The emerging role of molecular pathology in directing the systemic treatment of endometrial cancer

Following the discovery of the four molecular subtypes of endometrial cancer (EC) by The Cancer Genome Atlas (TCGA) in 2013, subsequent studies used surrogate markers to develop and validate a clinically relevant EC classification tool to recapitulate TCGA subtypes. Molecular classification combines focused sequencing (POLE) and immunohistochemistry (mismatch repair and p53 proteins) to assign patients with EC to one of four molecular subtypes: POLEmut, MMRd, p53abn and NSMP (no specific molecular profile). Unlike histopathological evaluation, the molecular subtyping of EC offers an objective and reproducible classification system that has been shown to have prognostic value and therapeutic implications. It is an exciting time in EC care where we have moved beyond treatment based on histomorphology alone, and molecular classification will now finally allow assessment of treatment efficacy within biologically similar tumours. It is now recommended that molecular classification should be considered for all ECs, and should be performed routinely in all high grade tumours. It is also recommended to incorporate molecular classification into standard pathology reporting and treatment decision-making algorithms. In this review, we will discuss how the molecular classification of EC can be used to guide both conventional and targeted therapy in this new molecular era.MTG8 - Moleculaire pathologie van gynecologische tumorenMolecular tumour pathology - and tumour genetic

The parent?infant dyad and the construction of the subjective self

Developmental psychology and psychopathology has in the past been more concerned with the quality of self-representation than with the development of the subjective agency which underpins our experience of feeling, thought and action, a key function of mentalisation. This review begins by contrasting a Cartesian view of pre-wired introspective subjectivity with a constructionist model based on the assumption of an innate contingency detector which orients the infant towards aspects of the social world that react congruently and in a specifically cued informative manner that expresses and facilitates the assimilation of cultural knowledge. Research on the neural mechanisms associated with mentalisation and social influences on its development are reviewed. It is suggested that the infant focuses on the attachment figure as a source of reliable information about the world. The construction of the sense of a subjective self is then an aspect of acquiring knowledge about the world through the caregiver's pedagogical communicative displays which in this context focuses on the child's thoughts and feelings. We argue that a number of possible mechanisms, including complementary activation of attachment and mentalisation, the disruptive effect of maltreatment on parent-child communication, the biobehavioural overlap of cues for learning and cues for attachment, may have a role in ensuring that the quality of relationship with the caregiver influences the development of the child's experience of thoughts and feelings

Selected Medical Interventions in Women With a Deleterious Brca Mutation: A Population-Based Study in British Columbia

Background: We examined the uptake of risk-reducing interventions, including bilateral mastectomy, risk-reducing salpingo-oophorectomy, oral contraceptive pills, tamoxifen, and raloxifene, for the entire population of women with a deleterious BRCA1 or BRCA2 mutation in the Canadian province of British Columbia. Methods: This retrospective population-based study used data available in British Columbia for all women who, between 1996 and 2014, were tested and found to have a BRCA mutation. Rates of risk-reducing interventions stratified according to the type of BRCA mutation and prior history of breast or gynecologic cancer (ovary, fallopian tube, peritoneal) are presented. Cancers diagnosed in women with a BRCA mutation after disclosure of their mutation status are also presented. Results: The final study cohort consisted of 885 patients with a deleterious BRCA1 (n = 474) or BRCA2 (n = 411) mutation. Of the women with no prior breast cancer, 30.8% carrying a BRCA1 mutation and 28.3% carrying a BRCA2 mutation underwent bilateral mastectomy. Of women with no prior gynecologic cancer, 64.7% carrying a BRCA1 mutation and 62.2% carrying a BRCA2 mutation underwent risk-reducing bilateral salpingo-oophorectomy. Rates of chemoprevention with oral contraceptive pills and tamoxifen or raloxifene were low in all groups. In this cohort, 23 gynecologic and 70 breast cancers were diagnosed after disclosure of BRCA mutation status. Conclusions: Our results suggest reasonable uptake of risk-reducing interventions in high-risk women. To minimize the occurrence of breast and ovarian cancer in women with a BRCA1 or BRCA2 mutation, more attention could be paid to ensuring that affected women receive proper counselling and follow-up

Mismatch repair deficiency as a predictive marker for response to adjuvant radiotherapy in endometrial cancer

BACKGROUND: Mismatch repair (MMR) deficiency is found in 20 to 40% of endometrial cancers (ECs) and was recently identified as a discerning feature of one of the four prognostic subgroups identified by The Cancer Genome Atlas. There is accumulating evidence that MMR proteins are involved in the DNA repair processes following radiotherapy. We investigated the predictive value of MMR status for response to adjuvant radiotherapy in patients with stage IB/II, grade 3 endometrioid endometrial cancer (EEC). METHODS: A retrospective multicenter cohort study was performed to compare patients with histopathologically confirmed stage IB/II grade 3 EEC with and without adjuvant radiotherapy. Patients were classified according to the Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE) identifying ECs as either MMR-deficient, POLE, p53abn or p53wt. Multivariable Cox regression analysis explored associations between adjuvant treatment and outcome. RESULTS: A total of 128 patients were analyzed, including 57 patients (43.0%) with MMR-deficient EECs. Baseline characteristics were comparable, except a higher proportion of MMR-deficient EECs were stage II (36.8% vs. 15.5%, p=0.006). Eighty-two patients (64.1%) received adjuvant radiotherapy (external beam [n=55], vaginal brachytherapy [n=27]). In multivariable analysis, adjuvant radiotherapy was associated with improved disease-specific survival in patients with MMR-deficient EECs (hazard ratio 0.19, 95%-CI 0.05-0.77), but not in patients with MMR-proficient EECs (hazard ratio 0.92, 95%-CI 0.37-2.31). CONCLUSION: Adjuvant radiotherapy improved survival in patients with MMR-deficient EECs. MMR status could be used as a predictive biomarker to select patients that benefit most from adjuvant radiotherapy

Ovarian Cancer Prevention and Screening

There has been much progress in ovarian cancer screening and prevention in recent years. Improved tools that combine genetic and epidemiologic factors to predict an individual's ovarian cancer risk are set to become available for tailoring preventive and screening approaches. The increasing evidence on tubal origins of a proportion of ovarian cancer has paved the way to use of opportunistic bilateral salpingectomy at tubal ligation and hysterectomy in the general population. Clinical trials are in progress to estimate the long-term effects on endocrine function. In women at high risk, risk reducing salpingo-oophorectomy remains the standard of care with the current focus on management of resulting noncancer outcomes, especially sexual dysfunction in younger women. This has led to evaluation of early bilateral salpingectomy and delayed oophorectomy in this population. Meanwhile, modeling suggests that BRCA mutation carriers should consider using the oral contraceptive pill for chemoprevention. In the general population, the largest ovarian cancer screening trial to date, the UK Collaborative Trial of Ovarian Cancer Screening reported a stage shift with annual multimodal screening using the longitudinal CA 125 Risk of Ovarian Cancer Algorithm but not with annual transvaginal ultrasound screening. There was no definitive mortality reduction with either screening strategy compared with no screening. Further follow-up until December 2018 in now underway. Stage shift and higher rates of optimal cytoreduction were also reported during 3- to 4-monthly multimodal screening in the United Kingdom and U.S. high-risk screening trials. Although all agree that there is not yet evidence to support general population screening, recommendations for high-risk screening vary between countries. A key finding from the screening trials has been the better performance of longitudinal algorithms compared with a single cutoff for CA 125. A major focus of ovarian cancer biomarker discovery work has been tumor DNA markers in both plasma and novel specimens such as cervical cytology samples

Quality of Life Research in Endometrial Cancer What Is Needed to Advance Progress in This Disease Site? Methodological Considerations From the Gynecologic Cancer InterGroup Symptom Benefit Working Group Brainstorming Session, Leiden 2012

Biological, physical and clinical aspects of cancer treatment with ionising radiatio

Data Set for the Reporting of Carcinomas of the Vulva: Recommendations From the International Collaboration on Cancer Reporting (ICCR)

A cogent and comprehensive pathologic report is essential for optimal patient management, cancer staging, and prognostication. This article details the International Collaboration on Cancer Reporting (ICCR) process and the development of the vulval carcinoma reporting data set. It describes the "core" and "noncore" elements to be included in pathology reports for vulval carcinoma, inclusive of clinical, macroscopic, microscopic, and ancillary testing considerations. It provides definitions and commentary for the evidence and/or consensus-based deliberations for each element included in the data set. The commentary also discusses controversial issues, such as p16/human papillomavirus testing, tumor grading and measurements, as well as elements that show promise and warrant further evidence-based study. A summary and discussion of the updated vulval cancer staging system by the International Federation of Obstetricians and Gynaecologists (FIGO) in 2021 is also provided. We hope the widespread implementation of this data set will facilitate consistent and accurate reporting, data collection, comparison of epidemiological and pathologic parameters between different populations, facilitate research, and serve as a platform to improve patient outcomes.Molecular tumour pathology - and tumour genetic