkers and EOC risk should be performed.

Purpose: About 60% of ovarian cancers are diagnosed at late stage, when 5-year survival is less than 30% in contrast to 90% for local disease. This has prompted search for early detection biomarkers. For initial testing, specimens taken months or years before ovarian cancer diagnosis are the best source of information to evaluate early detection biomarkers. Here we evaluate the most promising ovarian cancer screening biomarkers in prospectively collected samples from the European Prospective Investigation into Cancer and Nutrition study. Experimental Design: We measured CA125, HE4, CA72.4, and CA15.3 in 810 invasive epithelial ovarian cancer cases and 1,939 controls. We calculated the sensitivity at 95% and 98% specificity as well as area under the receiver operator curve (C-statistic) for each marker individually and in combination. In addition, we evaluated marker performance by stage at diagnosis and time between blood draw and diagnosis. Results: We observed the best discrimination between cases and controls within 6 months of diagnosis for CA125 (C-statistic = 0.92), then HE4 (0.84), CA72.4 (0.77), and CA15.3 (0.73). Marker performance declined with longer time between blood draw and diagnosis and for earlier staged disease. However, assessment of discriminatory ability at early stage was limited by small numbers. Combinations of markers performed modestly, but significantly better than any single marker. Conclusions: CA125 remains the single best marker for the early detection of invasive epithelial ovarian cancer, but can be slightly improved by combining with other markers. Identifying novel markers for ovarian cancer will require studies including larger numbers of early-stage cases. Clin Cancer Res; 22(18); 4664–75. ©2016 AACR. See related commentary by Skates, p. 4542

Los carcinomas de ovario y de endometrio son los tumores malignos ginecológicos más frecuentes en nuestro entorno. Se han descrito alteraciones genéticas recurrentes que son características de algunos tipos histológicos y que han permitido definir vías patogenéticas distintas tanto para ovario como para endometrio. Entre estas alteraciones, algunas afectan directamente las vías de señalización celular que regulan el crecimiento y proliferación de la célula. Estas vías representan una de las alteraciones clave implicadas en el desarrollo del cáncer y que han adquirido una trascendencia importante, desde la aplicación en la práctica clínica, de tratamientos dirigidos contra algunas de estas moléculas. Sin embargo, la comprensión de estas vías se complica por la presencia de múltiples interacciones entre ellas, así como redundancias que hacen que el bloqueo de las mismas no siempre produzca los efectos esperados. Dada la complejidad y redundancia de vías que transmiten la señal proliferativa desde la membrana hacia al núcleo, deben existir factores que centralicen la acción oncogénica, de forma que sobre ellas converjan diversas vías y sean representativos del grado de activación de los mismos y por tanto de interés pronóstico y terapéutico. Se seleccionaron 129 neoplasias de ovario que incluyeron 27 tumores benignos, 27 tumores borderline y 75 carcinomas de ovario, y 138 muestras de endometrio que incluyeron 120 carcinomas, 15 endometrios funcionales y atróficos y 3 hiperplasias endometriales. Se construyeron matrices de tejidos (tissue microarrays) a partir de 3 muestras de cada caso y se realizó estudio inmunohistoquímico con los anticuerpos para HER2, EGFR y las formas fosforiladas de AKT, ERK, 4E-BP1, p70S6K y S6. Los resultados se analizaron estadísticamente para valorar de forma descriptiva la expresión de estos marcadores, su relación con las variables clínico-patológicas, la relación entre ellos y con la supervivencia global y libre de enfermedad. De los parámetros estudiados, el estadio según los criterios de la FIGO y el grado de diferenciación fueron las únicas variables clínico-patológicas de valor pronóstico tanto en cáncer de ovario como de endometrio. De los marcadores, HER2 se asoció a peor pronóstico en cáncer de endometrio pero no de ovario, EGFR a mejor pronóstico en cáncer de endometrio. La sobreexpresión de p-4E-BP1 identifica carcinomas de ovario y de endometrio de peor pronóstico y su expresión se relaciona tanto con la activación de AKT como de ERK por lo que apoya su importancia como proteína centralizadora de la señal oncogénica procedente de cualquiera de las 2 vías, representando una buena diana para el tratamiento de estas pacientes., Ovarian and endometrial carcinomas are the most frequent gynecological malignant tumors in our area. Recurrent genetic alterations that are characteristic of some histological types have been described and have allowed the identification of pathogenetic pathways, in both endometrial and ovarian cancers. Among these alterations, some affect cell signaling pathways that regulate cell growth and cell proliferation. These pathways represent one of the hallmarks of cancer, and have become especially important since the appearance of new drugs that target specific molecules involved in their regulation. However, our understanding of these signaling pathways is complicated by the presence of multiple cross-talks between them, as well as multiple redundancies of molecules, both of with are probably responsible for some of the unexplained results that occur when one of the molecules involved is blocked by a drug. Due to the complexity and redundancy of cell signaling pathways that transmit the proliferative signal from the cellular membrane to the nucleus, there should be some factors that centralize the oncogenic action in a way that several stimuli could converge on them. These factors should be representative of the activation level of the oncogenic process, and therefore, should be of prognostic and therapeutic interest. 129 ovarian neoplasms were selected, including 27 benign tumors, 27 borderline tumors, and 75 ovarian carcinomas. Additionally, 138 endometrial samples were selected including 15 atrophic and functional endometria, 3 hyperplastic endometria and 120 endometrial carcinomas. Tissue microarrays were constructed using 3 samples from each case, and an immunohistochemical study with HER2, EGFR, and the phosphorylated forms of AKT, ERK, 4E-BP1, p70S6K and ribosomal protein S6 was performed. The results obtained were statistically analyzed to evaluate the correlation of these markers with clinicopathological features, the relationship between them, and their impact on overall survival and progression-free survival. Surgical stage defined by FIGO, and differentiation grade were the only clinicopathologic variants with prognostic significance in ovarian and endometrial cancer. Among the cell signaling markers evaluated, HER2 was associated with prognosis in endometrial cancer but not in ovarian cancer and EGFR with better survival in endometrial cancer. P-4E-BP1 overexpression identifies a subset of ovarian and endometrial cancers with worse prognosis, and its expression is related to the activation of AKT and ERK pathways, suggesting that it has a central role in cell signal transduction by both pathways, and therefore could be a therapeutic target in these patients.

[eng] Role of TGFβ in physiological angiogenesis and ovarian cancer Transforming Growth Factor Beta (TGFβ) is a signalling pathway involved in a wide range of cellular processes such as proliferation, differentiation, angiogenesis, migration and homeostasis. In addition, it has been broadly related with pathological situations like cancer or other diseases. In this thesis we have been focused on two of its receptors; the TβRI called ALK5, ubiquitously expressed, and ALK1, an endothelial cell-restricted receptor. In the first part of this work we have studied the role of ALK1 in angiogenesis. Loss of function mutations in ALK1 cause a subtype of hereditary haemorrhagic telangiectasias (HHTs) characterized by vasculature malformations. Currently, there is no suitable treatment to cure these patients. To study the ALK1 role in vascular development, we have used the retina mouse model and seeking to find a treatment for these patients, we have used a mouse model for HHTs. This mouse model has a heterozygous alteration in ALK1, as in homozygosis die at +/- mice resulted in abnormal endothelial cell proliferation mid-gestion. The alteration on ALK1 and increased retinal vessel width without affecting pericyte coverage, migration or elongation of the ECs. We have shown that genetic and pharmacological inhibition of PI3K signalling +/- abolished the increase in vessel width in ALK1 retinas and normalized vasculature. Overall, our results suggest the potential for using PI3K inhibitors as new therapeutic agents for treating HHTs. In the second part of this work we have searched for new therapeutic targets for treating epithelial ovarian cancer. Firstly, we analysed the TGFβ signalling pathway in these tumours. Using a Tissue Micro Array (TMA) with patient samples we found high Smad2 phosphorylation, a read-out of ALK5 activation, in epithelial ovarian cancer tumoral cells, independently of tumour subtype (high-grade serous or endometrioid). To evaluate the impact of TGFβ receptor inhibition on tumoral growth, we used different models of human epithelial ovarian cancer orthotopically grown in nude mice (OVAs); two high-grade serous carcinoma and one endometrioid carcinoma. We have confirmed that the histological properties and the levels of phosphoSmad2 expression pattern were maintained on the ovarian tumour mouse models compared to its human primary tumours samples. Treatment with a TGFβRI&II dual inhibitor, LY2109761, caused a significant reduction in tumour size in all these models, affecting cell proliferation rate. On the contrary, TGFβ inhibition did not affect ovarian tumour cell capacity to disseminate in our models. We identified Insulin Growth Factor (IGF)1 receptor as the signal positively regulated by TGFβ implicated in ovarian tumour cell proliferation. We have demonstrated that our TMA samples had high IGF1R protein levels and that phosphoSmad2 and IGF1R protein levels significantly positively correlated. Inhibition of IGF1R activity by treatment with a blocker antibody (IMC- A12) or with a tyrosine kinase inhibitor (linsitinib) inhibited ovarian tumoral growth in vivo. At the molecular level TGFβ signalling positively controls IGF1R levels by two mechanisms. Induction of mRNA IGF1R levels in some cell lines or tumour samples, whereas a change on IGF1R protein localization was observed in others. In fact, TGFβ inhibition decreased IGF1R protein levels by controlling its stability; increasing IGF1R internalization and degradation through the lysosome. When IGF1R levels were decreased by shRNA treatment, ovarian cancer cell lines grew less and LY2109761 lost its capacity to block tumoral ovarian cell proliferation. Overall, our results suggest an important role for the TGFβ signalling pathway in ovarian tumour cell growth through the control of IGF1R signalling pathway. Moreover, it identifies anti-TGFβ inhibitors as being of potential use in new therapies for ovarian cancer patients as an alternative to IGF1R inhibition, being used in clinical trials., [cat] Aquest treball estudia el paper de la família del Factor de Creixement Transformant (TGFβ) en el càncer d’ovari i en una altra patologia, la telangectàsia hemorràgica hereditària (HHT). Mutacions de pèrdua de funció del receptor ALK1 causen un subtipus de HHT caracteritzat per malformacions vasculars. Per analitzar el rol d'ALK1 en el desenvolupament vascular, hem utilitzat un model animal d'HHT. Les alteracions obtingudes han estat una proliferació anormal de les cèl.lules endotelials i un augment de l'amplitud dels vasos de la retina dels ratolins ALK1+/-. Hem demostrat que una inhibició genètica o farmacològica de la via de senyalització de PI3K aboleix l'augment de l'amplitud de vasos i la vasculatura queda normalitzada, suggerint el potencial ús dels inhibidors de PI3K com a nous agents terapèutics pel tractament d'aquests pacients. En la segona part d'aquest treball, hem buscat nous agents terapèutics pel tractament del càncer d'ovari. Utilitzant mostres de pacients, hem observat alts nivells de Smad2 fosforilat en les cèl.lules tumorals de càncer d'ovari, independentment del tipus de tumor. El tractament amb l'inhibidor de TGFβRI&II, LY2109761, en els models ortotòpics de càncer d'ovari causa una reducció significativa de la mida tumoral, afectant la proliferació cellular. Hem identificat el receptor del Factor de Creixement de la Insulina (IGF)1 com la via implicada en la proliferació de les cèl.lules tumorals d'ovari, la qual és regulada positivament per TGFβ. La inhibició de l'activitat d'IGF1R inhibeix el creixement del tumor d'ovari in vivo. A nivell molecular, TGFβ controla els nivells de mRNA d'IGF1R i també la seva internalització i degradació proteica a través del lisosoma. Quan els nivells d'IGF1R són disminuïts per la utilització d'un shRNA, LY2109761 perd la capacitat de bloquejar la proliferació de la cèl.lula tumoral d'ovari. Aquests resultats postulen que TGFβ. té un paper important en el creixement cellular del tumor d'ovari a través del control de la senyalització d'IGF1R. A més, identifica els inhibidors contra TGFβ com a noves teràpies pels pacients de càncer d'ovari com una alternativa als inhibidors d'IGF1R.

Resumen Fundamento y objetivo Tener una predisposicion hereditaria al cancer puede asociarse a un impacto psicologico. Uno de los objetivos del consejo genetico es favorecer la adaptacion psicologica a la nueva situacion, siendo necesarios instrumentos validados en este contexto. Por ser el autoconcepto un buen indicador de adaptacion a la enfermedad o al riesgo de tenerla, y una variable relevante en oncologia, el objetivo es adaptar culturalmente al castellano y validar la BRCA Self-Concept Scale . Material y metodo Ciento sesenta y cinco portadoras de mutacion en los genes BRCA respondieron al cuestionario previamente sometido a un proceso de traduccion-retrotraduccion, y a la Escala de Preocupacion por el Cancer (EPC) como medida de validez convergente. Se valoro la estructura del cuestionario mediante una prueba de expertos y un analisis factorial confirmatorio (AFC), se calculo el α de Cronbach de las 3 subescalas (Estigma, Vulnerabilidad y Control), y se correlacionaron con la EPC. Resultados La prueba de expertos y el AFC no confirman la estructura original del cuestionario. El modelo reespecificado (con los items 10 y 13 en Vulnerabilidad) muestra mejor ajuste: comparative fit index 0,973; Tucker-Lewis index 0,968; root mean square error of approximation 0,067. El α de Cronbach es de 0,83 para Estigma, de 0,84 para Vulnerabilidad, y de 0,61 para Control. Se encuentra evidencia de validez convergente con la EPC (rho de Spearman 0,631 para Estigma, 0,683 para Vulnerabilidad, y −0,363 para Control; p Conclusiones Los resultados apoyan la validez de la escala modificada de autoconcepto BRCA, siendo una medida potencialmente util para valorar la adaptacion a tener una alta predisposicion hereditaria al cancer.

El càncer constitueix la primera causa de mort als països industrialitzats. El risc de desenvolupar un càncer abans dels 75 anys per a un espanyol és del 25% és a dir un de cada quatre espanyols desenvoluparà un càncer al llarg de la seua vida. En l’actualitat existeix gran evidència científica de que l’exercici físic per si mateix o en combinació amb la dieta i el normo pes, és capaç de disminuir el risc de patir càncer ginecològic. Així mateix, mitjançant l’activitat física podem revertir els efectes perniciosos tant del tractament del càncer com de les seues seqüeles, i es pot arribar a recuperar l’estat de forma previ a la malaltia i millorar així la qualitat de vida de la pacient., Cancer is the first death cause in industrialised countries. The risk to develop cancer before 75 years old for a Spanish citizen is 25%, which means that one out of ten Spaniards will develop cancer throughout their lives. Nowadays, it has been scientifically proven that physical exercise by itself in combination with diet and normal weight is able to diminish the risk of suffering gynaecological cancer. Moreover, the practice of physical exercise can revert the negative effects of both the treatment against cancer and the aftermath of the disease. Consequently, it is even possible for the patient to recover good shape and quality of life., El cáncer constituye la primera causa de muerte en los países industrializados. El riesgo de desarrollar un cáncer antes de los 75 años para un español es del 25%, es decir uno de cada cuatro españoles desarrollará un cáncer a lo largo de su vida. En la actualidad existe una gran evidencia científica de que el ejercicio físico por si solo o en combinación con la dieta y el normo peso, es capaz de disminuir el riesgo de sufrir cáncer ginecológico. Así mismo, mediante la actividad física podemos revertir los efectos perniciosos tanto del tratamiento del cáncer como de las secuelas del mismo, pudiendo llegar a recuperar el estado de forma previo a la enfermedad y mejorar así la calidad de vida de la paciente.

In a search for new therapeutic targets for treating epithelial ovarian cancer, we analyzed the Transforming Growth Factor Beta (TGFβ) signaling pathway in these tumors. Using a TMA with patient samples we found high Smad2 phosphorylation in ovarian cancer tumoral cells, independently of tumor subtype (high-grade serous or endometrioid). To evaluate the impact of TGFβ receptor inhibition on tumoral growth, we used different models of human ovarian cancer orthotopically grown in nude mice (OVAs). Treatment with a TGFβRI&II dual inhibitor, LY2109761, caused a significant reduction in tumor size in all these models, affecting cell proliferation rate. We identified Insulin Growth Factor (IGF)1 receptor as the signal positively regulated by TGFβ implicated in ovarian tumor cell proliferation. Inhibition of IGF1R activity by treatment with a blocker antibody (IMC-A12) or with a tyrosine kinase inhibitor (linsitinib) inhibited ovarian tumoral growth in vivo. When IGF1R levels were decreased by shRNA treatment, LY2109761 lost its capacity to block tumoral ovarian cell proliferation. At the molecular level TGFβ induced mRNA IGF1R levels. Overall, our results suggest an important role for the TGFβ signaling pathway in ovarian tumor cell growth through the control of IGF1R signaling pathway. Moreover, it identifies anti-TGFβ inhibitors as being of potential use in new therapies for ovarian cancer patients as an alternative to IGF1R inhibition.

Background: Acrylamide was classified as “probably carcinogenic to humans (group 2A)” by the International Agency for Research on Cancer. Epithelial ovarian cancer (EOC) is the fourth cause of cancer mortality in women. Five epidemiological studies have evaluated the association between EOC risk and dietary acrylamide intake assessed using food frequency questionnaires, and one nested case–control study evaluated hemoglobin adducts of acrylamide (HbAA) and its metabolite glycidamide (HbGA) and EOC risk; the results of these studies were inconsistent. Methods: A nested case–control study in nonsmoking postmenopausal women (334 cases, 417 controls) was conducted within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Unconditional logistic regression models were used to estimate ORs and 95% confidence intervals (CI) for the association between HbAA, HbGA, HbAA+HbGA, and HbGA/HbAA and EOC and invasive serous EOC risk. Results: No overall associations were observed between biomarkers of acrylamide exposure analyzed in quintiles and EOC risk; however, positive associations were observed between some middle quintiles of HbGA and HbAA+HbGA. Elevated but nonstatistically significant ORs for serous EOC were observed for HbGA and HbAA+HbGA (ORQ5vsQ1, 1.91; 95% CI, 0.96–3.81 and ORQ5vsQ1, 1.90; 95% CI, 0.94–3.83, respectively); however, no linear dose–response trends were observed. Conclusion: This EPIC nested case–control study failed to observe a clear association between biomarkers of acrylamide exposure and the risk of EOC or invasive serous EOC. Impact: It is unlikely that dietary acrylamide exposure increases ovarian cancer risk; however, additional studies with larger sample size should be performed to exclude any possible association with EOC risk. Cancer Epidemiol Biomarkers Prev; 25(1); 127–34. ©2015 AACR.