BRCA1- and BRCA2-Associated Ovarian Cancer: different diseases?

__Abstract__ Ovarian cancer will develop in approximately 1.4% of the Dutch women accounting for approximately 1250 new patients yearly in the Netherlands, which is comparable with the incidence in other Western world countries. The disease mainly develops in women of 40 years of age and older, with the highest incidence around 60 years of age. Despite this relatively low incidence, ovarian cancer is the leading cause of death from gynaecological malignancies in the Netherlands, with about 1000 deaths annually. Ninety per cent of all ovarian cancers are of epithelial origin, and therefore can exhibit features of the different epithelia originating from the Mullerian ducts i.e. the epithelium lining the fallopian tubes, cervix, uterus, and part of the vagina. In this way, epithelial ovarian cancers (EOC) can be subdivided into serous, mucinous, endometrioid, clear cell, undifferentiated carcinomas and Brenner tumors.Most ovarian cancers are of serous histology (65-70%). Traditionally, differentiation grade has been classified in grade 1, 2 and 3, according to the Silverberg criteria. More recently another classification system for ovarian cancer has been introduced, subdividing into low-grade (Type I) and high-grade (Type II) tumors. Low-grade tumors have frequent mutations in the KRAS, BRAF, ERBB2, CTNNB1, PTEN, PIK3CA, ARID1A, and PPP2R1A genes, lack TP53 mutations and have a better outcome than high-grade tumors.Low-grade carcinomas exhibit low-grade nuclei with infrequent mitotic figures. This entity comprises low-grade serous, low-grade endometrioid, clear cell and mucinous carcinomas and Brenner tumors. High-grade carcinomas have high-grade nuclei and numerous mitotic figures, feature a high growth rate, are characterized by TP53 mutations and lack mutations of KRAS, BRAF, or ERBB2 and have molecular alterations that disturb expression of BRCA either by a mutation in the gene or by promoter methylation. High-grade carcinomas are assumed to originate de novo and comprise high-grade serous, high-grade endometrioid, mixed mesodermal tumors (carcinosarcomas) and undifferentiated carcinomas

Outcome of ovarian cancer after breast cancer in BRCA1 and BRCA2 mutation carriers

Background:It is unknown whether a history of breast cancer (BC) affects the outcome of BRCA1/2-associated epithelial ovarian cancer (EOC). This was investigated in the current analysis.Methods:We included 386 BRCA1/2-associated EOC patients diagnosed between 1980 and 2015. Progression-free survival (PFS), progression-free interval (PFI), overall survival (OS) and ovarian cancer-specific survival (OCSS) were compared between EOC patients with and without previous BC.Results:BRCA-associated EOC patients with, vs without, a BC history had a significantly worse PFS and PFI (multivariate hazard ratio (HR mult) 1.47; 95% confidence interval (CI) 1.03-2.08 and HR mult 1.43; 95% CI 1.01-2.03), and a non-significantly worse OS (HR mult 1.15; 95% CI 0.84-1.57) and OCSS (HR mult 1.18; 95% CI 0.85-1.62). Ovarian cancer-specific survival was significantly worse for the subgroup treated with adjuvant chemotherapy for BC (HR mult 1.99; 95% CI 1.21-3.31).Conclusions:Our results suggest that BRCA1/2-associated EOC patients with a previous BC have a worse outcome than EOC patients without BC, especially when treated with adjuvant chemotherapy

Outcome of ovarian cancer after breast cancer in BRCA1 and BRCA2 mutation carriers

Background: It is unknown whether a history of breast cancer (BC) affects the outcome of BRCA1/2-associated epithelial ovarian cancer (EOC). This was investigated in the current analysis. Methods: We included 386 BRCA1/2-associated EOC patients diagnosed between 1980 and 2015. Progression-free survival (PFS), progression-free interval (PFI), overall survival (OS) and ovarian cancer-specific survival (OCSS) were compared between EOC patients with and without previous BC. Results: BRCA-associated EOC patients with, vs without, a BC history had a significantly worse PFS and PFI (multivariate hazard ratio (HRmult) 1.47; 95% confidence interval (CI) 1.03-2.08 and HRmult 1.43; 95% CI 1.01-2.03), and a non-significantly worse OS (HRmult 1.15; 95% CI 0.84-1.57) and OCSS (HRmult 1.18; 95% CI 0.85-1.62). Ovarian cancer-specific survival was significantly worse for the subgroup treated with adjuvant chemotherapy for BC (HRmult 1.99; 95% CI 1.21-3.31). Conclusions: Our results suggest that BRCA1/2-associated EOC patients with a previous BC have a worse outcome than EOC patients without BC, especially when treated with adjuvant chemotherapy

Evaluation of a nationwide Dutch guideline to detect Lynch syndrome in patients with endometrial cancer

Objective: In the Netherlands a nationwide guideline was introduced in 2016, which recommended routine Lynch syndrome screening (LSS) for all women with endometrial cancer (EC) <70 years of age. LSS consists of immunohistochemical (IHC) staining for loss of mismatch repair (MMR) protein expression, supplemented with MLH1 methylation analysis if indicated. Test results are evaluated by the treating gynaecologist, who refers eligible patients to a clinical geneticist. We evaluated the implementation of this guideline. Methods: From the nation-wide pathology database we selected all women diagnosed with EC < 70 years of age, treated from 1.6.2016–1.6.2017 in 14 hospitals. We collected data on the results of LSS and follow up of cases with suspected LS. Results: In 183 out of 204 tumours (90%) LSS was performed. In 41 cases (22%) MMR protein expression was lost, in 25 cases due to hypermethylation of the MLH1 promotor. One patient was known with a pathogenic MLH1 variant. The option of genetic counselling was discussed with 12 of the 15 remaining patients, of whom three declined. After counselling by the genetic counsellor nine patients underwent germline testing. In two no pathogenic germline variant was detected, two were diagnosed with a pathogenic PMS2 variant, and five with a pathogenic MSH6 variant, in concordance with the IHC profiles. Conclusion: Coverage of LSS was high (90%), though referral for genetic counselling could be improved. Gynaecologists ought to be aware of the benefits and possible drawbacks of knowing mutational status, and require training in discussing this with their patients

Chemosensitivity and outcome of BRCA1- and BRCA2-associated ovarian cancer patients after first-line chemotherapy compared with sporadic ovarian cancer patients

Background: Because it is insufficiently clear whether BRCA-associated epithelial ovarian cancer (EOC) is more chemosensitive than sporadic EOC, we examined response to chemotherapy, progression-free survival (PFS) and overall survival (OS) in BRCA1- and BRCA2-associated versus sporadic EOC patients. Methods: Data about patient characteristics, response to and outcome after primary therapy, including chemotherapy, were collected from 99 BRCA1, 13 BRCA2 and 222 sporadic patients. Analyses were carried out using a chi-square test and Kaplan-Meier and Cox regression methods. Results: Complete response (CR) or no evidence of disease (NED) was observed in 87% of the BRCA1 patients, progressive disease (PD) in 2%, being 71% and 15%, respectively, in sporadic EOC patients (P = 0.002). In BRCA2 patients, 92% had CR/NED, and none PD (P = 0.27). Median PFS in BRCA1, BRCA2 and sporadic patients was 2.1 [95% confidence interval (CI) 1.9-2.5] years (P = 0.006), 5.6 (95% CI 0.0-11.5) years (P = 0.008) and 1.3 (95% CI 1.1-1.5) years, respectively. Median OS in the three groups was 5.9 (95% CI 4.7-7.0) years (P 10 years (P = 0.008), and 2.9 (95% CI 2.2-3.5) years, respectively. A trend for a longer PFS and OS in BRCA2 compared with BRCA1 patients was observed. Conclusion: Compared with sporadic EOC patients, both BRCA1- and BRCA2-associated patients have improved outcomes after primary therapy, including chemotherapy

Evaluation of a Web-Based Intervention for Patients with Gestational Trophoblastic Disease:A Randomized Controlled Trial

Objective: Gestational trophoblastic diseases (GTD) comprise a group of rare diseases originating from the trophoblast affecting women of childbearing age. Providing optimal information to patients with a rare disease is challenging because of the small number of patients and limited clinical expertise of many healthcare professionals. Both knowledge and lack of knowledge in patients may influence illness perception. We investigated whether a web-based interactive intervention influences illness perception and knowledge in women with GTD. Design: This was a multicenter randomized control trial conducted at general and academic hospitals in the Netherlands, including newly diagnosed GTD patients between 2017 and 2019. Methods: Sixty-nine patients were randomized between direct access or postponed access to an online tool on GTD and received online questionnaires about illness perception, knowledge, and anxiety. The main outcome measures were illness perception (primary outcome measure) and knowledge (secondary outcome measure). Results: Patients using the online tool were satisfied with the information from the tool (92%). Although they had a higher level of knowledge compared to the control group (p = 0.006), illness perception did not change. Also, no differences in levels of anxiety, depression, or distress were observed between the groups. Limitations: Participants had access to other information sources and many searched other websites. It is unknown what kind of websites were visited and when. It is unknown if the increased knowledge levels and low levels of distress will sustain over time as no long term follow-up took place. Healthcare professionals were not interviewed on how they experienced the consultation before and after using the tool by the patients. Conclusions: The online tool did not change illness perception but was shown to be valuable for newly diagnosed GTD patients to gain knowledge. The improvement in knowledge after digital education indicates that this tool can be used as an effective method of supporting GTD patients' informational needs without causing extra distress. Tweetable Abstract: A web-based tool for trophoblastic disease does not change illness perception of patients but is valuable to gain knowledge.</p

Evaluation of a Web-Based Intervention for Patients with Gestational Trophoblastic Disease: A Randomized Controlled Trial

Objective: Gestational trophoblastic diseases (GTD) comprise a group of rare diseases originating from the trophoblast affecting women of childbearing age. Providing optimal information to patients with a rare disease is challenging because of the small number of patients and limited clinical expertise of many healthcare professionals. Both knowledge and lack of knowledge in patients may influence illness perception. We investigated whether a web-based interactive intervention influences illness perception and knowledge in women with GTD. Design: This was a multicenter randomized control trial conducted at general and academic hospitals in the Netherlands, including newly diagnosed GTD patients between 2017 and 2019. Methods: Sixty-nine patients were randomized between direct access or postponed access to an online tool on GTD and received online questionnaires about illness perception, knowledge, and anxiety. The main outcome measures were illness perception (primary outcome measure) and knowledge (secondary outcome measure). Results: Patients using the online tool were satisfied with the information from the tool (92%). Although they had a higher level of knowledge compared to the control group (p = 0.006), illness perception did not change. Also, no differences in levels of anxiety, depression, or distress were observed between the groups. Limitations: Participants had access to other information sources and many searched other websites. It is unknown what kind of websites were visited and when. It is unknown if the increased knowledge levels and low levels of distress will sustain over time as no long term follow-up took place. Healthcare professionals were not interviewed on how they experienced the consultation before and after using the tool by the patients. Conclusions: The online tool did not change illness perception but was shown to be valuable for newly diagnosed GTD patients to gain knowledge. The improvement in knowledge after digital education indicates that this tool can be used as an effective method of supporting GTD patients' informational needs without causing extra distress. Tweetable Abstract: A web-based tool for trophoblastic disease does not change illness perception of patients but is valuable to gain knowledge