TLD-1, a novel liposomal doxorubicin, in patients with advanced solid tumors: Dose escalation and expansion part of a multicenter open-label phase I trial (SAKK 65/16).

BACKGROUND: TLD-1 is a novel liposomal doxorubicin that compared favorably to conventional doxorubicin liposomal formulations in preclinical models. This phase I first-in-human study aimed to define the maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), safety and preliminary activity of TLD-1 in patients with advanced solid tumors. PATIENTS AND METHODS: We recruited patients with advanced solid tumors who failed standard therapy and received up to 3 prior lines of palliative systemic chemotherapy. TLD-1 was administered intravenously every 3 weeks up to a maximum of 9 cycles (6 for patients with prior anthracyclines) from a starting dose of 10 mg/m2, according to an accelerated titration design followed by a modified continual reassessment method. RESULTS: 30 patients were enrolled between November 2018 and May 2021. No dose-limiting toxicities (DLT) were observed. Maximum administered dose of TLD-1 was 45 mg/m2, RP2D was defined at 40 mg/m2. Most frequent treatment-related adverse events (TRAE) of any grade included palmar-plantar erythrodysesthesia (PPE) (50% of patients), oral mucositis (50%), fatigue (30%) and skin rash (26.7%). Most common G3 TRAE included PPE in 4 patients (13.3%) and oral mucositis in 2 (6.7%). Overall objective response rate was 10% in the whole population and 23.1% among 13 patients with breast cancer; median time-to-treatment failure was 2.7 months. TLD-1 exhibit linear pharmacokinetics, with a median terminal half-life of 95 h. CONCLUSIONS: The new liposomal doxorubicin formulation TLD-1 showed a favourable safety profile and antitumor activity, particularly in breast cancer. RP2D was defined at 40 mg/m2 administered every 3 weeks. (NCT03387917).

Real-World Data on Institutional Implementation of Screening for Mismatch Repair Deficiency and Lynch Syndrome in Endometrial Cancer Patients.

Lynch syndrome is an inherited tumor syndrome caused by a pathogenic germline variant in DNA mismatch repair genes. As the leading cause of hereditary endometrial cancer, international guidelines recommend universal screening in women with endometrial cancer. However, testing for Lynch syndrome is not yet well established in clinical practice. The aim of this study was to evaluate adherence to our Lynch syndrome screening algorithm. A retrospective, single-center cohort study was conducted of all endometrial cancer patients undergoing surgical treatment at the Bern University Hospital, Switzerland, between 2017 and 2022. Adherence to immunohistochemical analysis of mismatch repair status, and, if indicated, to MLH1 promoter hypermethylation and to genetic counseling and testing was assessed. Of all 331 endometrial cancer patients, 102 (30.8%) were mismatch repair-deficient and 3 (0.9%) patients were diagnosed with Lynch syndrome. Overall screening adherence was 78.2%, with a notable improvement over the six years from 61.4% to 90.6%. A major reason for non-adherence was lack of provider recommendation for testing, with advanced patient age as a potential patient risk factor. Simplification of the algorithm through standardized reflex screening was recommended to provide optimal medical care for those affected and to allow for cascading testing of at-risk relatives.

Supervised exercise training in patients with cancer during anthracycline-based chemotherapy to mitigate cardiotoxicity: a randomized-controlled-trial.

Background: Exercise training (ET) has been shown to mitigate cardiotoxicity of anthracycline-based chemotherapies (AC) in animal models. Data from randomized controlled trials in patients with cancer are sparse. Methods: Patients with breast cancer or lymphoma receiving AC were recruited from four cancer centres and randomly assigned to 3 months supervised ET. Primary outcome was change in left ventricular global longitudinal strain (GLS) from baseline (before AC) to post AC (AC-end) compared between the EXduringAC group, who participated in an exercise intervention during AC including the provision of an activity tracker, and the control group EXpostAC, who received an activity tracker only. Secondary outcome parameters were changes in high sensitivity Troponin T (hsTnT), NT-pro-brain natriuretic peptide (NT-proBNP), peak oxygen consumption (peak VO2) and objectively measured physical activity (PA) during this same time-period. All assessments were repeated at a 12-week follow-up from AC-end, when also the EXpostAC group had completed the ET, that started after AC. In exploratory analyses, robust linear models were performed to assess the association of PA with changes in echocardiographic parameters and biomarkers of LV function. Results: Fifty-seven patients (median age 47 years; 95% women) were randomized to EXduringAC (n = 28) and EXpostAC (n = 29) group. At AC-end, GLS deteriorated in both study groups (albeit insignificantly) with 7.4% and 1.0% in EXduringAC (n = 18) and EXpostAC (n = 18), respectively, and hsTnT and NT-proBNP significantly increased in both groups, without difference between groups for any parameter. Change in peak VO2 (-1.0 and -1.1 ml/kg/min) at AC-end was also similar between groups as was duration of moderate-to-vigorous PA (MVPA) with a median of 33 [26, 47] min/day and 32 [21, 59] min/day in the EXduringAC and EXpostAC group, respectively. In the robust linear model including the pooled patient population, MVPA was significantly associated with a more negative GLS and lesser increase in hsTnT at AC-end. Conclusion: In this small scale RCT, supervised ET during AC was not superior to wearing a PA tracker to mitigate cardiotoxicity. The dose-response relationship between PA and cardioprotective effects during AC found in our and previous data supports the notion that PA should be recommended to patients undergoing AC. Clinical Trial Registration: ClinicalTrials.gov, identifier NCT03850171.

Eleven Years of Oncogenetic Consultations in a Swiss Center: Patient and Testing Characteristics.

Introduction: Oncogenetic counseling has been provided at the University Hospital of Bern since 2004. Since the public announcement by Ms. Angelina Jolie in 2013 that she had undergone bilateral prophylactic mastectomy, other oncogenetic centers have reported an increase in consultations. We conducted a retrospective review of the oncogenetic consultations at our center to evaluate the presence and the consequences of a potential "Angelina Jolie effect" and to characterize this patient population over a decade. Methods: All initial oncogenetic consultations between 2005 and 2015 were collected, using electronic records. Demographics, cancer type, testing, and mutation results, as well as consultation rates, were recorded. The yearly trends were analyzed using Joinpoint regression analysis (JPA). Results: In total, 823 patient cases were included, mostly women (84%), half of them with a positive personal cancer history. A hereditary breast and ovarian cancer (HBOC) risk was the main reason for consultation (72%). Moreover, 22% of patients had a previously detected familial mutation. Two-thirds underwent testing, which yielded a positive test result in 31% of the cases. According to JPA, the consultation rate increased throughout the decade, with a significant upward trend from 2013. Rates of testing and positive results remained stable over time. Most patients (86%) fulfilled the referral criteria of published guidelines. Discussion: At our center, we found retrospectively a disproportionate growth in the referral rate for HBOC cases compared to other oncological cases after the year 2013, but overall, no change in testing rates was detected.

Exceptional Response to Pembrolizumab in a Mismatch Repair-Deficient Aggressive Prostate Cancer with Somatic EPCAM, MSH2, and MSH6 Co-Deletion: A Case Report.

Mismatch repair-deficient (dMMR) prostate cancer (PCa) is a rare (1-5%) but highly actionable molecular subgroup of PCa, vulnerable to immune checkpoint inhibitors. Our case of sporadic dMMR PCa due to large monoallelic co-deletion of EPCAM, MSH2, and MSH6 features a clinically aggressive disease presentation and a major response to pembrolizumab. We report a 65-year-old patient with primary metastatic PCa, Gleason score 5 + 5 = 10, with penile and lymph node metastases at diagnosis. Patient showed rapid progression on first-line ADT and enzalutamide. Tumor next-generation sequencing (NGS) revealed microsatellite instability and a tumor mutational burden of 40.8 mutations/megabase. Immunohistochemistry showed co-loss of MSH2 and MSH6. Review of NGS row data confirmed large monoallelic deletion in chromosome 2p, including EPCAM, MSH2, and MSH6. No germline alterations in mismatch repair genes were detected. Patient showed excellent response to pembrolizumab, which is still ongoing. We conclude that early molecular tumor profiling is essential to enable personalized management of advanced PCa, especially in patients with aggressive or atypical disease course.

Acceptability and Usability of the Family Gene Toolkit for Swiss and Korean Families Harboring BRCA1/BRAC2 Pathogenic Variants: A Web-Based Platform for Cascade Genetic Testing.

The study adapted the Family Gene Toolkit and developed a customized web application for Swiss and Korean families harboring BRCA1 or BRCA2 pathogenic variants to support family communication of genetic testing results and promote cascade genetic testing among at-risk relatives. In the first step, narrative data from 68 women with BRCA1/BRCA2 pathogenic variants and clinician feedback informed a culturally sensitive adaptation of the content consistent with current risk management guidelines. In the second step, the Information Technology team developed the functions and the interface of the web application that will host the intervention. In the third step, a new sample of 18 women from families harboring BRCA1/BRCA2 pathogenic variants tested the acceptability and usability of the intervention using "think-aloud" interviews and a questionnaire. Participants expressed high levels of satisfaction with the intervention. They provided positive feedback for the information regarding active coping, strategies to enhance family communication, interactive elements, and illustrative stories. They reported that the information was useful and the web application was easy to navigate. Findings suggest that the Family Gene Toolkit is well-designed and can increase rates of cascade testing among at-risk relatives. Its efficacy will be tested in a subsequent randomized trial.

A New de novo BRCA1 Mutation in a Young Breast Cancer Patient: A Case Report.

Background: BRCA1 and BRCA2 genes represent the most investigated breast and ovarian cancer predisposition genes. Ten cases of pathogenic de novo BRCA1 variations and six cases of pathogenic de novo BRCA2 variation have been reported at present. Here, we report a new case of a de novo BRCA1 gene mutation. Case Presentation: A 30-year-old woman with no health issues and no family history for hereditary breast and ovarian cancer was diagnosed with a hormone receptor positive/HER2 negative invasive breast cancer. Genetic testing revealed a pathogenic variant in BRCA1 (c.4065_4068delTCAA) which was not found in her parents or sister. Conclusion: We report a new case of de novo BRCA1 mutation, confirmed by repeated germline testing of the index patient and her parents. The published BRCA1/2 de novo mutation rate is low. This is probably due - in part - to the strict testing criteria.

Occurrence of variants of unknown clinical significance in genetic testing for hereditary breast and ovarian cancer syndrome and Lynch syndrome: a literature review and analytical observational retrospective cohort study.

BACKGROUND AND PURPOSE: Over the last decade, the implementation of multigene panels for hereditary tumor syndrome has increased at our institution (Inselspital, University Hospital Berne, Switzerland). The aim of this study was to determine the prevalence of variants of unknown significance (VUS) in patients with suspected Lynch syndrome and suspected hereditary breast and ovarian cancer syndrome, the latter in connection with the trend toward ordering larger gene panels. RESULTS: Retrospectively collected data from 1057 patients at our institution showed at least one VUS in 126 different cases (11.9%). In patients undergoing genetic testing for BRCA1/2, the prevalence of VUS was 6%. When < 10 additional genes were tested in addition to BRCA1/2, the prevalence increased to 13.8%, and 31.8% for > 10 additional genes, respectively. The gene most frequently affected with a VUS was ATM. 6% of our patients who were tested for Lynch syndrome had a VUS result in either MLH1, MSH2 or MSH6. CONCLUSIONS: Our data demonstrate that panel testing statistically significantly increases VUS rates due to variants in non-BRCA genes. Good genetic counseling before and after obtaining results is therefore particularly important when conducting multigene panels to minimize patient uncertainty due to VUS results.

Employment trajectories of young women with breast cancer: an ongoing prospective cohort study in Italy and Switzerland.

PURPOSE: Despite extensive research on cancer and work-related outcomes, evidence from longitudinal cohort studies is limited, especially in young women with breast cancer (BC). We aimed to investigate employment trajectories in young BC survivors and to identify potential factors associated with changes in work activity. METHODS: The HOHO European prospective multicenter cohort study enrolled 300 young women (≤ 40 years) with newly diagnosed BC. Women completed surveys at baseline and every 6 months for 3 years, then yearly for up to 10 years to assess, among other variables, employment status, sociodemographic, medical, and treatment data. Symptoms were assessed by the Breast Cancer Prevention Trial symptom scales and single items from the Cancer Rehabilitation Evaluation System. Univariable and multivariable multinomial logistic regression analyses identified factors associated with changes in employment status. RESULTS: Among the 245 women included in this analysis, 85% were employed at the last individual post-baseline assessment (1 to 10 years). At 5 years, women had a 29.4% probability (95% CI: 23.6-35.5) of experiencing any reduction and a 14.9% probability (95% CI: 10.6-19.9) of experiencing any increase in work activities. Being enrolled in Switzerland (vs. Italy) and reporting more trouble in performing daily activities were significantly associated with work reduction. CONCLUSION: Our results suggest that most young BC survivors remain employed in the long-term. IMPLICATIONS FOR CANCER SURVIVORS: Regular evaluation of symptoms which may interfere with daily life and identification of financial discomfort is critical in providing timely and individually tailored interventions and in limiting unwanted reductions in work activities.

Relatives from Hereditary Breast and Ovarian Cancer and Lynch Syndrome Families Forgoing Genetic Testing: Findings from the Swiss CASCADE Cohort.

Cascade genetic testing of relatives from families with pathogenic variants associated with hereditary breast and ovarian cancer (HBOC) or Lynch syndrome (LS) has important implications for cancer prevention. We compared the characteristics of relatives from HBOC or LS families who did not have genetic testing (GT (-) group) with those who had genetic testing (GT (+) group), regardless of the outcome. Self-administered surveys collected cross-sectional data between September 2017 and December 2021 from relatives participating in the CASCADE cohort. We used multivariable logistic regression with LASSO variable selection. Among n = 115 relatives who completed the baseline survey, 38% (n = 44) were in the GT (-) group. Being male (OR: 2.79, 95% CI: 1.10-7.10) and without a previous cancer diagnosis (OR: 4.47, 95% CI: 1.03-19.42) increased the odds of being untested by almost three times. Individuals from families with fewer tested relatives had 29% higher odds of being untested (OR: 0.71, 95% CI: 0.55-0.92). Reasons for forgoing cascade testing were: lack of provider recommendation, lack of time and interest in testing, being afraid of discrimination, and high out-of-pocket costs. Multilevel interventions designed to increase awareness about clinical implications of HBOC and LS in males, referrals from non-specialists, and support for testing multiple family members could improve the uptake of cascade testing.

Combining BeEAM with Brentuximab Vedotin for High-Dose Therapy in CD30 Positive Lymphomas before Autologous Transplantation-A Phase I Study.

The prognosis for patients with CD30+ lymphomas (Hodgkin lymphoma and various T-cell lymphomas) relapsing after autologous stem cell transplantation (ASCT) is critical. Brentuximab vedotin (BV), an ADC targeting CD30, is an obvious candidate for inclusion into high-dose chemotherapy (HDCT) regimens to improve outcomes. This single center phase I trial investigated 12 patients with CD30+ lymphoma (AITL: n = 5; relapsed HL: n = 7; median of two previous treatment lines) undergoing ASCT. In a 3 + 3 dose escalation design, 12 patients received a single BV dose at three dose levels (DL) (0.9/1.2/1.8 mg/kg b.w.) prior to standard BeEAM. All patients were treated as planned; no dose limiting toxicities (DLTs) occurred at DL 1 and 2. At DL 3, one DLT (paralytic ileus, fully recovering) occurred. Grade III febrile neutropenia occurred in one patient, and two others had septic complications, all fully recovering. Median hospitalization was 23 days. Hematologic recovery was normal. Six of twelve (50%) patients achieved CR. PFS and OS at 1 year were 67% (n = 8/12) and 83% (n = 10/12), respectively. The addition of brentuximab to standard BeEAM HDCT seems to be safe. We observed a CR rate of 75% post-ASCT in a highly pretreated population. The efficacy of this novel HDCT combination with BV at a 1.8 mg/kg dose level needs to be explored in larger studies.

The Communication Chain of Genetic Risk: Analyses of Narrative Data Exploring Proband-Provider and Proband-Family Communication in Hereditary Breast and Ovarian Cancer.

Low uptake of genetic services among members of families with hereditary breast and ovarian cancer (HBOC) suggests limitations of proband-mediated communication of genetic risk. This study explored how genetic information proceeds from healthcare providers to probands and from probands to relatives, from the probands' perspectives. Using a grounded-theory approach, we analyzed narrative data collected with individual interviews and focus groups from a sample of 48 women identified as carriers of HBOC-associated pathogenic variants from three linguistic regions of Switzerland. The findings describe the "communication chain", confirming the difficulties of proband-mediated communication. Provider-proband communication is impacted by a three-level complexity in the way information about family communication is approached by providers, received by probands, and followed-up by the healthcare system. Probands' decisions regarding disclosure of genetic risk are governed by dynamic and often contradictory logics of action, interconnected with individual and family characteristics, eventually compelling probands to engage in an arbitrating process. The findings highlight the relevance of probands' involvement in the communication of genetic risk to relatives, suggesting the need to support them in navigating the complexity of family communication rather than replacing them in this process. Concrete actions at the clinical and health system levels are needed to improve proband-mediated communication.

Qualitative analysis of facilitators and barriers to centre- and home-based exercise training in breast cancer patients - a Swiss tertiary centre experience.

BACKGROUND: Exercise is an effective therapy for breast cancer patients to reduce fatigue and to improve health-related quality of life and physical function. Yet breast cancer patients often do not meet the recommended physical activity guidelines. To better understand why recommendations are not met and to improve long-term physical activity maintenance, this study aimed at identifying facilitators and barriers of breast cancer survivors to supervised, centre-based exercise within a cardio-oncological rehabilitation programme and to unsupervised, home-based exercise both during and after the completion of the programme, as well as strategies used to manage these barriers. METHODS: Breast cancer patients who had previously completed a structured centre-based exercise programme at a Swiss tertiary centre were recruited by mailed invitation letter. Semi-structured telephone interviews were conducted with consenting patients and subsequent thematic analysis was performed to identify common themes. RESULTS: Of the 37 eligible breast cancer patients, 19 patients (51%, mean age 48.9 ± 9.7 years) responded to our invitation. Baseline characteristics did not differ from the total eligible population. General facilitators for exercise were anticipated and experienced benefits on physical and mental health and enjoyment of exercise. Facilitators specific for supervised centre-based exercise were social support, accountability and the provision of structured exercise by the programme. Centre-based exercise barriers included physical, psychological and environmental barriers, whereby psychological barriers were reported predominantly in the context of home-based exercise. Strategies to manage these barriers were diverse and included the adaptation of training circumstances, behaviour change strategies and strategies to deal with side effects. CONCLUSIONS: This first study on facilitators of and barriers to exercise in breast cancer patients in Switzerland identified more barriers, particularly psychological barriers, for unsupervised home-based exercise than for supervised centre-based exercise. These findings support the importance of providing structured supervised exercise programmes for breast cancer patients and suggest that a special focus should be directed at the transition from supervised to self-organized exercise in order to enhance and maintain long-term exercise participation.

Intention to Inform Relatives, Rates of Cascade Testing, and Preference for Patient-Mediated Communication in Families Concerned with Hereditary Breast and Ovarian Cancer and Lynch Syndrome: The Swiss CASCADE Cohort.

Cascade screening for Tier 1 cancer genetic conditions is a significant public health intervention because it identifies untested relatives of individuals known to carry pathogenic variants associated with hereditary breast and ovarian cancer (HBOC) and Lynch syndrome (LS). The Swiss CASCADE is a family-based, open-ended cohort, including carriers of HBOC- and LS-associated pathogenic variants and their relatives. This paper describes rates of cascade screening in relatives from HBOC- and LS- harboring families, examines carriers' preferences for communication of testing results, and describes theory-based predictors of intention to invite relatives to a cascade screening program. Information has been provided by 304 index cases and 115 relatives recruited from September 2017 to December 2021. On average, 10 relatives per index case were potentially eligible for cascade screening. Approximately 65% of respondents wanted to invite relatives to the cohort, and approximately 50% indicated a preference for patient-mediated communication of testing results, possibly with the assistance of digital technology. Intention to invite relatives was higher for first- compared to second- and third-degree relatives, but was not different between syndromes or based on relatives' gender. The family environment and carrying pathogenic variants predicts intention to invite relatives. Information helps optimize delivery of tailored genetic services.

Swiss cost-effectiveness analysis of universal screening for Lynch syndrome of patients with colorectal cancer followed by cascade genetic testing of relatives.

BACKGROUND: We estimated the cost-effectiveness of universal DNA screening for Lynch syndrome (LS) among newly diagnosed patients with colorectal cancer (CRC) followed by cascade screening of relatives from the Swiss healthcare system perspective. METHODS: We integrated decision trees with Markov models to calculate incremental cost per quality-adjusted life-year saved by screening all patients with CRC (alternative strategy) compared with CRC tumour-based testing followed by DNA sequencing (current strategy). RESULTS: The alternative strategy has an incremental cost-effectiveness ratio of CHF65 058 compared with the current strategy, which is cost-effective according to Swiss standards. Based on annual incidence of CRC in Switzerland, universal DNA screening correctly identifies all 123 patients with CRC with LS, prevents 17 LS deaths and avoids 19 CRC cases, while the current strategy leads to 32 false negative results and 253 LS cases lost to follow-up. One way and probabilistic sensitivity analyses showed that universal DNA testing is cost-effective in around 80% of scenarios, and that the cost of DNA testing and the number of invited relatives per LS case determine the cost-effectiveness ratio. CONCLUSION: Results can inform policymakers, healthcare providers and insurance companies about the costs and benefits associated with universal screening for LS and cascade genetic testing of relatives.

Genetic Literacy and Communication of Genetic Information in Families Concerned with Hereditary Breast and Ovarian Cancer: A Cross-Study Comparison in Two Countries and within a Timeframe of More Than 10 Years.

Examining genetic literacy in families concerned with hereditary breast and ovarian cancer (HBOC) helps understand how genetic information is passed on from individuals who had genetic counseling to their at-risk relatives. This cross-study comparison explored genetic literacy both at the individual and the family level using data collected from three sequential studies conducted in the U.S. and Switzerland over ≥10 years. Participants were primarily females, at-risk or confirmed carriers of HBOC-associated pathogenic variants, who had genetic counselling, and ≥1 of their relatives who did not. Fifteen items assessed genetic literacy. Among 1933 individuals from 518 families, 38.5% had genetic counselling and 61.5% did not. Although genetic literacy was higher among participants who had counselling, some risk factors were poorly understood. At the individual level, genetic literacy was associated with having counselling, ≤5 years ago, higher education, and family history of cancer. At the family level, genetic literacy was associated with having counselling, higher education, and a cancer diagnosis. The findings suggest that specific genetic information should be emphasized during consultations, and that at-risk relatives feel less informed about inherited cancer risk, even if information is shared within families. There is a need to increase access to genetic information among at-risk individuals.

Using a Tailored Digital Health Intervention for Family Communication and Cascade Genetic Testing in Swiss and Korean Families With Hereditary Breast and Ovarian Cancer: Protocol for the DIALOGUE Study.

BACKGROUND: In hereditary breast and ovarian cancer (HBOC), family communication of genetic test results is essential for cascade genetic screening, that is, identifying and testing blood relatives of known mutation carriers to determine whether they also carry the pathogenic variant, and to propose preventive and clinical management options. However, up to 50% of blood relatives are unaware of relevant genetic information, suggesting that potential benefits of genetic testing are not communicated effectively within family networks. Technology can facilitate communication and genetic education within HBOC families. OBJECTIVE: The aims of this study are to develop the K-CASCADE (Korean-Cancer Predisposition Cascade Genetic Testing) cohort in Korea by expanding an infrastructure developed by the CASCADE (Cancer Predisposition Cascade Genetic Testing) Consortium in Switzerland; develop a digital health intervention to support the communication of cancer predisposition for Swiss and Korean HBOC families, based on linguistic and cultural adaptation of the Family Gene Toolkit; evaluate its efficacy on primary (family communication of genetic results and cascade testing) and secondary (psychological distress, genetic literacy, active coping, and decision making) outcomes; and explore its translatability using the reach, effectiveness, adoption, implementation, and maintenance framework. METHODS: The digital health intervention will be available in French, German, Italian, Korean, and English and can be accessed via the web, mobile phone, or tablet (ie, device-agnostic). K-CASCADE cohort of Korean HBOC mutation carriers and relatives will be based on the CASCADE infrastructure. Narrative data collected through individual interviews or mini focus groups from 20 to 24 HBOC family members per linguistic region and 6-10 health care providers involved in genetic services will identify the local cultures and context, and inform the content of the tailored messages. The efficacy of the digital health intervention against a comparison website will be assessed in a randomized trial with 104 HBOC mutation carriers (52 in each study arm). The translatability of the digital health intervention will be assessed using survey data collected from HBOC families and health care providers. RESULTS: Funding was received in October 2019. It is projected that data collection will be completed by January 2023 and results will be published in fall 2023. CONCLUSIONS: This study addresses the continuum of translational research, from developing an international research infrastructure and adapting an existing digital health intervention to testing its efficacy in a randomized controlled trial and exploring its translatability using an established framework. Adapting existing interventions, rather than developing new ones, takes advantage of previous valid experiences without duplicating efforts. Culturally sensitive web-based interventions that enhance family communication and understanding of genetic cancer risk are timely. This collaboration creates a research infrastructure between Switzerland and Korea that can be scaled up to cover other hereditary cancer syndromes. TRIAL REGISTRATION: ClinicalTrials.gov NCT04214210; https://clinicaltrials.gov/ct2/show/NCT04214210 and CRiS KCT0005643; https://cris.nih.go.kr/cris/. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/26264.

The Effect of Metformin vs Placebo on Sex Hormones in Canadian Cancer Trials Group MA.32.

BACKGROUND: Metformin has been associated with lower breast cancer (BC) risk and improved outcomes in observational studies. Multiple biologic mechanisms have been proposed, including a recent report of altered sex hormones. We evaluated the effect of metformin on sex hormones in MA.32, a phase III trial of nondiabetic BC subjects who were randomly assigned to metformin or placebo. METHODS: We studied the subgroup of postmenopausal hormone receptor-negative BC subjects not receiving endocrine treatment who provided fasting blood at baseline and at 6 months after being randomly assigned. Sex hormone-binding globulin, bioavailable testosterone, and estradiol levels were assayed using electrochemiluminescence immunoassay. Change from baseline to 6 months between study arms was compared using Wilcoxon sum rank tests and regression models. RESULTS: 312 women were eligible (141 metformin vs 171 placebo); the majority of subjects in each arm had T1/2, N0, HER2-negative BC and had received (neo)adjuvant chemotherapy. Mean age was 58.1 (SD=6.9) vs 57.5 (SD=7.9) years, mean body mass index (BMI) was 27.3 (SD=5.5) vs 28.9 (SD=6.4) kg/m2 for metformin vs placebo, respectively. Median estradiol decreased between baseline and 6 months on metformin vs placebo (-5.7 vs 0 pmol/L; P < .001) in univariable analysis and after controlling for baseline BMI and BMI change (P < .001). There was no change in sex hormone-binding globulin or bioavailable testosterone. CONCLUSION: Metformin lowered estradiol levels, independent of BMI. This observation suggests a new metformin effect that has potential relevance to estrogen sensitive cancers.

Examining information-seeking behavior in genetic testing for cancer predisposition: A qualitative interview study.

OBJECTIVE: This study aims to assess information needs and information sources and seeks to illustrate what at-risk individuals consider motivators of and barriers to information-seeking before and after genetic testing for cancer predisposition. METHODS: Semi-structured interviews with people seeking genetic counseling in Switzerland were analyzed qualitatively using thematic analysis. Wilson's model of information behavior was the theoretical framework. RESULTS: We identified four themes that illustrate motivators of and barriers to information-seeking: attitudes and emotions; knowledge; social environment; and demographic factors. We also elucidated information needs and collected participants' information sources. CONCLUSION: This study£s empirical approach helps healthcare professionals to understand their patients' behaviors and wishes concerning information-seeking more concretely than theoretical models alone. The study also identifies information gaps, especially outside the genetic counseling setting. PRACTICE IMPLICATIONS: Genetic counselors and other healthcare professionals need to purposefully assist patients in finding trustworthy and accessible information. Healthcare professionals in all disciplines need to be educated about predictive genetic testing.

Clinical behavior of recurrent hormone receptor-positive breast cancer by adjuvant endocrine therapy within the Breast International Group 1-98 clinical trial.

BACKGROUND: Endocrine therapy resistance is a major cause of distant recurrence (DR) in hormone receptor-positive breast cancer. This study evaluated differences in survival after DR in patients treated with different adjuvant endocrine therapy regimens in the Breast International Group (BIG) 1-98 trial. METHODS: BIG 1-98 compared 5 years of adjuvant treatment among 4 arms: tamoxifen (T), letrozole (L), tamoxifen followed by letrozole (TL), and letrozole followed by tamoxifen (LT). After a median follow-up of 8.1 years, 911 of 8010 patients (T, 302; L, 285; TL, 170; and LT, 154) had DR as the site of first recurrence. Univariate and multivariate Cox analyses were performed to determine features associated with post-DR survival. RESULTS: The median follow-up time after DR was 59 months (interquartile range, 29-88 months). Among all patients with DR, 38.1% were 65 years old or older at enrollment, 61.9% had tumors larger than 2 cm, and 69.7% were node positive. Neoadjuvant or adjuvant chemotherapy was administered to 35.6% of the patients. There was no difference in post-DR survival by treatment arm (median survival, 20.8 months for T, 17.9 months for L, 17.3 months for TL, and 20.8 months for LT; P = .21). In multivariate analysis, older patients (hazard ratio [HR], 1.35; 95% confidence interval [CI], 1.15-1.59) and patients with tumors larger than 2 cm (HR, 1.19; 95% CI, 1.00-1.41), 4 or more positive nodes (HR, 1.31; 95% CI, 1.05-1.64), progesterone receptor (PR)-negative tumors (HR, 1.25; 95% CI, 1.02-1.52), or shorter disease-free survival (DFS) had significantly worse post-DR survival. CONCLUSIONS: Treatment with adjuvant T, L, or their sequences was not associated with differences in survival after DR. Significant differences in survival were observed by age, primary tumor size, nodal and PR status, and DFS, and this suggests that traditional baseline high-risk features remain prognostic in the metastatic setting.