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Introduction Breast cancer is uncommon in men. Almost all male breast cancers are hormone receptor-positive, HER2-negative, although the pathogenesis is not always attributable to an endocrine condition. A few studies have compared biological characteristics or molecular signatures with breast cancers in women. We sought to evaluate whether hormone receptor-related gene expression is different in cancers from men compared to equivalent cancers from women. SET2,3 index measures non-proliferative hormone receptor-related transcriptional activity in the cancer (SET-ER/PR index) and adjusts this for a Baseline Prognosis Index (BPI) that combines the measurements of tumor and nodal stage with a 4-gene molecular subtype (ESR1, PGR, ERBB2, and AURKA). Methods We received aliquots of total RNA from male patients with breast cancer included in the retrospective cohort study of the EORTC 10085/BCG/TBCRC/BIG/NCTN International Male Breast Cancer Program (NCT01101425). SET2,3 assay was performed using the QuantiGene assay (Thermo Fisher) using bead-based hybridization and laser spectroscopy (Luminex). The statistical analyses were performed by the EORTC statistician. The primary objective of the study was the assessment of the prognostic value of the SET2,3 index score in patients with early-stage hormone receptor-positive, HER2-negative male breast cancer, treated with endocrine therapy. Clinical outcomes (recurrence-free survival – RFS; overall survival – OS) were estimated by Kaplan-Meier curves and secondarily compared using multivariable Cox models adjusted for continuous SET2,3 index, tumor size, nodal status, age, and chemotherapy and radiotherapy use. An exploratory analysis to compare the SET2,3 index scores distribution in female and male breast cancer patients was also performed using results from the same assay performed on cancers from women selected on the same inclusion criteria. Due to the low numbers of male patients treated with neoadjuvant treatment (N=6), this analysis was restricted to patients treated with adjuvant treatment (n=315 male and 660 female). Results Of the 321 male patients with breast cancer analyzed, treated between 1990 and 2010, 211 (65.7%) were categorized as high SET2,3 index score, reflecting a high endocrine activity in the cancer and low risk of recurrence, and 110 patients (34.3%) categorized as being low score, reflecting low endocrine activity and high risk of recurrence. At 5 years, the RFS was 75.0% (95% CI, 67.4-81.1) in the high SET2,3 group versus 60.7% (95% CI, 49.1-70.5) in the low SET2,3 group (HR univariate, 0.49; 95% CI, 0.34-0.70; P< 0.0001). The 5-year OS rate among patients with a high SET2,3 index was 84.3% (95% CI, 45.5-73.8), in contrast of 67.8% (95% CI, 56.6-76.7) in the low SET2,3 group (HR univariate, 0.44; 95% CI, 0.30-0.65; P< 0.0001). SET2,3 was independently prognostic for OS, but not RFS in multivariable Cox models. In patients classified as low SET2,3, the addition of neo/adjuvant chemotherapy to adjuvant endocrine therapy was associated with 5-year OS of 76.0% (95% CI, 59.5-86.4) and in patients who received endocrine therapy alone the 5-year OS was 61.3% (95% CI, 45.5-73.8), an absolute difference of 14.7 percentage points. Overall, we did not observe a difference in the distributions (median, interquartile range) of SET2,3 index between men (2.4, 1.9–2.6) and women (2.3, 2.0–2.7). Conclusion SET2,3 index measurements of endocrine-related transcriptional activity in male patients with breast cancer were not different from measurements in female patients with breast cancer. SET2,3 was prognostic in male breast cancer and our exploratory analysis suggests that chemotherapy might improve the poor prognosis for men with breast cancer that has low SET2,3 index. This study was funded by the Breast Cancer Research Foundation (BCRF). Citation Format: Danielle B. Zakon, Coralie Poncet, Fatima Cardoso, Neven Anouk, Vicente Valero, Stefan Aebi, Kim Benstead, Oliver Bogler, Lissandra Dal Lago, Judith Fraser, Carmela Caballero, Ingrid A. Hedenfalk, Larissa A. Korde, Barbro Linderholm, John WM Martens, Lavinia P. Middleton, Melissa Murray, Catherine M. Kelly, Cecilia Nilsson, Monika Nowaczyk, Stephanie Peeters, Melanie Beauvois, Peggy Porter, Carolien P. Schroder, Isabel T. Rubio, Kathryn Ruddy, Christi van Asperen, Danielle Van Den Weyngaert, Carolien HM van Deurzen, Elise van Leeuwen-Stok, Joanna M. Vermeij, John MS Bartlett, Antonio C. Wolff, Sharon H. Giordano, W. Fraser Symmans. PD6-11 Evaluation of the Sensitivity to Endocrine Therapy Index (SET2,3) in Early Male Breast Cancer: Results from an analysis in the EORTC 10085/TBCRC/BIG/NCTN International Male Breast Cancer Program [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD6-11.

Background: The risk of late distant recurrence (≥ 5 years) in post-menopausal patients with ER+ BC remains significant even after standard adjuvant endocrine therapy (ET). Obesity, which has reached high proportions in Western Countries, is one of the modifiable factors that can contribute to BC recurrences. While body mass index (BMI) is an easily available surrogate measure of adiposity, it might not reflect accurately patient adiposity, especially in post-menopausal patients. We therefore hypothesize that mammary adipocyte measurements might better capture the adiposity of the patient. In this study, we retrospectively evaluated the prognostic role of both BMI and adipocyte measurements in the SOLE trial. Patients & Methods: The SOLE trial (NCT00553410) consisted of 4,884 postmenopausal women with hormone receptor positive, lymph node-positive BC treated with 5 years of letrozole after having completed 4-6 years of adjuvant ET. BMI was available for 3,606 patients with ER+/HER2- BC and categorized according to the WHO classification (underweight: < 18.5, normal weight 18.5 – 24.9, overweight 25 – 29.9, obesity ≥ 30 kg/m2). Considering the small sample size, patients with underweight (n=35) were grouped together with patients with normal weight for the subsequent analyses. We evaluated the association between clinico-pathological characteristics and BMI using Fisher exact test and Kruskal-Wallis test. Given the previously reported association of BMI with distant recurrences (PMID: 21115856), we considered distant-relapse free interval (DRFI) as the main study endpoint. Cox regression analyses were adjusted for histology, chemotherapy (yes/no), type of local therapy, in addition to previously reported clinico-pathological variables (PMID: 29158011). Then, we conducted a stratified case-cohort study consisting of 311 patients (97 with distant relapse-cases) with successful digital assessment of adipocytes on normal mammary adipose tissue sample collected at surgery, as previously described (PMID: 33120083). Stratification factors were treatment arm and type of prior ET. Weighted Cox regression models (PMID: 17554753, 18712477) were used to evaluate prognostic association with adipocyte size (area in µm²) categorized in quartile of the 75th percentile (Q4 vs Q1-3), as done previously (PMID: 33753731). Results: 1392 (39%) patients were normal weight, 1315 (36%) were overweight and 899 (25%) were obese. Older age at diagnosis, lymph node involvement (≥4), large tumor size and menopausal status were associated with overweight and obesity. After a median follow-up of 84 months, no associations were found between DRFI and BMI in the univariable and multivariable analysis (adjusted HR overweight vs normal=0.99, 95%CI: 0.76 – 1.29, p=0.977 and HR obese vs normal=1.11, 95%CI: 0.84 - 1.47, p=0.425). In the case-cohort study, patients with larger adipocytes had an increased hazard of distant recurrence in the univariable and multivariable analysis (see table 1). Conclusion: In this study, we did not detect any association between BMI and survival outcomes. We however found that larger mammary adipocytes were independently associated with an increased hazard of distant recurrence. These results suggest that mammary adipocytes, which can be easily evaluated on H&E slides using digital pathology, should be considered as a novel marker to evaluate the risk of late recurrence in patients with breast cancer. Citation Format: Edoardo Isnaldi, François Richard, Giuseppe Marano, Patrizia Boracchi, Marion Maetens, Giuseppe Floris, Guy Jerusalem, Andrea Gombos, Alastair M. Thompson, Erika Hitre, Stefan Aebi, Marco Colleoni, Patrizia Dell’Orto, Roswitha Kammler, Patrick Neven, Giuseppe Viale, Meredith Regan, Elia Biganzoli, Christine Desmedt. Impact of increased adiposity on extended aromatase inhibitor treatment in postmenopausal patients with estrogen receptor positive (ER+) breast cancer: a retrospective analysis of the SOLE trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-05-28.

Clinico-pathologic characteristics of patients according to NGS results (success/failure).

Weighted Kaplan-Meier (KM) estimates of breast cancer-free interval (BCFI) and distant recurrence-free interval (DRFI) according to tumor subtype, separately by PIK3CA mutational status (mutated, MUT vs wild-type, WT). The 5-year event-free estimates (95% CI) are provided. Hazard ratio (HR) estimates (95% CI) and log-rank tests from weighted univariate models.

Purpose:Women with hormone receptor–positive early breast cancers have a persistent risk of relapse and biomarkers for late recurrence are needed. We sought to identify tumor genomic aberrations associated with increased late-recurrence risk.Experimental Design:In a secondary analysis of Study of Letrozole Extension trial, a case-cohort–like sampling selected 598 primary breast cancers for targeted next-generation sequencing analysis of gene mutations and copy-number gains (CNGs). Correlations of genomic aberrations with clinicopathologic factors and breast and distant recurrence-free intervals (BCFIs and DRFIs) were analyzed using weighted Cox models.Results:Analysis of mutations and CNGs was successfully performed for 403 and 350 samples, including 148 and 134 patients with breast cancer recurrences (median follow-up time, 5.2 years), respectively. The most frequent alterations were PIK3CA mutations (42%) and CNGs of CCND1 (15%), ERBB2 (10%), FGFR1 (8%), and MYC (8%). PIK3CA mutations and MYC CNGs were associated with lower (P = 0.03) and higher (P = 0.004) tumor grade, respectively; a higher Ki-67 was seen in tumor with CCND1, ERBB2, and MYC CNGs (P = 0.01, P < 0.001, and P = 0.03, respectively). FGFR1 CNG was associated with an increased risk of late events in univariate analyses [17/29 patients; BCFI: HR, 3.2; 95% confidence interval (CI), 1.48–6.92; P = 0.003 and DRFI: HR, 3.5; 95% CI, 1.61–7.75; P = 0.002) and in multivariable models adjusted for clinicopathologic factors.Conclusions:Postmenopausal women with hormone receptor–positive early breast cancer harboring FGFR1 CNG had an increased risk of late recurrence despite extended therapy. FGFR1 CNG may represent a useful prognostic biomarker for late recurrence and a therapeutic target.

BACKGROUND Late recurrences in postmenopausal women with hormone receptor-positive breast cancers remain an important challenge. Avoidance or delayed development of resistance represents the main objective in extended endocrine therapy (ET). In animal models, resistance was reversed with restoration of circulating estrogen levels during interruption of letrozole treatment. This phase III, randomized, open-label Study of Letrozole Extension (SOLE) studied the effect of extended intermittent letrozole treatment in comparison with continuous letrozole. In parallel, the SOLE estrogen substudy (SOLE-EST) analyzed the levels of estrogen during the interruption of treatment. PATIENTS AND METHODS SOLE enrolled 4884 postmenopausal women with hormone receptor-positive, lymph node-positive, operable breast cancer between December 2007 and October 2012 and among them, 104 patients were enrolled in SOLE-EST. They must have undergone local treatment and have completed 4-6 years of adjuvant ET. Patients were randomized between continuous letrozole (2.5 mg/day orally for 5 years) and intermittent letrozole treatment (2.5 mg/day for 9 months followed by a 3-month interruption in years 1-4 and then 2.5 mg/day during all of year 5). RESULTS Intention-to-treat population included 4851 women in SOLE (n��= 2425 in the intermittent and n��= 2426 in the continuous letrozole groups) and 103 women in SOLE-EST (n��= 78 in the intermittent and n��= 25 in the continuous letrozole groups). After a median follow-up of 84 months, 7-year disease-free survival (DFS) was 81.4% in the intermittent group and 81.5% in the continuous group (hazard ratio: 1.03, 95% confidence interval: 0.91-1.17). Reported adverse events were similar in both groups. Circulating estrogen recovery was demonstrated within 6 weeks after the stop of letrozole treatment. CONCLUSIONS Extended adjuvant ET by intermittent administration of letrozole did not improve DFS compared with continuous use, despite the recovery of circulating estrogen levels. The similar DFS coupled with previously reported quality-of-life advantages suggest intermittent extended treatment is a valid option for patients who require or prefer a treatment interruption.

Purpose:Women with hormone receptor–positive early breast cancers have a persistent risk of relapse and biomarkers for late recurrence are needed. We sought to identify tumor genomic aberrations associated with increased late-recurrence risk.Experimental Design:In a secondary analysis of Study of Letrozole Extension trial, a case-cohort–like sampling selected 598 primary breast cancers for targeted next-generation sequencing analysis of gene mutations and copy-number gains (CNGs). Correlations of genomic aberrations with clinicopathologic factors and breast and distant recurrence-free intervals (BCFIs and DRFIs) were analyzed using weighted Cox models.Results:Analysis of mutations and CNGs was successfully performed for 403 and 350 samples, including 148 and 134 patients with breast cancer recurrences (median follow-up time, 5.2 years), respectively. The most frequent alterations were PIK3CA mutations (42%) and CNGs of CCND1 (15%), ERBB2 (10%), FGFR1 (8%), and MYC (8%). PIK3CA mutations and MYC CNGs were associated with lower (P = 0.03) and higher (P = 0.004) tumor grade, respectively; a higher Ki-67 was seen in tumor with CCND1, ERBB2, and MYC CNGs (P = 0.01, P < 0.001, and P = 0.03, respectively). FGFR1 CNG was associated with an increased risk of late events in univariate analyses [17/29 patients; BCFI: HR, 3.2; 95% confidence interval (CI), 1.48–6.92; P = 0.003 and DRFI: HR, 3.5; 95% CI, 1.61–7.75; P = 0.002) and in multivariable models adjusted for clinicopathologic factors.Conclusions:Postmenopausal women with hormone receptor–positive early breast cancer harboring FGFR1 CNG had an increased risk of late recurrence despite extended therapy. FGFR1 CNG may represent a useful prognostic biomarker for late recurrence and a therapeutic target.

Introduction: Male breast cancer (BCa) is a rare disease accounting for less than 1% of all breast cancers (BC) and 1% of all cancers in males. The clinical management is largely extrapolated from female BCa. Few studies have examined the genomic landscape of male BCas, with six male BCas included in The Cancer Genome Atlas (TCGA). Familial studies of male BCas have shown genomic changes similar to female BCa, while a larger targeted sequencing study of 59 male breast cancers identified recurrent mutations affecting PIK3CA and GATA3. To date, there is still limited information regarding the genomic landscape of male BCas; particularly in the context of identifying targeted treatments. To reveal genomic changes that characterize male BCas in the context of known cancer driver genes linked to prognosis and targeted agents, we performed a targeted sequencing study on 248 male BCas from the International Male Breast Cancer Program. Methods: 248 primary M0, ER+ve, HER2-ve male BCas enrolled in the Part 1 (retrospective joint analysis) International Male Breast Cancer Program of 1483 patients diagnosed between 1990-2010 (Cardoso et al. Annals of Oncology, 2018) were processed for nucleic acid extraction from formalin-fixed paraffin embedded (FFPE) tissues. Using the Thermo Fisher Scientific Oncomine Comprehensive Assay v3 (OCAv3), a validated targeted sequencing panel currently used in the NCI-MATCH trial (NCT02465060), we evaluated mutational and copy number variations (CNVs) of genes that are prognostic or predictive to targeted therapies currently in use in the clinic or late-stage clinical trials. The OCAv3 DNA pan-cancer panel assays 115 genes for determining mutational status (48 full coding and 67 hotspot) as well as copy-number assessment in 43 genes. The OCAv3 uses Ampliseq-based technology linked to the Oncomine NGS workflow to identify actionable mutations and CNVs Results: Of the 248 samples assayed, 216 passed strict quality control parameters (87.1%). Using the Oncomine NGS workflow, actionable mutations at ≥5% variant allele frequency (VAF) were most frequently identified in PIK3CA (29.2%), BRCA2 (11.1%), NF1 (11.6%), indels in TP53 (10.6%), ATR (5.6%), ATRX (5.1%), indel BRCA2 (5.1%), TP53 point mutations (4.6%), MET (4.6%), ATM (4.6%), NOTCH2 (4.6%), CHEK1 (4.2%), FANCI (4.2%), PTEN (3.2%) with a number of additional genes identified at lower frequencies. Gene amplifications were most frequently detected in MYC (24.5%), FGFR1 (14.8%), CCND1 (12%), FGF3 (9.7%), FGF19 (9.7%), MDM2 (6.5%), CDK4 (1.4%), FGFR3, MDM4, ERBB2 (0.9% each), and FLT3, AR, MYCL, CDK6, IGF1R, FGFR4, KRAS, AKT3 and ESR1 (0.5% each). Although the results here describe the mutations and copy-number changes deemed to be actionable, further analysis of all non-actionable somatic mutations and CNVs will be presented and compared to female BCas previously assayed using the same panel. Conclusion: In this targeted sequencing study of the largest series of male BCas to our knowledge, we have revealed that PIK3CA continues to be a frequently altered gene in both male and female BCas. However, there is an enrichment of mutations in genes related to DNA repair in male BCs. Interestingly, while MYC is commonly amplified in female BCa, a higher frequency of amplified cases were seen in male BCas, in contrast to female BCas. Together with our previously generated transcriptional profiling data in this data set, we believe that both common and unique biological processes comprising male and female BCas will ultimately improve their clinical management and move towards the goal of precision medicine. This work has been funded by the Breast Cancer Research Foundation (BCRF). Citation Format: Jane Bayani, Coralie Poncet, Cheryl Crozier, Quang M Trinh, Megan Hopkins, Aime Lambert Uwimana, Tammy Piper, Carrie Cunningham, Monika Sobol, Stefan Aebi, Kim Benstead, Oliver Bogler, Lissandra Dal Lago, Florentine Hilbers, Ingrid Hedenfalk, Larissa Korde, Barbro Linderholm, John Martens, Lavinia Middleton, Melissa Murray, Catherine Kelly, Cecilia Nilsson, Monika Nowaczyk, Stephanie Peeters, Aleksandra Peric, Peggy Porter, Carolien Schröder, Isabel T Rubio, Kathryn J Ruddy, Christi van Asperen, Danielle Van Den Weyngaert, Carolien HM van Deurzen, Elise van Leeuwen-Stok, Joanna Vermeij, Eric Winer, Lincoln D Stein, Sharon H Giordano, Fatima Cardoso, John MS Bartlett. The genomic landscape of male breast cancers using the oncomine comprehensive assay for actionable mutations [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-10-03.

Background: In animal models of hormone receptor positive (HR+) breast cancer, acquired resistance to continued letrozole was shown to be reversed by estrogen-induced apoptosis. We hypothesized that the rise in estrogen levels during short treatment interruptions would resensitize breast cancer cells to letrozole and improve treatment outcome. SOLE tested the hypothesis that 3 mos treatment-free intervals during extended adjuvant therapy will improve disease-free survival (DFS). We previously reported the primary endpoint after 60 mos median follow-up: extended intermittent letrozole did not improve DFS vs extended continuous letrozole. However, only 9% of pts had breast cancer events, justifying updating the analysis with longer follow-up. The dynamic of recovery of estrogen levels after stopping letrozole therapy has not been previously reported. Methods: SOLE enrolled 4884 postmenopausal women with HR+ lymph node-positive BC who had completed 4-6 yrs of adjuvant endocrine therapy (19% SERM, 43% AI, 38% both; stratification factor). Pts were randomized to an additional 5 yrs continuous letrozole (2.5 mg daily; n=2441) vs 5 yrs intermittent letrozole (taken for the first 9 mos of yrs 1-4, and 12 mos in yr 5; n=2443). We report the final analysis of the SOLE trial after 84 mos median follow-up. In SOLE-EST, levels of estradiol (E2), estrone (E1) and estrone sulphate (E1S) at 0, 9, 10.5 and 12 mos after randomization were determined using a highly sensitive assay in a subgroup of 90 evaluable patients (21 in the continuous and 69 in the intermittent group). Results: There were 923 DFS events. 7 yr DFS was 81.5% in both groups. More pts had distant metastases in the continuous group (8.7% vs 7.5%) while second (non-breast) malignancies were more frequent in the intermittent group (5.5% vs 4.7%). Similar outcomes were observed for breast cancer-free interval (BCFI) (88.6% vs 88.0%), distant recurrence-free interval (DRFI) (91.6% vs 90.4%), and overall survival (OS) (90.6% vs 89.6%) for pts assigned intermittent vs continuous letrozole. In the intermittent group, median E2, E1 and E1S levels more than doubled compared with levels at 9 mos after randomization in the first 6 weeks after stopping letrozole during the treatment free interval while levels were stable for the 21 pts tested in the continuous group. Conclusions: Among postmenopausal women with HR+ BC, extended intermittent letrozole did not improve DFS vs continuous letrozole. Similar outcome was consistently observed for BCFI, DRFI and OS. The SOLE-EST substudy indicates an important increase in estrogen levels as soon as 6 weeks after stopping letrozole therapy in the intermittent group. Further investigation of prior exposure to aromatase inhibitors in relation with outcome and with E2, E1 and E1S levels in SOLE-EST are underway. Citation Format: Guy Jerusalem, Subrina Farah, Jacquie Chirgwin, Stefan Aebi, Per Karlsson, Patrick Neven, Erika Hitre, Marie-Pascale Graas, Edda Simoncini, Claus Kamby, Alastair Thompson, Sibylle Loibl, Joaquín Gavilá, Katsumasa Kuroi, Christian Marth, Bettina Müller, Seamus O'Reilly, Andrea Gombos, Thomas Ruhstaller, Harold Burstein, Manuela Rabaglio, Barbara Ruepp, Giuseppe Viale, Richard D Gelber, Alan S Coates, Angelo Di Leo, Aron Goldhirsch, Meredith Regan, Marco Colleoni. SOLE (study of letrozole extension), a phase 3 randomized clinical trial of continuous vs intermittent letrozole in postmenopausal women who have received 4-6 years of adjuvant endocrine therapy for lymph node-positive, early breast cancer (BC): Final analysis and sole estrogen substudy (SOLE-EST) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-12-01.

The implementation of pharmacogenetic testing into clinical practice has been a slow process so far. Here, we review the implementation of pre-treatment testing of dihydropyrimidine dehydrogenase gene (

Background: The SAKK 22/99 is a phase III randomized clinical trial launched by the Swiss Group for Clinical Cancer Research and the European Institute of Oncology in Milan in 99 for women with HER2-positive advanced breast cancer (ABC). 175 patients were randomized 1:1 from Sept 99 to Jan 2013 to receive first-line trastuzumab (T) alone followed at disease progression by the combination with chemo (Arm A) vs the upfront combination of T and chemo (Arm B). The results were published in 2017 (O. Pagani et al Ann Onc 28: 305–312, 2017). The outcome was similar for sequential T-chemo or upfront combination The patients’ treatment and FU continued until March 2022 and we now report the safety data after 135.2 months of median FU. Patients and methods: at the time of study termination 1 patient with SD was still receiving T alone in the study and T was continued after trial closure. The safety analyses include 86 pts allocated to arm A and 88 to arm B. 1 pt did not receive any trial treatment and was excluded from this analyses. 19 of the 86 patients in arm A stopped trial treatment after T alone, 67 continued with T+ chemo. Baseline characteristics were well balanced and are summarized in Table 1. Treatment The T loading dose of 4 mg/kg/iv was followed by 2 mg/kg/iv weekly. In the 1st-line population (84) chemo was weekly paclitaxel (90 mg/m2/iv-3/4 weeks). After amendment 1 chemo was at investigator’s choice (taxanes, vinorelbine, platin) according to label indications and could be stopped after 24 weeks (6–8 cycles) in responding patients or after unacceptable toxicity. Results: 7 patients in arm A (8%) and 11 in arm B (13%) stopped trial treatment due to toxicities (Fisher’s exact test, p=0.46). 3 of the 7 patients in arm A stopped under T alone and 4 under T+chemo (all paclitaxel weekly) Treatment durations of these 7 and 11 patients were 7.7 months (range 0.5 – 49) in arm A and 5.5 months (range 0.6 – 31 months) in arm B, respectively. Cardiovascular toxicities: The most common toxicities were thromboembolic events, blood pressure disorders and arrhythmia. 6 patients (7%) in arm A and 10 (11%) in arm B had cardiac events (Fisher’s exact test, p=0.43). G1-3 toxicities occurred in 2 (2%), 2 (2%) and 2 (2%) patients of arm A and in 5 (7%), 2 (2%) and 3 (3%) of arm B. We observed no grade 4 events. Split by treatment phase in arm A, G1-3 toxicities were seen in in 1 (1%), 2 (2%) and 1 (1%) patient under T alone (N=86) and in 1 (1%), 0 (0%) and 2 (3%) under T+chemo (N=67). LVEF-decline: 78 patients in arm A and 74 in arm B had sequential LVEF measurements. A decline ≥ 10% was found in 35 patients (45%) in arm A and in 20 (27%) in arm B (Fisher’s exact test, p=0.028). Among the 35 patients in arm A, 12 had the decline under T alone, 14 under T+chemo, and 9 under both T alone and T+chemo. A decline ≥ 20% was found in 10 patients (13%) in arm A and in 3 (4%) in arm B (Fisher’s exact test, p=0.08). Among the 10 patients in arm A, 7 had the decline under T alone, 3 under T+chemo. Sensory neuropathy 43 patients (50%) in arm A and 48 (54%) in arm B had neuropathy (Fisher’s exact test, p=0.65). G1-3 toxicity in arm A was developed by 26 (30%), 11 (13%) and 6 (7%) patients, respectively; in arm B 30 (34%), 12 (14%) and 6 (7%). No grades 4 events occurred. Conclusion: After more than 11 years of follow-up, no relevant toxicities were found in these patients receiving T for ABC. In particular, the incidence and grade of cardiac toxicity was low. The decline in LVEF was numerically higher in the arm A and in particular in the T alone group, but was not clinically relevant. Our data potentially suggest that T+chemo followed by T maintenance could have less cardiotoxicity than T followed by T+chemo. The possible causes for the difference in LVEF decline between the two arms are unclear, but could be related to treatment duration. The women in Arm A shows a trend to longer therapy: Median treatment duration (months) in Arm A was 7.92 (0.46 - 135.98) vs 6.62 (0.56 - 71.28) in Arm B. This long-term analysis confirms the favorable safety and good tolerability of the reported regimes. Table 2: Treatment duration Citation Format: Manuela Rabaglio, Daniel Dietrich, Bernhard Scheibe, Thomas Ruhstaller, Franco Nole, Serenella Eppenberger, Christian Oehlschlegel, Dagmar Hess, Christoph Mamot, Elisabetta Munzone, Bernhard Pestalozzi, Stefan Aebi, Marcus Vetter, Beat Thuerlimann, Roger von Moos, Khalil Zaman, Olivia Pagani. Safety analysis after 11 years of follow-up of the randomized phase III trial SAKK22/99: upfront chemotherapy in advanced HER2 positive breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-01-25.

Male breast cancer (BCa) is a rare disease accounting for less than 1% of all breast cancers and 1% of all cancers in males. The clinical management is largely extrapolated from female BCa. Several multigene assays are increasingly used to guide clinical treatment decisions in female BCa, however, there are limited data on the utility of these tests in male BCa. Here we present the gene expression results of 381 M0, ER+ve, HER2-ve male BCa patients enrolled in the Part 1 (retrospective analysis) of the International Male Breast Cancer Program. Using a custom NanoString™ panel comprised of the genes from the commercial risk tests Prosigna®, OncotypeDX®, and MammaPrint®, risk scores and intrinsic subtyping data were generated to recapitulate the commercial tests as described by us previously. We also examined the prognostic value of other risk scores such as the Genomic Grade Index (GGI), IHC4-mRNA and our prognostic 95-gene signature. In this sample set of male BCa, we demonstrated prognostic utility on univariate analysis. Across all signatures, patients whose samples were identified as low-risk experienced better outcomes than intermediate-risk, with those classed as high risk experiencing the poorest outcomes. As seen with female BCa, the concordance between tests was poor, with C-index values ranging from 40.3% to 78.2% and Kappa values ranging from 0.17 to 0.58. To our knowledge, this is the largest study of male breast cancers assayed to generate risk scores of the current commercial and academic risk tests demonstrating comparable clinical utility to female BCa., SCOPUS: ar.j, info:eu-repo/semantics/published

Background The impact of HER2-targeted therapy alone followed by the addition of chemotherapy at disease progression (PD) versus upfront combination was investigated by the SAKK 22/99 trial. The aim of this exploratory analysis of the SAKK 22/99 trial was to characterize the specific subset of patients deriving long-term benefit from trastuzumab monotherapy alone and to identify potential predictive factors of long-term response. Methods This is an unplanned post-hoc analysis of patients randomized to Arm A (trastuzumab monotherapy). Patients were divided in two groups: patients with durable clinical benefit from trastuzumab monotherapy and short-term responders without durable clinical benefit from trastuzumab monotherapy Univariate and multivariate analyses of clinical characteristics correlating with response duration was performed. Results Eighty six patients were randomized in arm A, 24 patients (28%) were long-term responders and 62 (72%) were short-term responders with a 5y-overall survival (OS) of 54% (95% CI 31–72) and of 18% (95%CI 10–30), respectively. Absence of ER expression, absence of PgR expression and presence of visceral disease emerged as possible negative predictive factors for durable clinical benefit. Conclusion Durable clinical benefit can be achieved with trastuzumab monotherapy in a subgroup of HER2-positive patients with advanced disease and it is predictive for longer OS. Further investigations of predictive biomarkers are necessary to better characterize this subgroup of patients and develop further de-escalating strategies. Trial registration NCT00004935; first posted 27.01.2003, retrospectively registered.

Introduction: Male breast cancer (MBC) is a rare disease accounting for less than 1% of all breast cancers (BC) and 1% of all cancers in males. The clinical management is largely extrapolated from female BC. Several multigene assays are increasingly used to guide clinical treatment decisions in female BC, however there is little data on the utility of these tests in MBC. Methods: Here we present the gene expression results of 380 M0, ER+ve, HER2-ve MBCs enrolled in the Part 1 (retrospective joint analysis) International Male Breast Cancer Program of 1483 patients diagnosed between 1990-2010 (Cardoso et al. Annals of Oncology, 2018). Using a custom Nanostring™ panel comprised of the genes from the commercial risk tests Prosigna®, OncotypeDx® and Mammaprint®, risk scores and intrinsic subtyping data were generated to recapitulate the commercial tests as described by Bayani and Yao et al (npjBreast Cancer, 2017). Survival outcomes by risk classification were analyzed using Cox models with time-dependent covariates when the proportional hazard assumption was not met and adjusted for clinical and treatment variables. Results: Prosigna-like risk scores identified 99 (26.1%) as low-risk, 159 (41.8%) as intermediate-risk, and 122 (32.1%) as high-risk. Using the TAILORx cut-off (25) for OncotypeDx-like risk of recurrence scoring, 158 (41.6%) were identified as low-risk, while 222 (58.4%) were identified as high-risk. MammaPrint-like results identified 175 (46.1%) as low-risk and 205 (53.9%) as high-risk. Overall, patients classified as high-risk had higher grade, more nodal involvement, larger tumors, and more frequently treated with chemotherapy than low-risk patients. Survival analyses demonstrated clear clinical utility for each test, showing patients at high-risk with poor relapse-free survival (RFS) as compared to patients classified as low-risk: Prosigna-like RFS at 3-years (HR=2.20, 95% CI, 1.28-3.80); Oncotype-like RFS at 3-years (HR=1.92, 95% CI, 1.17-3.17); MammaPrint-like RFS (HR=1.51, 95% CI, 1.00-2.27); with similar findings for distant relapse-free survival (DRFS) and overall survival (OS). Across outcomes and all gene signatures, patients with concordant Low/Low risk classification had better prognosis than those with concordant High/High risk classification. PAM50 intrinsic subtyping identified 147 (38.7%) as Luminal A, 57 (15.0%) as Luminal B, 80 (21.1%) as Her2-enriched and 96 (25.3%) as Basal-like; showing overall 34.5% concordance to clinic-pathological subtyping by central pathology (95% CI, 29.7%-39.5%). Comparison between the tests in the MBC cohort and a comparable cohort of female BC from the Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial processed in the same way will be presented. Conclusion: Common transcriptomic assays designed to assess residual risk, validated in female BC, provide similar information in male BC patients. Not surprisingly, disagreement between test results at the individual patient level was observed. To our knowledge, this is the largest study of MBC assayed to generate risk scores of the current commercial BC tests to demonstrate their clinical utility and their differences and similarity to female BC. This work has been funded by the Breast Cancer Research Foundation (BCRF). Citation Format: Bayani J, Poncet C, Yao CQ, Crozier C, Anouk N, Piper T, Cunningham C, Sobol M, Aebi S, Benstead K, Bogler O, Dal Lago L, Fraser J, Hilbers FH, Hedenfalk I, Korde L, Linderholm B, Martens J, Middleton L, Murray M, Kelly C, Nilsson C, Nowaczyk M, Peeters S, Peric A, Porter P, Schröder C, Rubio IT, Ruddy KJ, van Asperen C, Van Den Weyngaert D, van Deurzen C, van Leeuwen-Stok E, Vermeij J, Winer E, Boutros PC, Giordano SH, Cardoso F, Bartlett JM. Evaluation of multiple transcriptomic gene risk signatures in male breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-19-01.

Background Breast cancer is a leading cause of cancer-related death in women worldwide. Despite extensive studies in all areas of basic, clinical and applied research, accurate prognosis remains elusive, thus leading to overtreatment of many patients. Diagnosis could be improved by introducing multigene molecular scores in standard clinical practice. Several tests that work with formalin-fixed tissue have become routine. Molecular scores usually include several genes representing processes, response to oestrogens, progestogens and human epidermal growth factor receptor 2 (Her2), respectively, which are combined additively in single values. These multi-gene scores have the advantage of being more robust and reproducible than single-gene scores. Their utility may be further enhanced by combining them with classical diagnostic parameters. Here, we present an exploratory study comparing the RISK and research versions of Oncotype DX recurrence score (RS), Prosigna Risk of Recurrence (ROR) and EndoPredict (EP) with respect to their prognostic potential for ipsilateral recurrence and/or distant relapse in brain, and we compared the scores to the intrinsic subtypes based on PAM50. Methods RNA was extracted from formalin-fixed, paraffin-embedded (FFPE) tissue cores of primary tumours, local recurrences and brain metastases. Gene expression was measured on a NanoString nCounter Analysis System. Intrinsic subtypes and molecular scores were computed according to published literature and RISK, RS, ROR and EP were compared against each other and to the intrinsic subtypes Luminal A (lumA), Luminal B (lumB), Her2-enriched (Her2↑), Basal-like (basal), and Normal-like (normal) of PAM50. Local recurrences and brain metastases were compared to their corresponding primary tumours. Results All four molecular scores were highly correlated. Highest correlations were observed among genes related to proliferation while lower correlations were found among oestrogen-related genes. The scores were significantly higher in primary tumours progressing to brain metastases as compared to recurrence-free primary tumours and primary tumours that relapsed as local recurrences. Conclusions RISK and ROR-P are prognostic for primary tumours metastasizing to the brain. All four scores, RISK, RS, EP and ROR-P failed to discriminate between primary tumours that remained recurrence-free and primary tumours relapsing as local recurrences. Electronic supplementary material The online version of this article (10.1186/s12885-019-5752-8) contains supplementary material, which is available to authorized users.

Depuis nos recommandations publiees au FMS en 2016, de nouvelles connaissances, qui sont non seulement pertinentes pour les oncologues mais egalement pour les medecins de premier recours, sont disponibles.

2016 stellten wir im SMF Empfehlungen zum Management der haufigsten Nebenwirkungen von Immuntherapien vor. Inzwischen gibt es neue Erkenntnisse, die nicht nur fur Onkologen, sondern auch fur Grundversorger relevant sind.

Background: Isolated local or regional recurrence (ILRR) of breast cancer (BC) after mastectomy or lumpectomy indicates a poor prognosis and patients with ILRR hold a substantial risk of developing subsequent distant metastasis. Limited randomized evidence supports the recommendation of systemic treatment for hormone receptor-positive (HR+) lLRR. Cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors, such as palbociclib, have shown activity and safety in the first-line treatment of metastatic HR+/HER2-negative BC. The POLAR hypothesis is based on the results of the CALOR trial (IBCSG Trial 27-02), which showed effectiveness of adjuvant chemotherapy among patients with resected HR-negative ILRR, but not for HR+ ILRR. Considering these findings and compelling evidence supporting the activity of the combination of CDK4/6 inhibitors and endocrine therapy (ET), we hypothesize that palbociclib in combination with ET may be effective as adjuvant therapy in patients with HR+/HER2-negative resected ILRR of BC. Trial design: POLAR is a phase III open-label, multicenter, randomized trial of adjuvant palbociclib in combination with standard ET versus standard ET alone for women and men with histologically confirmed HR+/HER2-negative resected ILRR of BC. Protocol treatment consists of palbociclib (125 mg/d orally for 21 days, followed by 7 days rest) for 3 years plus standard ET for at least 3 years (Arm A) or standard ET for at least 3 years (Arm B). Patients must be enrolled within 6 months of complete gross excision of the ILRR. Patients may have started standard ET prior to entry. Randomization (1:1) is stratified according to (1) gender and menopausal status; (2) planned ET (oral aromatase inhibitor or tamoxifen vs. fulvestrant). The primary endpoint, invasive disease-free survival (iDFS), will be compared between treatment groups using a stratified log-rank test. The sample size provides 80% power to detect a 50% reduction in hazard (HR=0.50) for palbociclib plus ET versus ET-alone, using a log-rank test with two-sided α=0.05 test with 66 iDFS events. The 3-year iDFS is assumed to be 76% on the basis of patients in the CALOR trial who had ER+ ILRRs. Accrual: The trial will recruit 400 patients from approximately 50 Centers in Austria, France, Hungary, Italy, Spain and Switzerland. The first patient was randomized in August 2019. Accrual as of mid-June 2020 was 25 patients. The POLAR trial (IBCSG 59-19 / BIG 18-02) is sponsored and coordinated by IBCSG with financial support from Pfizer. The trial is conducted under the BIG umbrella in collaboration with ABCSG, GEICAM, SOLTI, SAKK and Unicancer. NCT03820830 Citation Format: Elisabetta Munzone, Stefan Aebi, Noelia Martínez Jañez, Uwe Güth, Meritxell Bellet, Barbara Pistilli, Marija Balic, Heidi Roschitzki-Voser, Meredith M Regan. Phase III open-label, multicenter, randomized trial of adjuvant palbociclib in combination with endocrine therapy versus endocrine therapy alone for patients with hormone receptor-positive / HER2-negative resected isolated locoregional recurrence of breast cancer - The POLAR Trial [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-26-02.

A missense variant (c.1637C>T, T546M) in ABCC11 encoding the MRP8 (multidrug resistance protein 8), a transporter of 5-fluorodeoxyuridine monophosphate, has been associated with an increased risk of 5-fluorouracil-related severe leukopenia. To validate this association, we investigated the impact of the ABCC11 variants c.1637C>T, c.538G>A and c.395+1087C>T on the risk of early-onset fluoropyrimidine-related toxicity in 514 cancer patients. The ABCC11 variant c.1637C>T was strongly associated with severe leukopenia in patients carrying risk variants in DPYD, encoding the key fluoropyrimidine-metabolizing enzyme dihydropyrimidine dehydrogenase (odds ratio (OR): 71.0; 95% confidence interval (CI): 2.5-2004.8; Pc.1637C>T*DPYD=0.013). In contrast, in patients without DPYD risk variants, no association with leukopenia (OR: 0.95; 95% CI: 0.34-2.6) or overall fluoropyrimidine-related toxicity (OR: 1.02; 95% CI: 0.5-2.1) was observed. Our study thus suggests that c.1637C>T affects fluoropyrimidine toxicity to leukocytes particularly in patients with high drug exposure, for example, because of reduced fluoropyrimidine catabolism.

To assess the proposed associations of the c.742-227G>A (rs2612091) polymorphism within the Enolase Superfamily Member 1 gene (ENOSF1) and two variants in the adjacent Thymidylate Synthase gene (TYMS): the 5'VNTR 28bp-repeat (rs45445694) and 3'UTR 6bp-indel (rs11280056) with severe toxicity in fluoropyrimidine-treated cancer patients, we performed an individual patient data meta-analysis. Only studies investigating all three-abovementioned variants with fluoropyrimidine-related toxicities were considered for meta-analysis. Associations were tested individually for each study using multivariate regression. Meta-analysis was performed using a random-effects model. One-stage multivariate regressions including tests for independent SNP effects were applied to investigate individual effects of the variants. Multivariate haplotype regression analyses were performed on a pooled dataset to test multi-SNP effects. Of four studies including 2'067 patients, 1'912 were eligible for meta-analysis. All variants were exclusively associated with severe hand-foot-syndrome (HFS) (TYMS 2R: OR = 1.50, p = 0.0002; TYMS 6bp-ins: OR = 1.42 p = 0.0036; ENOSF1 c.742-227G: OR = 1.64 p A and the TYMS 28bp-repeat: each toxicity-associated allele increased the risk for severe HFS (OR = 1.32 per allele, p

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). 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. 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. 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: NCT00553410.

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. ispartof: BRITISH JOURNAL OF CANCER vol:120 issue:10 pages:959-967 ispartof: location:England status: published

Background: Male breast cancer (BC) is rare, managed by extrapolation from female BC. The International Male BC Program aims to better characterize and manage this disease. We report the results of part I, a retrospective joint analysis of cases diagnosed during a 20-year period.Methods: Patients with follow-up and tumor samples, treated between 1990 and 2010, in 93 centers/9 countries. Samples were centrally analyzed in three laboratories (the United Kingdom, the Netherlands and the United States).Results: Of 1822 patients enrolled, 1483 were analyzed; 63.5% were diagnosed between 2001 and 2010, 57 (5.1%) had metastatic disease (M1). Median age at diagnosis: 68.4 years. Of 1054 M0 cases, 56.2% were node-negative (N0) and 48.5% had T1 tumors; 4% had breast conserving surgery (BCS), 18% sentinel lymph-node biopsy; half received adjuvant radiotherapy; 29.8% (neo) adjuvant chemotherapy and 76.8% adjuvant endocrine therapy (ET), mostly tamoxifen (88.4%). Per central pathology, for M0 tumors: 84.8% ductal invasive carcinomas, 51.5% grade 2; 99.3% estrogen receptor (ER)-positive; 81.9% progesterone receptor (PR)-positive; 96.9% androgen receptor (AR)-positive [ER, PR or AR Allred score >= 3]; 61.1% Ki67 expression low (Conclusions: Male BC is usually ER, PR and AR-positive, Luminal B-like/HER2-negative. Of note, 56% patients had T1 tumors but only 4% had BCS. ER was highly positive in> 90% of cases but only 77% received adjuvant ET. ER, PR and AR were associated with OS and RFS, whereas grade, Ki67 and IHC surrogates were not. Significant improvement in survival over time was observed.

BACKGROUND Ovarian cancer is frequently lethal despite aggressive multimodal therapy, and new therapies are therefore needed. Retinoids are potential candidate drugs: they prevent the development of ovarian carcinoma and enhance the efficacy of cytotoxic drugs in ovarian cancer cells. At present, little is known about the retinoid receptor expression in ovarian cancer. PATIENTS AND METHODS The retinoid receptors comprise two classes, retinoic acid receptors (RARs) and retinoid X receptors (RXRs), each with three subclasses, alpha, beta and gamma. We investigated the expression of the subtypes RARalpha, RARgamma, RXRalpha and RXRbeta by immunohistochemistry in ovarian cancers of 80 patients, and assessed their prognostic significance. In addition, we quantified the expression of retinoid receptor mRNA using real-time PCR and correlated the results with clinical characteristics. RESULTS RARalpha and RXRbeta were highly expressed in a majority of ovarian cancers, particularly in advanced stages. High expression of RARalpha was an independent negative prognostic factor of survival in addition to FIGO stage, age and p53 accumulation. The mRNA expression of retinoid receptors did not correlate with clinical properties of the tumors. CONCLUSIONS Retinoic acid receptors are frequently and strongly expressed in epithelial ovarian cancer and may be indicators of an adverse prognosis. This study provides the molecular basis for the therapeutic use of retinoids in ovarian cancer.

The 1st International Consensus Conference for Breast Cancer in Young Women (BCY1) took place in November 2012, in Dublin, Ireland organized by the European School of Oncology (ESO). Consensus recommendations for management of breast cancer in young women were developed and areas of research priorities were identified. This manuscript summarizes these international consensus recommendations, which are also endorsed by the European Society of Breast Specialists (EUSOMA). (C) 2014 Elsevier Ltd. All rights reserved

Introduction Nivolumab (NIV) was recently approved in several countries for patients with pretreated advanced NSCLC. NIV is not cost-effective compared with docetaxel (DOC) for the treatment of squamous NSCLC. However, its cost-effectiveness for nonsquamous NSCLC and the consequences of programmed death ligand 1 (PD-L1) testing are unknown. Methods This literature-based health economic study used CheckMate-057 trial data to model the incremental cost-effectiveness ratio (ICER) of NIV versus DOC in the Swiss health care setting. The effect of PD-L1 positivity for patient selection was assessed. Results In the base case model, NIV (mean cost CHF66,208; mean effect 0.69 quality-adjusted life-years [QALYs]) compared with DOC (mean cost CHF37,618; mean effect 0.53 QALYs) resulted in an ICER of CHF177,478/QALY gained. Treating only patients with PD-L1–positive tumors (threshold ≥10%) with NIV compared with treating all patients with DOC produced a base case ICER of CHF124,891/QALY gained. Reduced drug price, dose, or treatment duration decreased the ICER partly below a willingness-to-pay threshold of CHF100,000/QALY. Health state utilities strongly influenced cost-effectiveness. Conclusions Compared with DOC, NIV is not cost-effective for the treatment of nonsquamous NSCLC at current prices in the Swiss health care setting. Price reduction or PD-L1 testing and selection of patients for NIV on the basis of test positivity improves cost-effectiveness compared with DOC.

2011 wurde Ipilimumab als erster «immune checkpoint»-Inhibitor in der Schweiz zugelassen. 2015 kamen mit Pembrolizumab und Nivolumab neue Praparate auf den Markt. Dies fuhrte zu einem weiteren Anstieg von onkologischen Immuntherapien an unserem Spital und gab Anlass zum vorliegenden Artikel. Onkologische Immuntherapien sind inzwischen so verbreitet, dass die Komplikationen und deren Behandlung in Grundzugen den praktizierenden Kolleginnen und Kollegen bekannt sein mussen.

En 2011, l’ipilimumab a ete le premier inhibiteur de point de controle immunitaire («immune checkpoint») autorise en Suisse. En 2015, de nouveaux medicaments, le pembrolizumab et le nivolumab, ont ete introduits sur le marche, ce qui s’est traduit par une utilisation accrue des immunotherapies oncologiques dans notre hopital et a donne lieu au present article. Les immunotherapies oncologiques sont entre-temps devenues si repandues que les collegues praticiens doivent connaitre dans les grandes lignes les complications et leur traitement.

Frauen mit Genmutationen und Uberlebende nach Tumoren mit therapeutischer Radiatio der Brustwand haben ein stark erhohtes Brustkrebsrisiko. Familiare Pradisposition, insbesondere der Nachweis gewisser Genmutationen, kann das Erkrankungsrisiko bis zu 80% erhohen. Die prophylaktische bilaterale Mastektomie ist die effektivste ­Methode, das Brustkrebsrisiko erheblich zu reduzieren.

Les femmes porteuses de mutations genetiques ou ayant survecu a des tumeurs apres radiotherapie thoracique presentent un risque eleve de cancer du sein. Les predispositions familiales, et en particulier la mise en evidence de certaines mutations genetiques, peuvent augmenter le risque jusqu’a 80%. La mastectomie bilaterale prophylactique est la meilleure methode pour reduire efficacement le risque de cancer du sein.

Background: We assessed adherence to the European Society of Medical Oncology (ESMO)/Multinational Association of Supportive Care in Cancer recommendations for prophylaxis of chemotherapy-induced nausea and vomiting (CINV) at our institution. Patients and methods: The charts of 299 patients starting a new chemotherapy between November 2008 and April 2009 were reviewed. Baseline characteristics and prophylaxis of CINV during the first cycle were recorded, and adherence to ESMO recommendations was determined. Chi-square tests and logistic regression were used to test for predictors of adherence. Results: Prophylaxis of acute CINV was not adherent in 39% of the patients: 39 of 54 patients with low emetogenic chemotherapy had a serotonin antagonist, and 24 of 100 with moderately emetogenic therapy had a neurokinin antagonist. Nevertheless, 71% of the patients treated with highly emetogenic therapy received the guideline-specified prescription. Prophylaxis of delayed CINV was not adherent in 89% of the patients: 101 of 125 patients with highly or moderately emetogenic single-day chemotherapy received a serotonin antagonist. Male gender (odds ratio (OR) 0.484, 95% confidence interval (CI) 0.291-0.806; P = 0.005) and hematologic neoplasia (OR 2.151, 95% CI 1.19-3.887; P = 0.011) were independent predictors of non-adherence. Age (OR 0.981, 95% CI 0.964-0.998; P = 0.029) and inpatient treatment (OR 0.457, 95% CI 0.25-0.836; P = 0.011) indicated a lower risk of non-adherence. Conclusion: Contrary to older studies reporting frequent omissions of corticosteroids, the current study demonstrated significant overuse of serotonin antagonists for prophylaxis of delayed CINV

Aims: The importance of polymorphisms in the dihydropyrimidine dehydrogenase gene (DPYD) for the prediction of severe toxicity in 5-fluorouracil (5-FU)-based chemotherapy is still unclear. This study aims to assess the predictive value of DPYD variation with respect to previously described DPYD variants for 5-FU toxicity. It represents the first analysis of the gene at the haplotype level, also capturing potentially important genetic variation located outside the coding regions of DPYD. Materials & methods: The entire coding sequence and exon-flanking intronic regions of DPYD were sequenced in 111 cancer patients receiving fluoropyrimidine-based chemotherapy. DPYD haplotypes were inferred and their associations with severe 5-FU toxicity were assessed. Results: None of the previously described deleterious variants (IVS14+1G>A, c.2846A>T and c.1679T>G) were detected in 24 patients who experienced severe 5-FU toxicity. A potential association was observed between a haplotype containing three novel intronic polymorphisms (IVS5+18G>A, IVS6+139G>A and IVS9–51T>G) and a synonymous mutation (c.1236G>A), which was observed five- out of eight-times in patients with severe adverse effects. Conclusion: The association of a haplotype containing no nonsynonymous or splice-site polymorphisms indicates that additional important genetic variation may be located in noncoding gene regions. Furthermore, a comparison with other studies suggests that the relative importance of particular DPYD mutations (IVS14+1G>A and c.2846A>T) for predicting severe 5-FU toxicity differs geographically across Europe.

Quality of life (QL) is an important consideration when comparing adjuvant therapies for early breast cancer, especially if they differ substantially in toxicity. We evaluated QL and Q-TWiST among patients randomised to adjuvant dose-intensive epirubicin and cyclophosphamide administered with filgrastim and progenitor cell support (DI-EC) or standard-dose anthracycline-based chemotherapy (SD-CT). We estimated the duration of chemotherapy toxicity (TOX), time without disease symptoms and toxicity (TWiST), and time following relapse (REL). Patients scored QL indicators. Mean durations for the three transition times were weighted with patient reported utilities to obtain mean Q-TWiST. Patients receiving DI-EC reported worse QL during TOX, especially treatment burden (month 3: P