iKNOWgynetics - A web-based learning concept to empower primary care gynecologists to participate in the care of patients with a family history of breast and ovarian cancer.

Familial cancer burden and genetics play an increasingly important role in the early detection and prevention of gynecological cancers. However, people with hereditary cancer risks are often identified late when they already have cancer. We aimed at developing and evaluating a training concept for primary care gynecologists-iKNOWgynetics-to improve their knowledge and awareness of genetic cancer syndromes and their ability to identify patients with increased familial cancer risks based on up-to-date evidence and current guidelines (in Germany, primary care includes all doctors treating patients on an outpatient basis without a clear separation of the expertise of the doctor or of their specialty). Starting off with a needs assessment among primary care gynecologists, we developed and evaluated an online training concept-using a web-based learning platform in combination with a live virtual seminar-to convey practice-relevant knowledge about familial cancer. After registration, participants get access to the web-based learning platform (www.iknowgynetics.de) to prepare for the virtual seminars and to use it as online reference to re-access the contents after the training. Evaluation included multiple-choice (MC) questions on knowledge and participants' self-efficacy to implement the acquired knowledge, which were administered in a pre-post design. Of 109 participants, 103 (94.5%) filled out pre- and post-questionnaires. Eighty-five participants were gynecologists in primary care from Berlin (81.2%) and Brandenburg (18.8%) and had an average of 24.1 years (SD = 8.5 years) of professional experience. After the training, participants answered significantly more knowledge questions correctly (M = 15.2 of 17, SD = 1.3) than before (M = 13.8 of 17, SD = 1.7) (p < 0.01) and felt more confident to be able to apply referral criteria for specialized counseling in practice (p < 0.001). The online-based training iKNOWgynetics considers the busy schedule of primary care gynecologists and supports them in acquiring practice-relevant information on familial cancer risks and on how to identify healthy persons at risk, which may ultimately help to improve the prevention of gynecological cancers. In future studies, the reported concept could be transferred to other entities.

How breast cancer therapies impact body image - real-world data from a prospective cohort study collecting patient-reported outcomes.

BACKGROUND: In breast cancer patients body image (BI) is a crucial aspect of quality of life (QoL). This study examined the postoperative impact of different surgical approaches on long-term BI analyzing real-world data to guide pre- and postoperative patient care and preserve QoL. METHODS: EORTC QLQ-BR23 BI scores were collected electronically in 325 breast cancer patients within routine clinical care for a duration of 41.5 months (11/17/2016 - 4/30/2020) at predefined time points preoperatively and repeatedly up to two years after breast-conserving surgery (BCS) (n = 212), mastectomy alone (M) (n = 27) or mastectomy with immediate breast reconstruction (MIBR) (n = 86). Higher scores indicated better BI. A linear mixed regression model was used to analyze the impact of BCS, M and MIBR, as well as non-surgical therapies on BI at treatment initiation and over time. RESULTS: BI scores deteriorated by 5 points (95%-confidence interval (CI) -8.94 to -1.57, p≈0.005) immediately after BCS, by 7 points (95%-CI -12.13 to -1.80, p≈0.008) after MIBR and by 19 points (95%-CI -27.34 to -10.34, p < 0.001) after M. The change over time after BCS (+ 0.10 points per week, 95%-CI -0.17 to 0.38), MIBR (-0.07 points per week, 95%-CI -0.35 to 0.20) and M (+ 0.14 points per week, 95%-CI -0.19 to 0.48) were not statistically significant (each p > 0.05). At treatment initiation chemotherapy was associated with a 22-point decline (95%-CI -25.39 to -17.87, p < 0.001) in BI score, while radiotherapy was associated with a 5-point increase (95%-CI 1.74 to 9.02, p≈0.004). However, over time chemotherapy was associated with a score recovery (+ 0.28 points per week, 95%-CI 0.19 to 0.37, p < 0.001), whereas for radiotherapy a trend towards BI deterioration was observed (-0.11 points per week, 95%-CI -0.23 to 0.02, p≈0.101). CONCLUSIONS: Breast cancer surgery negatively affects BI. BCS and MIBR presumably harm BI less than M in the early postoperative period. Our data suggests BI to be deteriorating in the long term after MIBR while improving after BCS or M. Radiotherapy seems to have an additional negative long-term impact on BI. These findings should be confirmed in further studies to enable evidence-based patient information as part of preoperative shared decision-making and postoperative patient care.

Quality of life after risk-reducing salpingo-oophorectomy in women with a pathogenic BRCA variant.

BACKGROUND: Risk-reducing salpingo-oophorectomy (RRSO) is recommended to women with a pathogenic BRCA variant, but as a main side effect, RRSO could lead to an early onset of menopause. AIM: To evaluate the impact of RRSO and preoperative menopausal status on menopausal symptoms, sexual functioning, and quality of life (QOL). METHODS: The study was conducted between November 2019 and April 2020. Women were included who tested positive for a pathogenic BRCA1/2 variant between 2015 and 2018. Depression levels, QOL, and global health status were measured and compared with those of women who opted against RRSO. Furthermore, women who underwent RRSO treatment were asked to report menopausal complaints that they experienced at 1 month postsurgery and any current complaints. OUTCOMES: RRSO had no significant impact on QOL, but women who were premenopausal at the time of surgery reported more sexual complaints than postmenopausal women. RESULTS: In total, 134 carriers of a BRCA mutation were included: 90 (67%) underwent RRSO and 44 (33%) did not. At the time of the survey, neither the control nor experimental group experienced significant changes in QOL (b = -0.18, P = .59). Women who underwent RRSO reported a significantly lower global health status (b = -0.66, P = .05). Women who were premenopausal at the time of surgery were bothered more by sexual symptoms (b = 0.91, P = .19) but experienced fewer vasomotor complaints (b = -1.09, P = .13) than women who were postmenopausal at the time of RRSO. CLINICAL IMPLICATIONS: The decrease of sexual functioning after RRSO should be an integral part of preoperative counseling because it is important for BRCA carriers, especially for premenopausal women. STRENGTHS AND LIMITATIONS: Some strengths of the present study were the long follow-up, a high response rate, and the existence of a control group, whereas defining menopausal status by last menstrual bleeding and self-report of data (eg, breast cancer history) increased the risk of errors. CONCLUSION: Our study indicated that women who underwent RRSO experienced no difference in QOL when compared with women without RRSO and that patients with premenopausal status seemed to be at higher risk to experience sexual complaints after surgery.

Interdisciplinary risk counseling for hereditary breast and ovarian cancer: real-world data from a specialized center.

PURPOSE: Hereditary breast and ovarian cancer has long been established to affect a considerable number of patients and their families. By identifying those at risk ideally before they have been diagnosed with breast and/or ovarian cancer, access to preventive measures, intensified screening and special therapeutic options can be obtained, and thus, prognosis can be altered beneficially. Therefore, a standardized screening and counseling process has been established in Germany under the aegis of the German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC). As one of these specialized clinics, the HBOC-Center at Charité offers genetic counseling as well as genetic analysis based on the GC-HBOC standards. This analysis aims first at depicting this process from screening through counseling to genetic analysis as well as the patient collective and second at correlating the results of genetic analysis performed. Thus, real-world data from an HBOC-Center with a substantial patient collective and a high frequency of pathogenic variants in various genes shall be presented. METHODS: The data of 2531 people having been counseled at the HBOC-Center at Charité in 2016 and 2017 were analyzed in terms of patient and family history as well as pathogenic variants detected during genetic analysis with the TruRisk® gene panel when genetic analysis was conducted. This standardized analysis is compiled and regularly adjusted by the GC-HBOC. The following genes were included at time of research: BRCA1, BRCA2, ATM, CDH1, CHEK2, PALB2, RAD51C, RAD51D, NBN, and TP53. RESULTS: Genetic analysis was conducted in 59.8% of all cases meeting the criteria for genetic analysis and 286 pathogenic variants were detected among 278 (30.3%) counselees tested using the TruRisk® gene panel. These were primarily found in the genes BRCA1 (44.8%) and BRCA2 (28.3%) but also in CHEK2 (12.2%), ATM (5.6%) and PALB2 (3.5%). The highest prevalence of pathogenic variants was seen among the families with both ovarian and breast cancer (50.5%), followed by families with ovarian cancer only (43.2%) and families with breast cancer only (35.6%)-these differences are statistically significant (p < 0.001). Considering breast cancer subtypes, the highest rate of pathogenic variants was detected among patients with triple-negative breast cancer (40.7%) and among patients who had had been diagnosed with triple-negative breast cancer before the age of 40 (53.4%)-both observations proved to be statistically significant (p = 0.003 and p = 0.001). CONCLUSION: Genetic counseling and analysis provide the foundation in the prevention and therapy of hereditary breast and ovarian cancer. The rate of pathogenic variants detected is associated with family history as well as breast cancer subtype and age at diagnosis, and can reach considerable dimensions. Therefore, a standardized process of identification, genetic counseling and genetic analysis deems mandatory.

Breast cancer risk in BRCA1/2 mutation carriers and noncarriers under prospective intensified surveillance.

Comparably little is known about breast cancer (BC) risks in women from families tested negative for BRCA1/2 mutations despite an indicative family history, as opposed to BRCA1/2 mutation carriers. We determined the age-dependent risks of first and contralateral breast cancer (FBC, CBC) both in noncarriers and carriers of BRCA1/2 mutations, who participated in an intensified breast imaging surveillance program. The study was conducted between January 1, 2005, and September 30, 2017, at 12 university centers of the German Consortium for Hereditary Breast and Ovarian Cancer. Two cohorts were prospectively followed up for incident FBC (n = 4,380; 16,398 person-years [PY], median baseline age: 39 years) and CBC (n = 2,993; 10,090 PY, median baseline age: 42 years). Cumulative FBC risk at age 60 was 61.8% (95% CI 52.8-70.9%) for BRCA1 mutation carriers, 43.2% (95% CI 32.1-56.3%) for BRCA2 mutation carriers and 15.7% (95% CI 11.9-20.4%) for noncarriers. FBC risks were significantly higher than in the general population, with incidence rate ratios of 23.9 (95% CI 18.9-29.8) for BRCA1 mutation carriers, 13.5 (95% CI 9.2-19.1) for BRCA2 mutation carriers and 4.9 (95% CI 3.8-6.3) for BRCA1/2 noncarriers. Cumulative CBC risk 10 years after FBC was 25.1% (95% CI 19.6-31.9%) for BRCA1 mutation carriers, 6.6% (95% CI 3.4-12.5%) for BRCA2 mutation carriers and 3.6% (95% CI 2.2-5.7%) for noncarriers. CBC risk in noncarriers was similar to women with unilateral BC from the general population. Further studies are needed to confirm whether less intensified surveillance is justified in women from BRCA1/2 negative families with elevated risk.

Cancer surveillance and distress among adult pathogenic TP53 germline variant carriers in Germany: A multicenter feasibility and acceptance survey.

BACKGROUND: Li-Fraumeni syndrome (LFS) is a high-risk cancer predisposition syndrome caused by pathogenic germline variants of TP53. Cancer surveillance has noted a significant survival advantage in individuals with LFS; however, little is known about the feasibility, acceptance, and psychosocial effects of such a program. METHODS: Pathogenic TP53 germline variant carriers completed a 7-part questionnaire evaluating sociodemographics, cancer history, surveillance participation, reasons for nonadherence, worries, and distress adapted from the Cancer Worry Scale. Counselees' common concerns and suggestions were assessed in MAXQDA Analytics Pro 12. RESULTS: Forty-nine participants (46 females and 3 males), aged 40.0 ± 12.6 years, formed the study population; 43 (88%) had a personal cancer history (including multiple cancers in 10 [20%]). Forty-three individuals participated (88%) in surveillance during the study or formerly. Willingness to undergo surveillance was influenced by satisfaction with genetic testing and counseling (P = .019 [Fisher-Yates test]) but not by sociodemographics, cancer history, or distress level. Almost one-third of the participants reported logistical difficulties in implementing surveillance because of the high frequency of medical visits, scheduling difficulties, and the travel distance to their surveillance providers. Self-reported distress and perceived emotional burden for family members and partners were moderate (median for self-reported distress, 3.3; median for perceived emotional burden, 3.0). For both, the interquartile range was moderate to very high (2.7-3.7 and 3.0-3.7, respectively). CONCLUSIONS: Individuals with LFS require efficient counseling as well as an accessible, well-organized, interdisciplinary, standardized surveillance program to increase adherence and psychological coping.

High-risk breast cancer surveillance with MRI: 10-year experience from the German consortium for hereditary breast and ovarian cancer.

PURPOSE: To report on 10 years of high-risk service screening with annual MRI in the German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC). METHODS: A cohort of 4,573 high-risk, previously unaffected women (954 BRCA1 carriers, 598 BRCA2 carriers, 3021 BRCA1/2 non-carriers) participating in the GC-HBOC surveillance program was prospectively followed. Screening outcomes for 14,142 screening rounds with MRI between 2006 and 2015 were analyzed and stratified by risk group, type of screening round, and age. RESULTS: A total of 221 primary breast cancers (185 invasive, 36 in situ) were diagnosed within 12 months of an annual screening round with MRI. Of all cancers, 84.5% (174/206, 15 unknown) were stage 0 or I. In BRCA1 carriers, 16.9% (10/59, 5 unknown) of all incident cancers (screen-detected and interval cancers combined) and in BRCA2 carriers 12.5% (3/24, 4 unknown) were stage IIA or higher, compared to only 4.8% (2/42, 2 unknown) in high-risk BRCA1/2 non-carriers. Program sensitivity was 89.6% (95% CI 84.9-93.0) with no significant differences in sensitivity between risk groups or by age. Specificity was significantly lower in the first screening round (84.6%, 95% CI 83.6-85.7) than in subsequent screening rounds (91.1%, 95% CI 90.6-91.7), p < 0.001. Cancer detection rates (CDRs) and as a result positive predictive values were strongly dependent on type of screening round, risk group and patient age. CDRs ranged from 43.5‰ (95% CI 29.8-62.9) for the first screening round in BRCA2 carriers to 2.9‰ (95% CI 1.3-6.3) for subsequent screening rounds in high-risk non-carriers in the age group 30 to 39 years. CONCLUSIONS: High-risk screening with MRI was successfully implemented in the GC-HBOC with high sensitivity and specificity. Risk prediction and inclusion criteria in high-risk non-carriers need to be adjusted to improve CDRs and thus screening efficacy in these patients.

Prevalence of pathogenic BRCA1/2 germline mutations among 802 women with unilateral triple-negative breast cancer without family cancer history.

BACKGROUND: There is no international consensus up to which age women with a diagnosis of triple-negative breast cancer (TNBC) and no family history of breast or ovarian cancer should be offered genetic testing for germline BRCA1 and BRCA2 (gBRCA) mutations. Here, we explored the association of age at TNBC diagnosis with the prevalence of pathogenic gBRCA mutations in this patient group. METHODS: The study comprised 802 women (median age 40 years, range 19-76) with oestrogen receptor, progesterone receptor, and human epidermal growth factor receptor type 2 negative breast cancers, who had no relatives with breast or ovarian cancer. All women were tested for pathogenic gBRCA mutations. Logistic regression analysis was used to explore the association between age at TNBC diagnosis and the presence of a pathogenic gBRCA mutation. RESULTS: A total of 127 women with TNBC (15.8%) were gBRCA mutation carriers (BRCA1: n = 118, 14.7%; BRCA2: n = 9, 1.1%). The mutation prevalence was 32.9% in the age group 20-29 years compared to 6.9% in the age group 60-69 years. Logistic regression analysis revealed a significant increase of mutation frequency with decreasing age at diagnosis (odds ratio 1.87 per 10 year decrease, 95%CI 1.50-2.32, p < 0.001). gBRCA mutation risk was predicted to be > 10% for women diagnosed below approximately 50 years. CONCLUSIONS: Based on the general understanding that a heterozygous mutation probability of 10% or greater justifies gBRCA mutation screening, women with TNBC diagnosed before the age of 50 years and no familial history of breast and ovarian cancer should be tested for gBRCA mutations. In Germany, this would concern approximately 880 women with newly diagnosed TNBC per year, of whom approximately 150 are expected to be identified as carriers of a pathogenic gBRCA mutation.

Prevalence of BRCA1/2 germline mutations in 21†401 families with breast and ovarian cancer.

PURPOSE: To characterise the prevalence of pathogenic germline mutations in BRCA1 and BRCA2 in families with breast cancer (BC) and ovarian cancer (OC) history. PATIENTS AND METHODS: Data from 21 401 families were gathered between 1996 and 2014 in a clinical setting in the German Consortium for Hereditary Breast and Ovarian Cancer, comprising full pedigrees with cancer status of all individual members at the time of first counselling, and BRCA1/2 mutation status of the index patient. RESULTS: The overall BRCA1/2 mutation prevalence was 24.0% (95% CI 23.4% to 24.6%). Highest mutation frequencies were observed in families with at least two OCs (41.9%, 95% CI 36.1% to 48.0%) and families with at least one breast and one OC (41.6%, 95% CI 40.3% to 43.0%), followed by male BC with at least one female BC or OC (35.8%; 95% CI 32.2% to 39.6%). In families with a single case of early BC (<36 years), mutations were found in 13.7% (95% CI 11.9% to 15.7%). Postmenopausal unilateral or bilateral BC did not increase the probability of mutation detection. Occurrence of premenopausal BC and OC in the same woman led to higher mutation frequencies compared with the occurrence of these two cancers in different individuals (49.0%; 95% CI 41.0% to 57.0% vs 31.5%; 95% CI 28.0% to 35.2%). CONCLUSIONS: Our data provide guidance for healthcare professionals and decision-makers to identify individuals who should undergo genetic testing for hereditary breast and ovarian cancer. Moreover, it supports informed decision-making of counselees on the uptake of genetic testing.

Closure of the cervical os in patients after fertility preserving treatment for early cervical cancer - results of a prospective observational study.

INTRODUCTION: Up to 50% of the infants delivered after radical vaginal trachelectomy (RVT) are born prematurely. An effective strategy to reduce this number could be the closure of the cervical os (CCO). PATIENTS AND METHODS: Fifteen pregnant patients who had a RVT due to early cervical cancer were included in this prospective case control study. All patients were scheduled for CCO early in the second trimester. CCO was performed in 12 patients. Their data were compared to data from 125 pregnancies after a RVT without CCO. RESULTS: The patients who had CCO were compared to patients without CCO. One patient had an early rupture of the amniotic membranes prior to CCO. Two patients chose not to undergo CCO. In 12 patients CCO was performed without complications. There was no early preterm delivery in the CCO group as compared to a rate of 5% in 125 pregnancies in the non-CCO group. DISCUSSION: We developed a protocol to reduce the risk of preterm deliveries after a RVT. Digital examinations should be avoided. Vaginal checks for pH can discover ascending infections - the main cause of preterm deliveries after a RVT. Infections should be treated adequately. CCO can further reduce the risk of preterm deliveries after a RVT.

Follow-up after radical vaginal trachelectomy (RVT): patients' problems and physicians' difficulties.

PURPOSE: Patients after radical vaginal trachelectomy (RVT) need specific follow-up treatment because their problems differ from those of other gyneco-oncologic patients. Anatomic changes after surgery complicate examinations. Recognition and treatment of these issues require physician's expertise. PATIENTS AND METHODS: We evaluated the follow-up data of 70 patients who underwent RVT for early cervical cancer between 03/2010 and 12/2013. The follow-up interval in the first 2 years was 3 and 6 months in the following 2 years. We used a tailored protocol to describe the special problems after RVT. RESULTS: Cervical stenosis was one of the central problems independent of time interval to RVT. Physicians' most significant problem was to locate the exact position of the neo-cervix and thus to receive valid pap smears. CONCLUSIONS: Follow-up of patients after RVT needs special expertise because the symptoms differ from those after hysterectomy and examinations ensuring oncologic safety require special attention.

Validation of the Manchester scoring system for predicting BRCA1/2 mutations in 9,390 families suspected of having hereditary breast and ovarian cancer.

The Manchester scoring system (MSS) allows the calculation of the probability for the presence of mutations in BRCA1 or BRCA2 genes in families suspected of having hereditary breast and ovarian cancer. In 9,390 families, we determined the predictive performance of the MSS without (MSS-2004) and with (MSS-2009) consideration of pathology parameters. Moreover, we validated a recalibrated version of the MSS-2009 (MSS-recal). Families were included in the registry of the German Consortium for Hereditary Breast and Ovarian Cancer, using defined clinical criteria. Receiver operating characteristics (ROC) analysis was used to determine the predictive performance. The recalibrated model was developed using logistic regression analysis and tested using an independent random validation sample. The area under the ROC curves regarding a mutation in any of the two BRCA genes was 0.77 (95%CI 0.75-0.79) for MSS-2004, 0.80 (95%CI 0.78-0.82) for MSS-2009, and 0.82 (95%CI 0.80-0.83) for MSS-recal. Sensitivity at the 10% mutation probability cutoff was similar for all three models (MSS-2004 92.2%, MSS-2009 92.2%, and MSS-recal 90.3%), but specificity of MSS-recal (46.0%) was considerably higher than that of MSS-2004 (25.4%) and MSS-2009 (32.3%). In the MSS-recal model, almost all predictors of the original MSS were significantly predictive. However, the score values of some predictors, for example, high grade triple negative breast cancers, differed considerably from the originally proposed score values. The original MSS performed well in our sample of high risk families. The use of pathological parameters increased the predictive performance significantly. Recalibration improved the specificity considerably without losing much sensitivity.

Pattern of cancer recurrence in 320 patients after radical vaginal trachelectomy.

OBJECTIVE: The oncological outcome regarding disease-free survival and overall survival after radical vaginal trachelectomy (RVT) is the same as the rates after radical hysterectomy. We aim to analyze predictive and risk factors and death in patients with cervical cancer undergoing fertility preservation by laparoscopic lymphadenectomy and RVT. METHODS: Three hundred twenty patients with cervical cancer underwent RVT between March 1995 and February 2013. In our study, we examined recurrence rates analyzed by risk factors. We classified the presence of lymphovascular space invasion, depth of tumor infiltration, tumor size, and tumor grading as risk factors. The mean follow-up time was 48 months. RESULTS: Ten of the 320 patients had cancer recurrence. Recurrence appeared at a mean time of 26.1 months (3-108 months) after RVT. Five patients died within 8.8 months (4-15 months) after recurrence was diagnosed. Two of these 5 patients had distant metastasis at the time of recurrence. Five patients were treated successfully by surgery, and 4 patients were treated successfully by chemotherapy. The mean follow-up after the recurrence of these 5 patients is 76 months (6-120 months). None of the 10 patients with recurrences in our series showed significant high-risk factors. CONCLUSION: There seems to be no pattern in the recurrence of cancer after RVT. It is strictly mandatory to follow up the patients closely every 3 months after RVT to diagnose recurrence at an early stage so therapeutic options such as chemoradiation are still available. Once distant metastasis occurs, prognosis is not good.

Radical vaginal trachelectomy after laparoscopic staging and neoadjuvant chemotherapy in women with early-stage cervical cancer over 2 cm: oncologic, fertility, and neonatal outcome in a series of 20 patients.

OBJECTIVES: The aim of the study was to assess oncologic and fertility outcome of treatment in patients with cervical cancer of more than 2 cm seeking parenthood. METHODS: The regimen consisted of laparoscopic lymphadenectomy as a staging procedure to confirm no lymph node metastases before neoadjuvant chemotherapy (NACT) consisting of 2 or 3 cycles of paclitaxel/ifosfamide/cisplatin followed by radical vaginal trachelectomy (RVT). Oncologic and fertility outcome was evaluated prospectively. RESULTS: Twenty women were enrolled up to now. The mean age was 32 years (range, 26-41 years), and mean tumor size was 3 cm (range, 2.1-5.0 cm). Lymphadenectomy was performed before NACT without complications. During NACT, hematologic toxicity grade 3 was observed in 2 of 20 patients, and renal toxicity grade 3 in 1 of 20 patients. Radical vaginal trachelectomy was performed in 18 women until now with 2 intraoperative complications (ureter injury and injury of internal iliac vein). There were no severe postoperative or long-term complications. Complete pathologic remission was found in 9 of 18 patients. In 2 of 18 patients, chemoradiation was recommended because of insufficient pathologic response in the RVT specimen. After a mean follow-up of 23 months (range, 1-88 months), 1 relapse was observed. After RVT, 7 women tried to conceive until now. Seven pregnancies occurred in 5 women. Four children were born, 2 of whom were premature (31 weeks 2 days and 33 weeks 4 days of gestation); 1 pregnancy is ongoing. CONCLUSIONS: Laparoscopic lymphadenectomy followed by NACT and RVT in pN0 patients with cervical cancer of more than 2 cm seems to be an oncologically safe procedure with promising fertility outcomes.

Subtype-Specific Survival of Young Women with Breast Cancer and Its Interaction with the Germline BRCA Status.

Data are scarce on the role of pathogenic germline variants in BRCA1 and BRCA2 (gBRCAm) in subtype-specific survival in young women who develop breast cancer under the age of 40. This retrospective, real-world cohort study assessed the distant disease-free survival (DDFS) and overall survival (OS) of young women diagnosed with breast cancer between 2008 and 2019 while taking into consideration the interaction of clinical subtypes and the gBRCA status. Among 473 women, HR+/Her2- was the most common subtype (49.0%), followed by TNBC (31.3%), HR+/Her2+ (13.7%), and Her2+/HR- (5.9%). The gBRCA status was known for 319 cases (gBRCAwt (wild-type - without pathogenic variants in BRCA1 or BRCA2): 204, gBRCA1m: 83, gBRCA2m: 31, 1 patient with both). The distribution of clinical subtypes varied depending on the gBRCA status (p < 0.001). In survival analysis with a median follow-up of 43 months, the unadjusted DDFS and OS were worse for gBRCAwt TNBC compared to both HR+ subtypes, but not for gBRCAm TNBC patients. T-stage, nodal involvement, and the gBRCA status were identified as significant for survival in TNBC. In TNBC, gBRCAm was associated with better DDFS and OS than gBRCAwt (5-year DDFS 81.4% vs. 54.3%, p = 0.012 and 5-year OS 96.7% vs. 62.7%, p < 0.001). In contrast, in HR+/Her2- patients, gBRCAm patients showed a tendency for worse survival, though not statistically significant. Subtype-specific survival in young women with breast cancer needs to be evaluated in interaction with the gBRCA status. For TNBC, gBRCAm is of favorable prognostic value for overall survival, while patients with gBRCAwt TNBC need to be considered to have the highest risk for adverse survival outcomes.

Talking about Familial Breast and Ovarian Cancer Risk-Evaluation of a Psychosocial Training Module for Gynecologists in Germany.

Primary care gynecologists are increasingly integrated into the care of patients with hereditary breast and ovarian cancer (HBOC) risks. These physicians should not only have basic genetic knowledge; they should also feel able to sensitively address an increased HBOC risk and deal with emotional, stressful situations in this context. Our project aimed at developing a training module, 'iKNOWgynetics', addressing psychosocial challenges in the context of HBOC care for primary care gynecologists. We developed the psychosocial training module in three phases: first, we conducted an online survey with n = 35 women with a family history of breast or ovarian cancer to assess patients' experiences and needs. Second, based on the results of the needs assessment, we developed the training module. Third, we evaluated the training by assessing physicians' (n = 109) self-efficacy with regard to communication skills in the context of HBOC before and after the training. In the needs assessment, seven psychosocial themes emerged. These themes, complementing a review of the literature, informed the training curriculum. The training was divided into two parts: (1) communicating with women before genetic testing and (2) care co-management for women with HBOC after genetic testing. After the training, participants reported a significant increase in self-efficacy in three domains: communicating empathetically, educating patients in a comprehensible way and dealing with emotionally challenging situations. Our results highlight the relevance of psychosocial issues for patients with HBOC. A genetic literacy training module that integrates aspects of psychosocial care increases physicians' confidence in dealing with emotionally challenging situations before and after their patients' genetic testing. Thus, such trainings may improve the care of women with hereditary cancer risks.

Value of diagnostic procedures in rectovaginal endometriosis.

OBJECTIVE: Rectovaginal endometriosis has the potential to infiltrate into the rectal wall. The recognition of infiltration prior to surgery is of utmost importance since only infiltrative disease should be treated by partial or complete rectal resection. This study compares different imaging procedures in rectovaginal endometriosis cases in an everyday clinical setting. METHODS: Seventy nine consecutive women diagnosed with rectovaginal endometriosis were included in this prospective study. Preoperatively, all women had a rectovaginal gynaecological examination and transvaginal sonography. Furthermore, MRI or rectal endosonography imaging procedures together with a rectosigmoidoscopy and estimation of a serum Ca125 were undertaken. Sensitivity and specificity of all diagnostic tools were compared with the intraoperative findings. RESULTS: The procedure with the highest accuracy was bimanual rectovaginal gynaecological examination (sensitivity: 0.92/specificity: 0.32). Rectal endosonography obtained a sensitivity of 0.44 and a specificity of 0.77. All other diagnostic procedures such as Ca125 (sensitivity: 0.42/specificity: 0.81), MRI (sensitivity: 0.41/specificity: 0.83), transvaginal sonography (sensitivity: 0.2/ specificity: 0.79) and rectosigmoidoscopy (sensitivity: 0.03/specificity: 0.92) were only of limited value. CONCLUSION: The diagnostic method with the highest sensitivity to detect bowel infiltration in an everyday clinical setting is the gynaecological examination. It is followed by rectal endosonography. However, none of the currently available preoperative diagnostic tools can predict infiltrative growth of rectovaginal endometriosis with any certainty. Hence, infiltrative growth still needs to be verified by operative assessment.

Primary Prevention and Early Detection of Hereditary Breast Cancer.

Background: Primary prevention and early detection of hereditary breast cancer has been one of the main topics of breast cancer research in recent decades. The knowledge of risk factors for breast cancer has been increasing continuously just like the recommendations for risk management. Pathogenic germline variants (mutations, class 4/5) of risk genes are significant susceptibility factors in healthy individuals. At the same time, germline mutations serve as biomarkers for targeted therapy in breast cancer treatment. Therefore, management of healthy mutation carriers to enable primary prevention is in the focus as much as the consideration of pathogenic germline variants for therapeutic decisions. Since 1996, the German Consortium has provided quality-assured care for counselees and patients with familial burden of breast and ovarian cancer. Summary: Currently, there are 23 university centers with over 100 cooperating DKG-certified breast and gynecological cancer centers. These centers provide standardized, evidence-based, and knowledge-generating care, which includes aspects of primary as well as secondary and tertiary prevention. An important aspect of quality assurance and development was the inclusion of the HBOC centers in the certification system of the German Cancer Society (GCS). Since 2020, the centers have been regularly audited and their quality standards continuously reviewed according to quality indicators adapted to the current state of research. The standard of care at GC-HBOC' centers involves the evaluation as well as evolution of various aspects of care like inclusion criteria, identification of new risk genes, management of variants of unknown significance (class 3), evaluation of risk-reducing options, intensified surveillance, and communication of risks. Among these, the possibility of intensified surveillance in the GC-HBOC for early detection of breast cancer is an important component of individual risk management for many counselees. As has been shown in recent years, in carriers of pathogenic variants in high-risk genes, this approach enables the detection of breast cancer at very early, more favorable stages although no reduction of mortality has been demonstrated yet. The key component of the intensified surveillance is annual contrast-enhanced breast MRI, supplemented by up to biannual breast ultrasound and mammography usually starting at age 40. Key Messages: Apart from early detection, the central goal of care is the prevention of cancer. By utilizing individualized risk calculation, the optimal timeframe for risk-reducing surgery can be estimated, and counselees can be supported in reaching preference-sensitive decisions.

Paradigmatic Approach to Support Personalized Counseling With Digital Health (iKNOW).

iKNOW is the first evidence-based digital tool to support personalized counseling for women in Germany with a hereditary cancer risk. The counseling tool is designed for carriers of pathogenic gBRCA (germline breast cancer gene) variants that increase the lifetime risk of breast and ovarian cancer. Carriers of pathogenic variants are confronted with complex, individualized risk information, and physicians must be able to convey this information in a comprehensible way to enable preference-sensitive health decisions. In this paper, we elaborate on the clinical, regulatory, and practical premises of personalized counseling in Germany. By operationalizing these premises, we formulate 5 design principles that, we suggest, are specific enough to develop a digital tool (eg, iKNOW), yet wide-ranging enough to inform the development of counseling tools for personalized medicine more generally: (1) digital counseling tools should implement the current standard of care (eg, based on guidelines); (2) digital counseling tools should help to both standardize and personalize the counseling process (eg, by enabling the preference-sensitive selection of counseling contents from a common information base); (3) digital counseling tools should make complex information easy to access both cognitively (eg, by using evidenced-based risk communication formats) and technically (eg, by means of responsive design for various devices); (4) digital counseling tools should respect the counselee's data privacy rights (eg, through strict pseudonymization and opt-in consent); and (5) digital counseling tools should be systematically and iteratively evaluated with the users in mind (eg, using formative prototype testing to ensure a user-centric design and a summative multicenter, randomized controlled trial). On the basis of these paradigmatic design principles, we hope that iKNOW can serve as a blueprint for the development of more digital innovations to support personalized counseling approaches in cancer medicine.

Prevalence of Pathogenic Germline Variants in Women with Non-Familial Unilateral Triple-Negative Breast Cancer.

Introduction: International guidelines recommend genetic testing for women with familial breast cancer at an expected prevalence of pathogenic germline variants (PVs) of at least 10%. In a study sample of the German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC), we have previously shown that women with TNBC diagnosed before the age of 50 years but without a family history of breast or ovarian cancer (sTNBC) meet this criterion. The present study investigates the PV prevalence in BRCA1, BRCA2, and nine additional cancer predisposition genes in an extended sTNBC study sample including a cohort of women with a later age at sTNBC diagnosis. Patients and Methods: In 1,600 women with sTNBC (median age at diagnosis: 41 years, range 19-78 years), we investigated the association between age at diagnosis and PV occurrence in cancer predisposition genes using logistic regression. Results: 260 sTNBC patients (16.2%) were found to have a PV in cancer predisposition genes (BRCA1: n = 170 [10.6%]; BRCA2: n = 46 [2.9%], other: n = 44 [2.8%]). The PV prevalence in women diagnosed between 50 and 59 years (n = 194) was 11.3% (22/194). Logistic regression showed a significant increase in PV prevalence with decreasing age at diagnosis (OR 1.41 per 10 years younger age at diagnosis; 95% confidence interval: 1.21-1.65; p < 0.001). The PV prevalence predicted by the model was above 10% for diagnoses before the age of 56.8 years. Conclusion: Based on the data presented, we recommend genetic testing by gene panel analysis for sTNBC patients diagnosed before the age of 60 years. Due to the still uncertain estimate for women with sTNBC diagnosed above the age of 60 years, further studies are needed.