Atezolizumab and chemotherapy for advanced or recurrent endometrial cancer (AtTEnd): a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: At the time of AtTEnd trial design, standard treatment for advanced or recurrent endometrial cancer included carboplatin and paclitaxel chemotherapy. This trial assessed whether combining atezolizumab with chemotherapy might improve outcomes in this population. METHODS: AtTEnd was a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial done in 89 hospitals in 11 countries across Europe, Australia, New Zealand, and Asia. Enrolled patients were aged 18 years or older, and had advanced or recurrent endometrial carcinoma or carcinosarcoma, an Eastern Cooperative Oncology Group performance status of 0-2, and received no previous systemic chemotherapy for recurrence. Patients were randomly assigned (2:1) using an interactive web response system (block size of six) to either atezolizumab 1200 mg or placebo given intravenously with chemotherapy (carboplatin at area under the curve of 5 or 6 and paclitaxel 175 mg/m2 intravenously on day 1 every 21 days) for 6-8 cycles, then continued until progression. Stratification factors were country, histological subtype, advanced or recurrent status, and mismatch repair (MMR) status. Participants and treating clinicians were masked to group allocation. The hierarchically tested co-primary endpoints were progression-free survival (in patients with MMR-deficient [dMMR] tumours, and in the overall population) and overall survival (in the overall population). Primary analyses were done in the intention-to-treat population, defined as all randomly assigned patients who gave their full consent to participation in the study and data processing. Safety was assessed in all patients included in the intention-to-treat population who received at least one dose of study treatment. Here, we report the primary progression-free survival and the interim overall survival results. This study is ongoing and is registered with ClinicalTrials.gov, NCT03603184. FINDINGS: Between Oct 3, 2018, and Jan 7, 2022, 551 patients were randomly assigned to atezolizumab (n=362) or placebo (n=189). Two patients in the atezolizumab group were excluded from all analyses due to lack of consent. Median follow-up was 28·3 months (IQR 21·2-37·6). 81 (23%) patients in the atezolizumab group and 44 (23%) patients in the placebo group had dMMR disease by central assessment. In the dMMR population, median progression-free survival was not estimable (95% CI 12·4 months-not estimable [NE]) in the atezolizumab group and 6·9 months (6·3-10·1) in the placebo group (hazard ratio [HR] 0·36, 95% CI 0·23-0·57; p=0·0005). In the overall population, median progression-free survival was 10·1 months (95% CI 9·5-12·3) in the atezolizumab group and 8·9 months (8·1-9·6) in the placebo group (HR 0·74, 95% CI 0·61-0·91; p=0·022). Median overall survival was 38·7 months (95% CI 30·6-NE) in the atezolizumab group and 30·2 months (25·0-37·2) in the placebo group (HR 0·82, 95% CI 0·63-1·07; log-rank p=0·048). The p value for the interim analysis of overall survival did not cross the stopping boundary; therefore, the trial will continue until the required number of events are recorded. The most common grade 3-4 adverse events were neutropenia (97 [27%] of 356 patients in the atezolizumab group vs 51 [28%] of 185 in the placebo group) and anaemia (49 [14%] vs 24 [13%]). Treatment-related serious adverse events occurred in 46 (13%) patients in the atezolizumab group and six (3%) patients in the placebo group. Treatment-related deaths occurred in two patients (pneumonia in one patient in each group). INTERPRETATION: Atezolizumab plus chemotherapy increased progression-free survival in patients with advanced or recurrent endometrial carcinoma, particularly in those with dMMR carcinomas, suggesting the addition of atezolizumab to standard chemotherapy as first-line treatment in this specific subgroup. FUNDING: F Hoffmann-La Roche.

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.

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.

Cumulative incidence of cardiovascular events under tamoxifen and letrozole alone and in sequence: a report from the BIG 1-98 trial.

BACKGROUND: Compared to tamoxifen, adjuvant treatment with aromatase inhibitors improves disease outcomes of postmenopausal women with hormone receptor-positive early breast cancer. In the international, randomized, double-blind BIG 1-98 trial, 8010 women were randomized to receive tamoxifen, letrozole, or sequential use of the agents for 5 years. With a focus on switching between agents, we investigated cardiovascular events over the entire 5-year treatment period. METHODS: Of the 6182 patients enrolled, 6144 started trial treatment and were included in this analysis. Adverse events occurring during study treatment until 30 days after cessation were considered. Eight cardiovascular event types were defined. Cumulative incidence of events were estimated using the Kaplan-Meier method, without consideration for competing events. Multivariable Cox models estimated hazard ratios (HR) with 95% confidence intervals (CI) for pairwise comparisons of treatment arms. RESULTS: While on study treatment, 6.5% of patients (n = 397) had any cardiac events reported; for 2.4%, the event was grades 3-5, of which 11 (0.2%) were grade 5. Letrozole monotherapy was associated with higher risk of grade 1-5 ischemic heart disease (HR = 1.81; 95% CI, 1.06-3.08) compared with tamoxifen monotherapy. Patients assigned sequential tamoxifen →letrozole (HR = 1.59; 95% CI, 0.92-2.74) or sequential letrozole → tamoxifen (HR = 1.20; 95% CI, 0.68-2.14) showed a lesser degree of risk elevation. Patients assigned to tamoxifen-containing regimens had significantly higher risk of grade 1-5 thromboembolic events (tamoxifen monotherapy HR = 2.10; 95% CI, 1.42-3.12; tamoxifen → letrozole HR = 1.96; 95% CI, 1.32-2.92; letrozole → tamoxifen HR = 1.56; 95% CI 1.03-2.35) as compared with patients assigned letrozole alone. CONCLUSION: When initiating or switching between adjuvant endocrine treatments in postmenopausal patients, age and medical history, with special attention to prior cardiovascular events, should be balanced with expected benefit of the treatment.

Correction: Quality of life under extended continuous versus intermittent adjuvant letrozole in lymph node-positive, early breast cancer patients: the SOLE randomised phase 3 trial.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Quality of life under extended continuous versus intermittent adjuvant letrozole in lymph node-positive, early breast cancer patients: the SOLE randomised phase 3 trial.

BACKGROUND: In the phase III SOLE trial, the extended use of intermittent versus continuous letrozole for 5 years did not improve disease-free survival in postmenopausal women with hormone receptor-positive breast cancer. Intermittent therapy with 3-month breaks may be beneficial for patients' quality of life (QoL). METHODS: In the SOLE QoL sub-study, 956 patients completed the Breast Cancer Prevention Trial (BCPT) symptom and further QoL scales up to 24 months after randomisation. Differences in change of QoL from baseline between the two administration schedules were tested at 12 and 24 months using repeated measures mixed-models. The primary outcome was change in hot flushes at 12 months. RESULTS: There was no difference in hot flushes at 12 months between the two schedules, but patients receiving intermittent letrozole reported significantly more improvement at 24 months. They also indicated less worsening in vaginal problems, musculoskeletal pain, sleep disturbance, physical well-being and mood at 12 months. Overall, 25-30% of patients reported a clinically relevant worsening in key symptoms and global QoL. CONCLUSION: Less symptom worsening was observed during the first year of extended treatment with the intermittent administration. For women experiencing an increased symptom burden of extended adjuvant endocrine therapy, an intermittent administration is a safe alternative. CLINICAL TRIAL INFORMATION: Clinical trial information: NCT00651456.

Osteoporosis therapy and outcomes for postmenopausal patients with hormone receptor-positive breast cancer: NCIC CTG MA.27.

BACKGROUND: Breast cancer patients in the MA.27 trial had similar outcomes with steroidal aromatase inhibitor (AI) exemestane and nonsteroidal anastrozole. AIs increase the risk of osteoporosis. This study examined the effects of self-reported osteoporosis and osteoporosis therapy (OPT) on outcomes. METHODS: The MA.27 phase 3 adjuvant trial enrolled 7576 postmenopausal women. The primary outcome was event-free survival (EFS), and the secondary outcome was distant disease-free survival (DDFS). Patients were permitted bisphosphonates to prevent or treat osteopenia/osteoporosis. In a multivariate, stratified Cox regression, factors were significant with a 2-sided Wald test P value ≤ .05. RESULTS: Osteoporosis was reported at the baseline by 654 of the 7576 women (8.6%) and in total by 1294 patients. Oral OPT was received at the baseline by 815 of the 7576 women (10.8%) and in total by 2711 patients (36%). With a median follow-up of 4.1 years, 693 EFS events (9.15%) and 321 DDFS events (4.2%) occurred. Osteoporosis was not associated with EFS or DDFS. Few EFS events occurred before the initiation of OPT, with no substantive evidence of a time-differing effect on outcomes (nonproportional hazards). OPT (yes vs no) was significantly associated with improved EFS (hazard ratio [HR] for yes vs no, 0.67; 95% confidence interval [CI], 0.57-0.80; P < .001) and DDFS (HR, 0.57; 95% CI, 0.44-0.73; P <. 001). Time-differing (time-dependent) OPT was not (EFS; P = .45). OPT did not alter the incidence of visceral-only metastasis (P = .31). CONCLUSIONS: Oral OPT, administered to postmenopausal breast cancer patients receiving adjuvant AI therapy, was associated with improved EFS and DDFS; the time of OPT initiation (a time-dependent effect) did not affect the outcome. OPT did not alter the risk of visceral metastasis. Cancer 2017;123:2444-51. © 2017 American Cancer Society.

Impact of CYP19A1 and ESR1 variants on early-onset side effects during combined endocrine therapy in the TEXT trial.

BACKGROUND: Single nucleotide polymorphisms (SNPs) in the estrogen receptor 1 (ESR1) and cytochrome P450 19A1 (CYP19A1) genes have been associated with breast cancer risk, endocrine therapy response and side effects, mainly in postmenopausal women with early breast cancer. This analysis aimed to assess the association of selected germline CYP19A1 and ESR1 SNPs with early-onset hot flashes, sweating and musculoskeletal symptoms in premenopausal patients enrolled in the Tamoxifen and Exemestane Trial (TEXT). METHODS: Blood was collected from consenting premenopausal women with hormone-responsive early breast cancer, randomly assigned to 5-years of tamoxifen plus ovarian suppression (OFS) or exemestane plus OFS. DNA was extracted with QIAamp kits and genotyped for two CYP19A1 (rs4646 and rs10046) and three ESR1 (rs2077647, rs2234693 and rs9340799) SNPs by a real-time pyrosequencing technique. Adverse events (AEs) were recorded at baseline and 3-monthly during the first year. Associations of the genotype variants with grade ≥2 early-onset targeted AEs of hot flashes/sweating or musculoskeletal events were assessed using logistic regression models. RESULTS: There were 2660 premenopausal patients with breast cancer in the intention-to-treat population of TEXT, and 1967 (74 %) are included in this translational study. The CYP19A1 rs10046 variant T/T, represented in 23 % of women, was associated with a reduced incidence of grade ≥2 hot flashes/sweating (univariate odds ratio (OR) = 0.78; 95 % CI 0.63-0.97; P = 0.03), more strongly in patients assigned exemestane + OFS (TT vs CT/CC: OR = 0.65, 95 % CI = 0.48-0.89) than assigned tamoxifen + OFS (OR = 0.94, 95 % CI = 0.69-1.27, interaction P = 0.03). No association with any of the CYP19A1/ESR1 genotypes and musculoskeletal AEs was found. CONCLUSION: The CYP19A1 rs10046 variant T/T favors lower incidence of hot flashes/sweating under exemestane + OFS treatment, suggesting endocrine-mediated effects. Based on findings from others, this SNP may potentially enhance treatment adherence and treatment efficacy. We plan to evaluate the clinical impact of this polymorphism during time, pending sufficient median follow up. TRIAL REGISTRATION: ClinicalTrials.gov NCT00066703, registered August 6, 2003.

Feasibility and cost-effectiveness of genetic counselling for all patients with newly diagnosed ovarian cancer: a single-centre retrospective study.

BACKGROUND AND AIMS OF THE STUDY: Due to its importance for treatment and potential prevention in family members, germline testing for BRCA1/2 in patients with newly diagnosed ovarian cancer is decisive and considered a standard of care. Maintenance therapy with poly(ADP-ribose) polymerase (PARP) inhibitors substantially improves progression-free survival in patients with BRCA mutations and homologous recombination-deficient tumours by inducing synthetic lethality. In Switzerland, they are licensed only for these patients. Therefore, it is crucial to test patients early while they are receiving adjuvant chemotherapy. This study aimed to determine whether genetic counselling followed by homologous recombination deficiency testing is feasible for initialising maintenance therapy within eight weeks and cost-effective in daily practice in Switzerland compared to somatic tumour analysis of all patients at diagnosis. METHODS: This single-centre retrospective study included 44 patients with newly diagnosed high-grade serous ovarian cancer of a Federation of Gynaecology and Obstetrics (FIGO) stage of IIIA-IVB diagnosed between 12/2020 and 12/2022. It collected the outcomes of genetic counselling, germline testing, and somatic Geneva test for homologous recombination deficiency. Delays in initiating maintenance therapy, total testing costs per patient, and progression-free survival were examined to assess feasibility and cost-effectiveness in clinical practice. RESULTS: Thirty-seven of 44 patients (84%) with newly diagnosed ovarian cancer received counselling, of which 34 (77%) were tested for germline BRCA and other homologous recombination repair gene mutations. Five (15%) BRCA and three (9%) other homologous recombination deficiency mutations were identified. Eleven of the remaining 26 patients (42%) had tumours with somatic homologous recombination deficiency. The mean time to the initiation of maintenance therapy of 5.2 weeks was not longer than in studies for market authorisation (SOLO1, PAOLA, and PRIMA). The mean testing costs per patient were 3880 Swiss Franks (CHF), compared to 5624 CHF if all patients were tested at diagnosis with the myChoice CDx test (p <0.0001). CONCLUSION: Using genetic counselling to consent patients with newly diagnosed ovarian cancer for germline testing fulfils the international gold standard. Subsequent somatic homologous recombination deficiency analysis complements testing and identifies more patients who will benefit from PARP inhibitor maintenance therapy. Contrary to previous health cost model studies, the procedure does not increase testing costs in the Swiss population and does not delay maintenance therapy. Therefore, all patients should be offered a primary germline analysis. The challenge for the future will be to ensure sufficient resources for prompt genetic counselling and germline testing.

Timing of cardio-oncological rehabilitation and cardiorespiratory fitness in patients receiving cardiotoxic chemotherapy: a longitudinal observational study.

AIMS: Anthracycline-based chemotherapy has well-known cardiotoxic effects, butmay also cause skeletal muscle myopathy and negatively affect cardiorespiratory fitness and quality of life. The effectiveness of exercise training in improving cardiorespiratory fitness and quality of life during chemotherapy is highly variable. We set out to determine how the effect of exercise training on cardiorespiratory fitness (primary outcome) and quality of life (secondary outcome) in cancer patients is affected by the type of therapy they receive (cardiotoxic therapy with or without anthracyclines; non-cardiotoxic therapy) and the timing of the exercise training (during or after therapy). METHODS: Consecutive patients with cancer who participated in an exercise-based cardio-oncology rehabilitation programme at a university hospital in Switzerland between January 2014 and February 2022 were eligible. Patients were grouped based on chemotherapy (anthracycline vs non-anthracycline) and timing of exercise training (during vs after chemotherapy). Peak oxygen uptake (VO2) was assessed with cardiopulmonary exercise testing (n = 200), and quality of life with the Functional Assessment of Cancer Therapies questionnaire (n = 77). Robust linear models were performed for change in peak VO2 including type and timing of cardiotoxic therapies, age, training impulse and baseline peak VO2; change in quality of life was analysed with cumulative linked models. RESULTS: In all patients with valid VO2 (n = 164), median change in peak VO2 from before to after exercise training was 2.3 ml/kg/min (range: -10.1-15.9). The highest median change in peak VO2 was 4.1 ml/kg/min (interquartile range [IQR]: 0.7-7.7) in patients who completed exercise training during non-anthracycline cardiotoxic or non-cardiotoxic therapies, followed by 2.8 ml/kg/min (IQR: 1.2-5.3) and 2.3 ml/kg/min (IQR: 0.1-4.6) in patients who completed exercise training after anthracycline and after non-anthracycline cardiotoxic or non-cardiotoxic therapies, respectively. In patients who completed exercise training during anthracycline therapy, peak VO2 decreased by a median of -2.1 ml/kg/min (IQR: -4.7-2.0). In the robust linear model, there was a significant interaction between type and timing of cancer treatment for anthracycline therapy, with greater increases in peak VO2 when exercise training was performed after anthracycline therapy. For quality of life, higher baseline scores were negatively associated with changes in quality of life. CONCLUSION: In our cohort, the increase in cardiorespiratory fitness was diminished when exercise training was performed concurrently with anthracyclines. For patients with cardiotoxic treatments other than anthracyclines, cardiorespiratory fitness and quality of life was not associated with timing of exercise training.

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.

Population pharmacokinetics of TLD-1, a novel liposomal doxorubicin, in a phase I trial.

STUDY OBJECTIVES: TLD-1 is a novel pegylated liposomal doxorubicin (PLD) formulation aiming to optimise the PLD efficacy-toxicity ratio. We aimed to characterise TLD-1's population pharmacokinetics using non-compartmental analysis and nonlinear mixed-effects modelling. METHODS: The PK of TLD-1 was analysed by performing a non-compartmental analysis of longitudinal doxorubicin plasma concentration measurements obtained from a clinical trial in 30 patients with advanced solid tumours across a 4.5-fold dose range. Furthermore, a joint parent-metabolite PK model of doxorubicinentrapped, doxorubicinfree, and metabolite doxorubicinol was developed. Interindividual and interoccasion variability around the typical PK parameters and potential covariates to explain parts of this variability were explored. RESULTS: Medians  ± standard deviations of dose-normalised doxorubicinentrapped+free Cmax and AUC0-∞ were 0.342 ± 0.134 mg/L and 40.1 ± 18.9 mg·h/L, respectively. The median half-life (95 h) was 23.5 h longer than the half-life of currently marketed PLD. The novel joint parent-metabolite model comprised a one-compartment model with linear release (doxorubicinentrapped), a two-compartment model with linear elimination (doxorubicinfree), and a one-compartment model with linear elimination for doxorubicinol. Body surface area on the volumes of distribution for free doxorubicin was the only significant covariate. CONCLUSION: The population PK of TLD-1, including its release and main metabolite, were successfully characterised using non-compartmental and compartmental analyses. Based on its long half-life, TLD-1 presents a promising candidate for further clinical development. The PK characteristics form the basis to investigate TLD-1 exposure-response (i.e., clinical efficacy) and exposure-toxicity relationships in the future. Once such relationships have been established, the developed population PK model can be further used in model-informed precision dosing strategies. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov-NCT03387917-January 2, 2018.

Factors influencing 5-year persistence to adjuvant endocrine therapy in young women with breast cancer.

PURPOSE: Although younger age has been negatively associated with persistence to adjuvant endocrine therapy (ET), factors contributing to non-persistence remain poorly understood. We assessed factors associated with non-persistence to ET and described the 5-year trajectories of quality of life (QoL) and symptoms in young women (≤40 years) with hormone receptor-positive breast cancer (BC). METHODS: We retrieved data on clinical characteristics and non-persistence from the medical annual records in the European cohort of the "Helping Ourselves, Helping Others: The Young Women's BC Study" (IBCSG 43-09 HOHO). Women completed surveys at baseline, biannually for three years, and annually for another seven years. Data collection included sociodemographic information, QoL aspects assessed by the Cancer Rehabilitation Evaluation System-Short Form and symptoms assessed by the Breast Cancer Prevention Trial symptom scales. Cox regression models were applied to identify factors associated with non-persistence. RESULTS: The cumulative risk of interrupting ET within 5 years was 27.7 % (95 % CI, 21.5-35.2). The QoL subscale scores remained stable over 5 years, with slight improvements in the physical subscale. Hot flashes decreased (p < 0.001), while vaginal problems intensified (p < 0.001) over time. Being married without children and having difficulties interacting and communicating with the medical team were significantly associated with non-persistence. CONCLUSIONS: Discussing the desire to conceive with partnered childless women and establishing a good relationship with the medical team may be important in addressing the non-persistence in young BC survivors. As recent data suggests the safety of pausing ET to conceive, this approach may be a reasonable future option to limit non-persistence.

Adjunctive Statistical Standardization of Adjuvant Estrogen Receptor and Progesterone Receptor in Canadian Cancer Trials Group MA.27 Postmenopausal Breast Cancer Trial of Exemestane Versus Anastrozole.

PURPOSE: ASCO/College of American Pathologists guidelines recommend reporting estrogen receptor (ER) and progesterone receptor (PgR) as positive with (1%-100%) staining. Statistically standardized quantitated positivity could indicate differential associations of positivity with breast cancer outcomes. METHODS: MA.27 (ClinicalTrials.gov identifier: NCT00066573) was a phase III adjuvant trial of exemestane versus anastrozole in postmenopausal women with early-stage breast cancer. Immunochemistry ER and PgR HSCORE and % positivity (%+) were centrally assessed by machine image quantitation and statistically standardized to mean 0 and standard deviation (SD) 1 after Box-Cox variance stabilization transformations of square for ER; for PgR, (1) natural logarithm (0.1 added to 0 HSCOREs and 0%+) and (2) square root. Our primary end point was MA.27 distant disease-free survival (DDFS) at a median 4.1-year follow-up, and secondary end point was event-free survival (EFS). Univariate survival with cut points at SDs about a mean of 0 (≤-1; (-1, 0]; (0, 1]; >1) was described with Kaplan-Meier plots and examined with Wilcoxon (Peto-Prentice) test statistic. Adjusted Cox multivariable regressions had two-sided Wald tests and nominal significance P < .05. RESULTS: Of 7,576 women accrued, 3,048 women's tumors had machine-quantitated image analysis results: 2,900 (95%) for ER, 2,726 (89%) for PgR, and 2,582 (85% of 3,048) with both ER and PgR. Higher statistically standardized ER and PgR HSCORE and %+ were associated with better univariate DDFS and EFS (P < .001). In multivariable assessments, ER HSCORE and %+ were not significantly associated (P = .52-.88) with DDFS in models with PgR, whereas higher PgR HSCORE and %+ were significantly associated with better DDFS (P = .001) in models with ER. CONCLUSION: Adjunctive statistical standardization differentiated quantitated levels of ER and PgR. Patients with higher ER- and PgR-standardized units had superior DDFS compared with those with HSCOREs and %+ ≤-1.

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.

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.

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.

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.

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.