Search

Electrochemotherapy (ECT) is a treatment for both primary and secondary cutaneous tumours. The international Network for sharing practices on ECT group investigates treatment outcomes after ECT using a common database with defined parameters.Twenty-eight centres across Europe prospectively uploaded data over an 11-year period. Response rates were investigated in relation to primary diagnosis, tumour size, choice of electrode type, route of bleomycin administration, electrical parameters recorded and previous irradiation in the treated field.Nine hundred eighty-seven patients, with 2482 tumour lesions were included in analysis. The overall response (OR) rate was 85% (complete response [CR]: 70%, partial response rate: 15%, stable disease: 11%, and progressive disease: 2%). For different histologies, OR and CR rates for metastases of malignant melanoma were 82% and 64%, basal cell carcinoma were 96% and 85%, breast cancer metastases were 77% and 62%, squamous cell carcinoma were 80% and 63% as well as Kaposi's sarcoma were 98% and 91%, respectively. Variance was demonstrated across histotypes (p 0.0001) and in accordance with size of lesion treated (dichotomised at diameter of 3 cm (p 0.0001). Hexagonal electrodes were generally used for larger tumours, but for tumours up to 3 cm, linear array electrodes provided better tumour control than hexagonal electrodes (80%:74%, p 0.003). For tumours more than 2 cm, intravenous administration was superior to intratumoural (IT) administration (p 0.05). Current recorded varied across tumour histologies and size but did not influence response rate. In previously irradiated areas, responses were selectively lower for IT administration.These cumulative data endorse efficiency of ECT across a broad range of histotypes. Analysis of 2482 lesions details subgroup analysis on treatment response informing future treatment choices.

Background In the phase III IMpassion130 trial, combining atezolizumab with first-line nanoparticle albumin-bound-paclitaxel for advanced triple-negative breast cancer (aTNBC) showed a statistically significant progression-free survival (PFS) benefit in the intention-to-treat (ITT) and programmed death-ligand 1 (PD-L1)-positive populations, and a clinically meaningful overall survival (OS) effect in PD-L1-positive aTNBC. The phase III KEYNOTE-355 trial adding pembrolizumab to chemotherapy for aTNBC showed similar PFS effects. IMpassion131 evaluated first-line atezolizumab–paclitaxel in aTNBC. Patients and methods Eligible patients [no prior systemic therapy or ≥12 months since (neo)adjuvant chemotherapy] were randomised 2:1 to atezolizumab 840 mg or placebo (days 1, 15), both with paclitaxel 90 mg/m2 (days 1, 8, 15), every 28 days until disease progression or unacceptable toxicity. Stratification factors were tumour PD-L1 status, prior taxane, liver metastases and geographical region. The primary endpoint was investigator-assessed PFS, tested hierarchically first in the PD-L1-positive [immune cell expression ≥1%, VENTANA PD-L1 (SP142) assay] population, and then in the ITT population. OS was a secondary endpoint. Results Of 651 randomised patients, 45% had PD-L1-positive aTNBC. At the primary PFS analysis, adding atezolizumab to paclitaxel did not improve investigator-assessed PFS in the PD-L1-positive population [hazard ratio (HR) 0.82, 95% confidence interval (CI) 0.60-1.12; P = 0.20; median PFS 6.0 months with atezolizumab–paclitaxel versus 5.7 months with placebo–paclitaxel]. In the PD-L1-positive population, atezolizumab–paclitaxel was associated with more favourable unconfirmed best overall response rate (63% versus 55% with placebo–paclitaxel) and median duration of response (7.2 versus 5.5 months, respectively). Final OS results showed no difference between arms (HR 1.11, 95% CI 0.76-1.64; median 22.1 months with atezolizumab–paclitaxel versus 28.3 months with placebo–paclitaxel in the PD-L1-positive population). Results in the ITT population were consistent with the PD-L1-positive population. The safety profile was consistent with known effects of each study drug. Conclusion Combining atezolizumab with paclitaxel did not improve PFS or OS versus paclitaxel alone. ClinicalTrials.gov NCT03125902.

Background The phase III CLinical Evaluation Of Pertuzumab And TRAstuzumab (CLEOPATRA) trial established the combination of pertuzumab, trastuzumab and docetaxel as standard first-line therapy for human epidermal growth factor receptor 2 (HER2)-positive locally recurrent/metastatic breast cancer (LR/mBC). The multicentre single-arm PERtUzumab global SafEty (PERUSE) study assessed the safety and efficacy of pertuzumab and trastuzumab combined with investigator-selected taxane in this setting. Patients and methods Eligible patients with inoperable HER2-positive LR/mBC and no prior systemic therapy for LR/mBC (except endocrine therapy) received docetaxel, paclitaxel or nab-paclitaxel with trastuzumab and pertuzumab until disease progression or unacceptable toxicity. The primary endpoint was safety. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). Prespecified subgroup analyses included subgroups according to taxane, hormone receptor (HR) status and prior trastuzumab. Exploratory univariable analyses identified potential prognostic factors; those that remained significant in multivariable analysis were used to analyse PFS and OS in subgroups with all, some or none of these factors. Results Of 1436 treated patients, 588 (41%) initially received paclitaxel and 918 (64%) had HR-positive disease. The most common grade ≥3 adverse events were neutropenia (10%, mainly with docetaxel) and diarrhoea (8%). At the final analysis (median follow-up: 5.7 years), median PFS was 20.7 [95% confidence interval (CI) 18.9-23.1] months overall and was similar irrespective of HR status or taxane. Median OS was 65.3 (95% CI 60.9-70.9) months overall. OS was similar regardless of taxane backbone but was more favourable in patients with HR-positive than HR-negative LR/mBC. In exploratory analyses, trastuzumab-pretreated patients with visceral disease had the shortest median PFS (13.1 months) and OS (46.3 months). Conclusions Mature results from PERUSE show a safety and efficacy profile consistent with results from CLEOPATRA and median OS exceeding 5 years. Results suggest that paclitaxel is a valid alternative to docetaxel as backbone chemotherapy. Exploratory analyses suggest risk factors that could guide future trial design.

Background: In the pivotal BOLERO-2 trial, everolimus (EVE) + exemestane (EXE) more than doubled the median progression-free survival (PFS) vs EXE alone in hormone receptor positive (HR+), human epidermal growth factor-receptor 2-negative (HER2-) advanced breast cancer (ABC) recurring/progressing on/after prior non-steroidal aromatase inhibitors (NSAIs). BRAWO is a German non-interventional study conducted in patients (pts) with HR+, HER2–ABC receiving EVE + EXE, according to Summary of Product Characteristics (SmPC), in routine clinical practice. Here we report the final PFS and safety results. Methods: This multicenter study documented 2100 pts between October 2012 and December 2017 across 341 sites in Germany. Postmenopausal women with HR+, HER2– ABC with recurrence or progression after a NSAI were included. Primary observation parameters included the evaluation of the effectiveness of EVE + EXE used in routine care for the entire pt group. Results: In the final analysis, out of the 2100 documented pts, 2074 were included in the full analysis set. The median time since the primary diagnosis was 7.1 years and the median time from first sign of relapse (local recurrence or distant metastases) was 2.1 years. At baseline, 54.1% of pts presented with visceral metastases and 50.1% had an ECOG performance status of 0. Approximately, 63% of pts started with EVE 10 mg (median duration of exposure: 5.1 months; 95% CI, 4.6-5.4), while 34.1% started with EVE 5 mg (median duration of exposure: 4.6 months; 95% CI, 4.1-5.2). The distribution of treatment lines was as follows: first line, 28.7% (n=595); second line, 31.9% (n=662); third line, 18.1% (n=376); fourth line, 10.7% (n=221) and, fifth line and later, 10.6% (n=220). Treatment was discontinued by 55.7% of pts (n=1170) due to progressive disease and 26% of pts (n=546) due to adverse events. The Kaplan-Meier estimate of the median PFS was 6.6 months (95% CI, 6.2-7.0). The best overall responses, based on clinical routine, were complete response, 0.8% (n=17), partial response, 7.4% (n=150), and stable disease, 41.3% (n=842). The general safety profile was consistent with the previously reported safety findings. The most common adverse events were stomatitis (any grade: 42.6%, grade 3: 3.8%, grade 4: Conclusions: Data from BRAWO support EVE + EXE as a suitable treatment option with a reasonable safety profile for HR+, HER2− ABC recurring or progressing on/after prior NSAIs. Citation Format: Lüftner D, Schuetz F, Schneeweiss A, Grischke E-M, Bloch W, Decker T, Uleer C, Salat C, Förster F, Schmidt M, Mundhenke C, Tesch H, Jackisch C, Fischer T, Guderian G, Hanson S, Fasching P. Everolimus + exemestane for HR+ advanced breast cancer in routine clinical practice- Final results from the non-interventional trial, BRAWO [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 P6-18-08.

Background Talazoparib (1 mg/day) exhibited promising efficacy and safety in patients with advanced breast cancer during ABRAZO (NCT02034916); this study evaluated patient-reported outcomes (PROs). Patients and methods ABRAZO is a two-cohort, two-stage, phase 2 study of talazoparib in patients with advanced breast cancer after a response to prior platinum-based therapy (cohort 1 [C1], n = 49) or ≥3 platinum-free cytotoxic-based regimens (cohort 2 [C2], n = 35). PROs were assessed on day 1 (baseline), every 6 weeks for an initial 24 weeks, and every 12 weeks thereafter until progression, using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (QLQ-C30) and its breast cancer module, QLQ-BR23. Results Global health status/quality of life (GHS/QoL) was maintained from baseline across all time points for both C1 and C2. For C1 and C2, median time to deterioration (TTD) of GHS/QoL (95% confidence interval [CI]) was 2.8 (2.1, 3.0) and 5.5 (4.2, 5.7) months, respectively. Median TTD for all QLQ-C30 functional scales for C1 and C2 ranged 2.1–3.1 months and 4.2–5.6 months, respectively; median TTD for all QLQ-BR23 symptom scales ranged 2.6–4.0 months and 4.2–5.6 months, respectively. There were no statistically significant differences in estimated overall change from baseline in the GHS/QoL scale for both cohorts (C1: −2.6 [95% CI, −7.8, 2.5]; C2: 1.2 [95% CI, −5.5, 8.0]). Significant overall improvements in the breast symptoms and arm symptoms and the future perspective of patients in C1 and C2 were observed, despite the statistically significant and clinically meaningful overall deterioration among patients regarding their role functioning (in C1) and dyspnoea symptoms (in C2). Conclusion Despite the statistically significant and clinically meaningful overall deterioration among patients regarding their role functioning (in C1) and dyspnoea symptoms (in C2), patients in both C1 and C2 reported significant overall improvements in their breast symptoms, arm symptoms and future perspective, and their GHS/QoL was maintained from baseline.

This abstract was withdrawn by the authors.

Background: Talazoparib (TALA; 1 mg/d) was well tolerated and exhibited promising antitumor activity in ABRAZO, a 2-cohort, 2-stage, open-label phase 2 study (NCT02034916) in patients (pts) with locally advanced or metastatic breast cancer and gBRCA1/2 mutations following platinum-based therapy (cohort 1 [C1]) or ≥3 platinum-free cytotoxic-based regimens (cohort 2 [C2]). This analysis evaluates health-related quality of life (QoL) for both cohorts. Methods: QoL was assessed on day 1 (baseline) and every 6 weeks for the initial 24 weeks and every 12 weeks thereafter, or sooner if progression was clinically suspected, using the EORTC QLQ-C30 and its breast cancer module, QLQ-BR23. For all scales, results were summarized using descriptive statistics for each cohort and at each time point, based on Characters (max 3400 including title, body and table [including spaces]): 3363 No abbreviations in title; title sentence case; define acronyms; no figures Category: Psychosocial, QOL, and Educational Aspects – Other 2 observed values and changes from baseline (clinically meaningful defined as ≥10-point change from baseline). Time to deterioration (TTD; defined as ≥10-point decrease in global health status [GHS]/functional scales or increase in symptom scales) analyses using survival analysis methods were carried out on the GHS/functional scales of QLQ-C30 and symptom scales of QLQ-BR23. Results:GHS was maintained from baseline across all time points for both C1 and C2 except at week 24 in C2, when a statistically significant but not clinically meaningful improvement in GHS was observed. In C1, statistically significant and clinically meaningful improvement was observed at specific time points in 4 functional scales (body image, week 6; sexual functioning, week 24; sexual enjoyment, week 36; and future perspective, weeks 6, 18, and 24) and in 3 symptom scales (dyspnea, week 24; insomnia, week 24; and breast symptoms, weeks 6 and 36). Statistically significant and clinically meaningful deterioration in C1 was observed in 2 functional scales (emotional functioning, week 12 and end of treatment, and role functioning, end of treatment) and in 1 symptom scale (fatigue, week 6). In C2, statistically significant and clinically meaningful improvement was observed at specific time points in 4 functional scales (role functioning, week 24; social functioning, week 24; sexual enjoyment, week 18; and future perspective, weeks 6, 12, and 18) and in 5 symptom scales (nausea/vomiting, week 18; pain, weeks 12, 18, and 24; insomnia, week 24; breast symptoms, weeks 12 and 18; and arm symptoms, week 48). For C2, no statistically significant and clinically meaningful deterioration was observed for any functional or symptoms scales across all time points, except in the dyspnea symptom scale at week 18. For C1 and C2, the median (95% confidence interval) TTD of GHS was 2.8 (2.1-3.0) and 5.5 (4.2-5.7) months, respectively. The median TTD for all QLQ-C30 functional scales for C1 and C2 ranged 2.1-3.1 and 4.2-5.6 months, respectively; the median TTD for all QLQ-BR23 symptoms scales ranged 2.6-4.0 and 4.2-5.6 months, respectively. Conclusions: The QoL of TALA-treated patients during ABRAZO was maintained. QoL is being evaluated among atients with germline BRCA1/2 mutated advanced BC treated with TALA vs physician's choice chemotherapy in the phase 3 EMBRACA trial (NCT01945775). Citation Format: Hurvitz SA, Turner NC, Telli ML, Rugo HS, Mailliez A, Ettl J, Grischke E-M, Mina LA, Balmaña J, Fasching PA, Tudor C, Quek RGW, Hannah AL, Robson ME, Wardley AM. Health-related quality of life during a phase 2 study of talazoparib in patients with advanced breast cancer and germline BRCA1/2 mutations (ABRAZO) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-19-05.

Background: Talazoparib (TALA) is a dual-mechanism poly (ADP-ribose) polymerase (PARP) inhibitor that traps PARP on DNA. Efficacy results of this phase 2 trial were previously presented (Turner et al, ASCO 2017, abstract 1007). This study included sparse pharmacokinetic (PK) sampling for patients through cycle 4 of therapy. Exploratory analyses included assessment of exposure versus parameters of efficacy and safety. Methods: ABRAZO (NCT02034916) was a parallel-cohort, open-label phase 2 study of TALA (1 mg/d) following (i) platinum-based therapy (cohort 1) or (ii) ≥3 platinum-free cytotoxic-based regimens (cohort 2) in patients with locally advanced or metastatic breast cancer and germline BRCA1/2 mutation. Sparse PK sampling was performed on day 1 of cycles 1-4, consisting of a predose sample collected ≤60 minutes prior to dosing and 2 postdose samples collected ≥30 minutes after dosing (time of food ingestion prior to the dose was collected). The collection times of the 2 postdose samples were separated by ≥2 hours. Efficacy parameters included radiographic progression-free survival (rPFS) by central review and objective response rate (ORR). Safety parameters included incidence of overall adverse events (AEs) and grade ≥3 AEs. Individual AUCs (area under concentration-time curves) for exposure-response analyses were predicted by population PK analyses. Results: Patients were divided into AUC tertiles: low (median, 109.0 ng*hr/mL; n=27), intermediate (median, 170.8 ng*hr/mL; n=27), and high (median, 219.2 ng*hr/mL; n=27). Median rPFS was 5.3 months (95% confidence interval [CI], 3.1, 8.3) in the lowest AUC tertile, 5.6 months (95% CI, 3.7, 8.4) in the intermediate AUC tertile, and 5.3 months (95% CI, 3.9, 5.6) in the highest AUC tertile. The ORR was 22.2% (95% CI, 8.6, 42.3) in the lowest AUC tertile, 25.9% (95% CI, 11.1, 46.3) in the intermediate AUC tertile, and 37.0% (95% CI, 19.4, 57.6) in the highest AUC tertile. AEs of any grade were reported in 11 patients (40.7%) in the lowest AUC tertile, 21 patients (77.8%) in the intermediate AUC tertile, and 22 patients (81.5%) in the highest AUC tertile. Grade ≥3 AEs were reported in 8 patients (29.6%) in the lowest AUC tertile and in 18 patients (66.7%) in the intermediate and highest AUC tertiles. The most common AEs in all 3 exposure tertiles were anemia, thrombocytopenia, and neutropenia. Conclusions: Median rPFS did not change with increasing systemic exposure. There may be a trend to higher ORR in patients with highest systemic exposure. A larger percentage of patients experienced AEs with elevated systemic exposure. Increased response rates with greater exposure does not translate to improved rPFS. These results should be interpreted with caution due to the low patient numbers in each cohort. Citation Format: Telli ML, Turner NC, Mailliez A, Ettl J, Grischke E-M, Mina LA, Balmaña J, Hurvitz SA, Wardley AM, Fasching PA, Tudor C, Nguyen L, Hannah AL, Robson ME, Rugo HS. ABRAZO: Exposure-efficacy and -safety analyses of breast cancer patients with germline BRCA1/2 mutations receiving talazoparib in a phase 2 open-label trial [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-14-03.

Response rates in HER2-overexpressing EBC treated with neoadjuvant chemotherapy and trastuzumab (T) have been improved by addition of pertuzumab (P). The prospective, phase II, neoadjuvant WSG-ADAPT HER2+/HR- trial assessed whether patients with strong early response to dual blockade alone might achieve pathological complete response (pCR) comparable to that of patients receiving dual blockade and chemotherapy. Female patients with HER2+/HR- EBC (M0) were randomized (5:2) to 12 weeks of T + P +/- weekly paclitaxel (pac) at 80 mg/m(2). Early response was defined as proliferation decrease a parts per thousand 30% of Ki-67 (versus baseline) or low cellularity (< 500 invasive tumor cells) in the 3-week biopsy. The trial was designed to test non-inferiority for pCR in early responding patients of the T + P arm versus all chemotherapy-treated patients. From February 2014 to December 2015, 160 patients were screened, 92 were randomized to T + P and 42 to T + P+pac. Baseline characteristics were well balanced (median age 54 versus 51.5 years, cT2 51.1 versus 52.4%, cN0 54.3 versus 61.9%);91.3% of patients completed T + P per protocol and 92.9% T + P+pac. The pCR rate in the T + P+pac arm was 90.5%, compared with 36.3% in the T + P arm as a whole. In the T + P arm, 24/92 were classified as non-responders, and their pCR rate was only 8.3% compared with 44.7% in responders (38/92) and 42.9% in patients with unclassified early response (30/92). No new safety signals were observed in the study population. Addition of taxane monotherapy to dual HER2 blockade in a 12-week neoadjuvant setting substantially increases pCR rates in HER2+/HR- EBC compared with dual blockade alone, even within early responders to dual blockade. Early non-response under dual blockade strongly predicts failure to achieve pCR.

Background: Immune and apoptosis biomarkers are potential prognostic/predictive markers in HER2+ EBC. High PD-L1 expression was shown to be predictive for lower pCR after chemotherapy+trastuzumab+/-pertuzumab, particularly in HER2+, ER- disease. Yet, HER2+ EBC co-expressing hormone receptors is a distinct entity. The ADAPT HER2+/HR+ phase II trial (n=376) compared 12 weeks of neoadjuvant T-DM1 + ET vs. trastuzumab (T)+ET and demonstrated pCR rates of about 41% in both (well tolerated) T-DM1 arms. Methods: In order to identify potential early predictors for pCR (i.e. no invasive tumor in breast and lymph nodes), immune markers (PDL1 on infiltrating immune cells (IIC) and on tumor cells (TC); CD8 in invasive margin and in tumor center) and apoptosis markers (bcl-2; mcl-2) were determined by immunohistochemistry (IHC; H-scores) in core biopsy sections obtained at primary diagnosis and at cycle 2. For multivariate logistic regression, each biomarker (separately), clinical factors (Ki-67, cT, cN) and therapy were entered. All analyses were exploratory. Results:Biomarkers were available in up to 326 patients (pts) at baseline and up to 170 pts at 3 weeks (due to low tumor content in 2nd core biopsy). Baseline IIC-PDL1 was associated with pCR in the T-DM1 arm (OR 2.89; 95%CI: 1.11-7.51); IIC-PDL1 at cycle 2 was not associated with pCR. PD-L1 expression in TC was rare (2%); cycle-2 TC-PD-L1 was associated with pCR in all pts and in the pooled TDM-1 arms. High baseline CD8 in tumor center was associated with pCR in the whole cohort (OR 2.4; CI: 1.04 – 5.5) and in the T+ET arm (OR=10.1; CI: 1.12 - 91.6) and at cycle 2 in all pts (OR=9.52; CI: 2.17 – 41), in pooled TDM-1 arms (OR=15.7; CI: 2.49 – 99), and in TDM-1+ET (OR=25.05; CI: 2.12 – 295). Increases in this marker also predicted pCR in all pts, pooled TDM-1, and in TDM-1+ET. Association of cycle-2 CD8 in tumor center with pCR persisted in multivariate models. Lower baseline CD8 in invasive margin was associated with pCR in the T-DM1 arm (OR=0.09; CI: 0.01-0.69), but at cycle 2 in all pts (OR=18.1; CI: 1.60 – 204) and in pooled TDM-1 arms (OR=23.5; CI: 1.1 - 500). This positive impact persisted in multivariate models. Bcl-2 expression at baseline was associated with non-pCR in all pts (OR=0.28, CI: 0.12 - 0.66), in the pooled T-DM1 arms (OR=0.216, CI: 0.08 - 0.61), and particularly in the T-DM1+ET arm (OR=0.14; CI: 0.03 - 0.71). This association persisted in multivariate analysis. At cycle 2, lower bcl-2 had OR=0.16 (CI: 0.03 - 0.96) in the pooled T-DM1 arms. No association with efficacy was seen for mcl-1. Conclusions: The WSG-ADAPT HER2+/HR+ phase II trial is the first international trial to focus on HER2+/HR+ EBC alone and the first to show substantial pCR rates of > 40% after only 12 weeks of T-DM1 -- without standard chemotherapy. Expression of bcl-2 may affect resistance to T-DM1. High immune activity at baseline and/or cycle 2 seems to be associated with pCR. The association of CD8 expression and its changes with therapy efficacy is complex and could depend on ET. Further biomarker analyses are ongoing and will be presented at the meeting. Citation Format: Harbeck N, Nitz UA, Matthias C, Kates R, Braun M, Kümmel S, Schumacher C, Potenberg J, Kraemer S, Kleine-Tebbe A, Augustin D, Aktas B, Forstbauer H, Tio J, Liedtke C, Grischke E-M, de Haas SL, Deurloo R, Schumacher J, Wuerstlein R, Kreipe HH, Gluz O. The role of immune and apoptosis markers for prediction of pCR in the WSG-ADAPT HER2+/HR+ phase II trial evaluating 12-weeks of neoadjuvant TDM1 ± endocrine therapy (ET) versus T + ET in HER2-positive hormone-receptor-positive early breast cancer (EBC) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-09-05.

Background: In luminal early breast cancer (EBC) with limited nodal involvement, current guidelines recommend to use multigene assays in addition to conventional clinicopathological factors for decision making regarding adjuvant chemotherapy (CT). The WSG PRIME Study prospectively evaluated the impact of the 70-gene signature (MammaPrint®) and the corresponding molecular subtype (BluePrint®) on clinical therapy decisions in EBC. Methods: WSG PRIME recruited 452 consecutive patients (pts) in 34 centers with ER+ and/or PR+ HER- pN0-1 EBC (04/15-03/16). Of the 430 evaluable pts, 309 had pN0 and 121 pN1 disease; median age was 58 years (68% post-menopausal). MammaPrint®, TargetPrint®, and BluePrint® results were provided prospectively, after therapy decisions based on clinicopathological factors and/or local IHC (ER/PR/Ki67) had been ascertained. Results: The WSG PRIME study observed a switch in CT decisions based on the multigene test results of 28.4 % (95% CI 23.3-33.4%). In 57 pts (13.3%), the decision switched from CT to no-CT, in 65 (15.1%) from no-CT to CT; in 107 (24.9%) pts a CT decision and in 201 (46.7%) a no-CT decision was maintained. Physicians strongly adhered to test results, most notably when initial CT recommendation was discordant with the test: 62/72 (86.1%) switched from no-CT to CT following MammaPrint® high risk, with 84.7% in N0 and 92.3% in N1. For MammaPrint® low risk, 56/80 (70%) switched from CT to no-CT; this percentage was similar in pN0 and pN1. Overall adherence (all pts) was 92.9% (CT) for high risk and 90.1% (no-CT) for low risk. Regarding subtype, 1/430 tumors was classified as HER2-enriched by BluePrint®; of the 6 basal-like tumors by IHC, 2 were molecularly re-classified as luminal A and 4 as luminal B. Of the 424 luminal-A/-B-like tumors by IHC, only 283 (66.7%) were subtyped concordantly by BluePrint®; 40% (61/152) of the luminal-B-like tumors were re-classified as luminal A and 29% (79/272) of the luminal-A-like tumors were re-classified as luminal B. Switches in CT decisions were strongly impacted by molecular subtype, with 142/152 (93.4%) of molecular luminal B pts eventually scheduled for CT and 247/272 (90.8%) of molecular luminal A pts for no-CT. After the test results, physicians' confidence in their therapy decision increased in 141 (32.9%) of the cases. Conclusions: In a decision impact study, the true percentage of CT saved by a prognostic test depends on cohort characteristics. Yet, the WSG PRIME study showed that the70-gene signature (MammaPrint®) and the corresponding molecular subtype (BluePrint®) strongly impacted clinical therapy decisions in EBC with up to 3 involved lymph nodes. There was a substantial discordance between clinical and molecular luminal subtypes. After receiving the test results, physicians focused their indications for adjuvant CT on MammaPrint high-risk luminal-B-like tumors. Where test results were discordant with clinical assessment, physicians mostly omitted CT in MammaPrint low risk patients. Recently, the prospective MINDACT trial had shown that this did not compromise outcome.Background: In luminal early breast cancer (EBC) with limited nodal involvement, current guidelines recommend to use multigene assays in addition to conventional clinicopathological factors for decision making regarding adjuvant chemotherapy (CT). The WSG PRIME Study prospectively evaluated the impact of the 70-gene signature (MammaPrint®) and the corresponding molecular subtype (BluePrint®) on clinical therapy decisions in EBC. Methods: WSG PRIME recruited 452 consecutive patients (pts) in 34 centers with ER+ and/or PR+ HER- pN0-1 EBC (04/15-03/16). Of the 430 evaluable pts, 309 had pN0 and 121 pN1 disease; median age was 58 years (68% post-menopausal). MammaPrint®, TargetPrint®, and BluePrint® results were provided prospectively, after therapy decisions based on clinicopathological factors and/or local IHC (ER/PR/Ki67) had been ascertained. Results: The WSG PRIME study observed a switch in CT decisions based on the multigene test results of 28.4 % (95% CI 23.3-33.4%). In 57 pts (13.3%), the decision switched from CT to no-CT, in 65 (15.1%) from no-CT to CT; in 107 (24.9%) pts a CT decision and in 201 (46.7%) a no-CT decision was maintained. Physicians strongly adhered to test results, most notably when initial CT recommendation was discordant with the test: 62/72 (86.1%) switched from no-CT to CT following MammaPrint® high risk, with 84.7% in N0 and 92.3% in N1. For MammaPrint® low risk, 56/80 (70%) switched from CT to no-CT; this percentage was similar in pN0 and pN1. Overall adherence (all pts) was 92.9% (CT) for high risk and 90.1% (no-CT) for low risk. Regarding subtype, 1/430 tumors was classified as HER2-enriched by BluePrint®; of the 6 basal-like tumors by IHC, 2 were molecularly re-classified as luminal A and 4 as luminal B. Of the 424 luminal-A/-B-like tumors by IHC, only 283 (66.7%) were subtyped concordantly by BluePrint®; 40% (61/152) of the luminal-B-like tumors were re-classified as luminal A and 29% (79/272) of the luminal-A-like tumors were re-classified as luminal B. Switches in CT decisions were strongly impacted by molecular subtype, with 142/152 (93.4%) of molecular luminal B pts eventually scheduled for CT and 247/272 (90.8%) of molecular luminal A pts for no-CT. After the test results, physicians' confidence in their therapy decision increased in 141 (32.9%) of the cases. Conclusions: In a decision impact study, the true percentage of CT saved by a prognostic test depends on cohort characteristics. Yet, the WSG PRIME study showed that the70-gene signature (MammaPrint®) and the corresponding molecular subtype (BluePrint®) strongly impacted clinical therapy decisions in EBC with up to 3 involved lymph nodes. There was a substantial discordance between clinical and molecular luminal subtypes. After receiving the test results, physicians focused their indications for adjuvant CT on MammaPrint high-risk luminal-B-like tumors. Where test results were discordant with clinical assessment, physicians mostly omitted CT in MammaPrint low risk patients. Recently, the prospective MINDACT trial had shown that this did not compromise outcome. Citation Format: Wuerstlein R, Gluz O, Kates R, Persoon M, Wasmayr M, Knauer M, Koplmüller R, Grischke E-M, Schem C, Thill M, Hasmueller S, Griesinger F, Koehler A, Otremba B, Schindlbeck C, Reimer T, Krauter J, Tome O, Otto F, Friedrichs K, Albert U-S, Gebauer G, Nitz U, Harbeck N. Results of multigene assay (MammaPrint®) and molecular subtyping (BluePrint®) substantially impact treatment decision making in early breast cancer: Final analysis of the WSG PRIME decision impact study [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-09-10.

Background: The addition of first-line ribociclib (RIB; cyclin-dependent kinase 4/6 inhibitor) to letrozole (LET) significantly improved progression-free survival (PFS) compared with placebo (PBO) + LET in patients (pts) with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) advanced breast cancer (ABC) in the Phase III MONALEESA-2 study. Identifying biomarkers that predict response to treatment remains a key challenge in pts with HR+ ABC. Here we analyze results from MONALEESA-2 by molecular alterations detected in circulating tumor DNA (ctDNA) at baseline, including PIK3CA mutations and other alterations considered to be important in HR+ ABC. Methods: Postmenopausal women (N=668) with HR+, HER2– ABC who had not received any prior therapy for ABC were randomized 1:1 to RIB (600 mg/day; 3-weeks-on/1-week-off) + LET (2.5 mg/day; continuous) or PBO + LET. The primary endpoint was PFS. Biomarker analysis of the ctDNA mutation profile was an exploratory endpoint. Plasma samples for ctDNA analysis were collected at baseline and end of treatment. ctDNA was analyzed using next-generation sequencing with a targeted panel of ˜550 genes. Results: Baseline ctDNA was successfully sequenced in 494 pts (RIB + LET: n=212; PBO + LET: n=215); 67 (14%) of 494 pts were removed from the analysis due to limited tumor DNA in circulation. 427 (86%) pts had ≥1 alteration, including 1,573 mutations, 513 short insertions/deletions, 166 amplifications, and 8 translocations. Alterations (frequency) were commonly observed in the following genes: PIK3CA (33%), TP53 (12%), ZNF703/FGFR1 (5%), and ESR1 (4%), and in genes involved in receptor tyrosine kinase (RTK) signaling (12%). RIB + LET treatment benefit was consistent in pts with wild-type (WT) and altered PIK3CA, and in pts with WT and altered TP53 (Table). RIB + LET improved PFS regardless of RTK or ZNF703/FGFR1 alterations. However, there was a weak trend for increased benefit in pts with WT vs altered RTK genes and in pts with WT vs altered ZNF703/FGFR1 genes. These results should be interpreted with caution due to the small number of pts with these alterations. There were too few ESR1 alterations for firm conclusions to be drawn. Events, n/NMedian PFS, months Gene(s)RIB + LETPBO + LETRIB + LETPBO + LETHazard ratio (95% confidence interval)PIK3CAWT54/14393/14229.614.70.44 (0.31–0.62)Altered40/6955/7319.212.70.53 (0.35–0.81)TP53WT72/180129/19427.614.70.44 (0.33–0.59)Altered22/3219/2110.25.50.43 (0.23–0.83)ZNF703/FGFR1WT88/202139/20524.814.60.47 (0.36–0.62)Altered6/109/1010.611.40.73 (0.23–2.29)RTKWT81/189128/18724.814.40.46 (0.35–0.61)Altered13/2320/2821.311.40.72 (0.34–1.53) Conclusions: Consistent RIB + LET treatment benefit was observed compared with PBO + LET, irrespective of the status of baseline ctDNA biomarkers. Citation Format: Hortobagyi GN, Stemmer S, Campone M, Sonke GS, Arteaga CL, Paluch-Shimon S, Petrakova K, Villanueva C, Nusch A, Grischke E-M, Chan A, Jakobsen E, Marschner N, Hart LL, Alba E, Ohnstand HO, Blau S, Yardley DA, Solovieff N, Su F, Germa C, Yap Y-S. First-line ribociclib + letrozole in hormone receptor-positive, HER2-negative advanced breast cancer: Efficacy by baseline circulating tumor DNA alterations in MONALEESA-2 [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD4-06.

Purpose: The WSG-PRIMe Study prospectively evaluated the impact of the 70-gene signature MammaPrint® (MP) and the 80-gene molecular subtyping assay BluePrint® on clinical therapy decisions in luminal early breast cancer. Methods: 452 hormone receptor (HR)-positive and HER2-negative patients were recruited (N0, N1). Physicians provided initial therapy recommendations based on clinicopathological factors. After prospective risk classification by MammaPrint/BluePrint was revealed, post-test treatment recommendations and actual treatment were recorded. Decisional Conflict and anxiety were measured by questionnaires. Results: Post-test switch (in chemotherapy (CT) recommendation) occurred in 29.1% of cases. Overall, physician adherence to MP risk assessment was 92.3% for low-risk and 94.3% for high-risk MP scores. Adherence was remarkably high in “discordant” groups: 74.7% of physicians initially recommending CT switched to CT omission following low-risk MP scores; conversely, 88.9% of physicians initially recommending CT omission switched to CT recommendations following high-risk MP scores. Most patients (99.2%) recommended to forgo CT post-test and 21.3% of patients with post-test CT recommendations did not undergo CT; among MP low-risk patients with pre-test and post-test CT recommendations, 40% did not actually undergo CT. Luminal subtype assessment by BluePrint was discordant with IHC assessment in 34% of patients. Patients’ State Anxiety scores improved significantly overall, particularly in MP low-risk patients. Trait Anxiety scores increased slightly in MP high risk and decreased slightly in MP low-risk patients. Conclusions: MammaPrint and BluePrint test results strongly impacted physicians’ therapy decisions in luminal EBC with up to three involved lymph nodes. The high adherence to genetically determined risk assessment represents a key prerequisite for achieving a personalized cost-effective approach to disease management of early breast cancer.

Background This multicenter, double-blind phase II study assessed the antitumor activity and toxicity profile of docetaxel with the antiangiogenic multikinase inhibitor sorafenib or matching placebo as a first-line treatment in patients with metastatic or locally advanced HER2-negative breast cancer. Patients and methods Patients were randomized 1:1 to receive docetaxel 100 mg/m2 on day 1 every 3 weeks in combination with sorafenib 400 mg bid or placebo on days 2–18 of each cycle until tumor progression, or unacceptable toxicity. Sorafenib/placebo could be continued at the investigator's discretion if docetaxel was stopped due to toxicity. Primary endpoint was progression free survival (PFS). Results From October 2008 to December 2013, 102 patients were randomized; 98 patients were evaluable. The trial was prematurely terminated due to slow accrual. Due to increased toxicity the dose of docetaxel was reduced to 75 mg/m2 and an increasing sorafenib dosing schedule was implemented as part of a protocol amendment. The addition of sorafenib to docetaxel did not improve PFS (8.2 vs. 7.3 months for docetaxel/placebo; HR 0.84, log rank p = 0.43), but led to higher rates of early treatment discontinuation. There were no statistically significant differences between sorafenib dosing schedules. Conclusions Addition of sorafenib to taxane-based first-line chemotherapy in patients with metastatic breast cancer failed to improve PFS and resulted in increased toxicity.

Background Previous data has shown that chemotherapy (CT)-induced amenorrhea was associated with a better DFS and OS in premenopausal patients with EBC, regardless of the hormone-receptor status (Swain et al. NEJM 2010 ). Methods 740 patients (pts) aged ≤45yrs treated with anthracycline/taxane-based CT for EBC from 4 German neo-/adjuvant trials were included. Centrally assessed estradiol and follicle-stimulating hormone (FSH) in paired blood samples collected at baseline and 4 weeks after the last therapy infusion were considered. CIOF was defined as estradiol 12.4IU/l after CT for those pts with premenopausal hormone levels at baseline. 4-year DFS and OS (rate, hazard ratio (HR) and 95% confidence interval (CI)) overall and in subgroups by hormone-receptor status (positive, negative) and age (≤30, 31-35, 36-40, >40yrs) are presented. Results Median follow-up was 49.6 (range 48.8-50.3) months. 4-year DFS and OS rates as well as HR overall and in subgroups are presented in the Table below. Pts with CIOF had a better DFS compared to pts without CIOF (HR=0.47, 95%CI 0.31-0.71). The DFS advantage was significant in pts with hormone-receptor positive (HR=0.38, 95%CI 0.22-0.64) EBC. A trend towards a better OS was observed only for pts with hormone-receptor positive EBC (HR=0.45, 95%CI 0.19-1.05). Within age groups, CIOF showed a statistically significant improvement in DFS only in women ≤30yrs (HR=0.21, 95%CI 0.05-0.97). No statistically significant OS benefit was observed in any of the age groups. Only pts >40yrs showed a trend towards a better OS (HR=0.35, 95%CI 0.11-1.16).Table180PDTableDFSOS4-year ratelog rank p-valueHR [95% CI]4-year ratelog rank p-valueHR [95% CI]CIOFno CIOFCIOFno CIOFoverall (n=740)84.465.0 40 (n=373)85.765.00.2070.53 [0.19-1.45]92.481.30.0720.35 [0.11-1.16] Conclusions Pts with CIOF after anthracycline/taxane-based CT for EBC show a better DFS, especially in women with hormone-receptor positive EBC or younger than 30 years. The improvement in DFS translates in a survival advantage in pts with hormone-receptor positive EBC. Legal entity responsible for the study German Breast Group (GBG). Funding The study was supported by Walter Schulz Stiftung. Disclosure A. Schneeweiss: Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Celgene; Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Research grant / Funding (institution): AbbVie; Research grant / Funding (institution): Molecular Partner; Honoraria (self), Speaker Bureau / Expert testimony: AstraZeneca; Honoraria (self): Pfizer; Honoraria (self): Novartis; Honoraria (self): MSD Oncology; Honoraria (self): Tesaro; Honoraria (self), Travel / Accommodation / Expenses: Lilly. C. Denkert: Shareholder / Stockholder / Stock options: Sividon Diagnostics; Honoraria (self): Teva; Honoraria (self): Novartis; Honoraria (self): Pfizer; Honoraria (self): Roche; Honoraria (self), Advisory / Consultancy: Amgen; Advisory / Consultancy: MSD Oncology; Advisory / Consultancy: Daiichi Sankyo; Licensing / Royalties: VMScope digital pathology software; Licensing / Royalties: Patent application: EP18209672 - cancer immunotherapy; Licensing / Royalties: Patent application EP20150702464 - therapy response; Licensing / Royalties: Patent application EP20150702464 - therapy response. M. Untch: Honoraria (institution), Non-remunerated activity/ies: Abbvie; Honoraria (institution), Non-remunerated activity/ies: Amgen GmbH; Honoraria (institution), Non-remunerated activity/ies: AstraZeneca; Honoraria (institution): BMS; Honoraria (institution), Non-remunerated activity/ies: Celgene GmbH; Honoraria (institution), Non-remunerated activity/ies: Daiji Sankyo; Honoraria (institution), Non-remunerated activity/ies: Eisai GmbH; Honoraria (institution), Non-remunerated activity/ies: Janssen Cilag; Honoraria (institution), Non-remunerated activity/ies: Lilly; Honoraria (institution), Non-remunerated activity/ies: MSD Merck; Honoraria (institution), Non-remunerated activity/ies: Mundipharma; Honoraria (institution), Non-remunerated activity/ies: Myriad Genetics; Honoraria (institution), Non-remunerated activity/ies: Odonate; Honoraria (institution), Non-remunerated activity/ies: Pfizer GmbH; Honoraria (institution): PUMA Biotechnology; Honoraria (institution), Non-remunerated activity/ies: Roche Pharma AG; Honoraria (institution), Non-remunerated activity/ies: Sanofi Aventis Deutschland GmbH; Honoraria (institution), Non-remunerated activity/ies: Sividon Diagnostics; Honoraria (institution), Non-remunerated activity/ies: TEVA Pharmaceuticals Ind Ltd; Honoraria (institution), Non-remunerated activity/ies: Novartis. P.A. Fasching: Honoraria (self), Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Biontech; Honoraria (self): Roche; Honoraria (self): Pfizer; Honoraria (self): Celgene; Honoraria (self): Daiichi-Sankyo; Honoraria (self): TEVA; Honoraria (self): AstraZeneca; Honoraria (self): Merck Sharp & Dohme; Honoraria (self): Myelo Therapeutics; Honoraria (self): Macrogenics; Honoraria (self): Eisai; Honoraria (self): PUMA; Research grant / Funding (institution): Cepheid. F. Marme: Honoraria (self): Roche; Honoraria (self): AstraZeneca; Honoraria (self): Pfizer; Honoraria (self): Tesaro; Honoraria (self): Novartis; Honoraria (self): Amgen; Honoraria (self): PharmaMar; Honoraria (self): GenomicHealth; Honoraria (self): CureVac; Honoraria (self): EISAI; Honoraria (self): Clovis; Honoraria (self): Celgene. M. van Mackelenbergh: Honoraria (self): AstraZeneca; Honoraria (self): Novartis; Honoraria (self): Amgen. V. Muller: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Amgem; Honoraria (self), Speaker Bureau / Expert testimony: AstraZeneca; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Diichi-Sankyo; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Eisai; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Novartis; Honoraria (self), Speaker Bureau / Expert testimony: Pfizer; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Roche; Honoraria (self), Speaker Bureau / Expert testimony: Celgene; Honoraria (self), Speaker Bureau / Expert testimony: Teva; Honoraria (self), Speaker Bureau / Expert testimony: Janssen-Cilag; Honoraria (self), Advisory / Consultancy: Genomic Health; Honoraria (self), Advisory / Consultancy: Hexal; Honoraria (self), Advisory / Consultancy: Pierre Fabre; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy: Lilly; Honoraria (self), Advisory / Consultancy: Tesaro; Honoraria (self), Advisory / Consultancy: Nektar; Research grant / Funding (institution): Seattle Genetics. S. Loibl: Research grant / Funding (institution): Roche; Research grant / Funding (institution): AbbVie; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Celgene; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Seattle Genetics; Research grant / Funding (institution): Teva; Research grant / Funding (institution): Vifor; Research grant / Funding (institution): PRIME; Research grant / Funding (institution): Daiichi; Licensing / Royalties: EP14153692.0 pending. All other authors have declared no conflicts of interest.

Background Loss-of-function mutations in genes encoding components of the homologous recombination (HR) machinery are associated with tumor sensitivity to poly (ADP-ribose) polymerase (PARP) inhibitors. In ABRAZO, the PARP inhibitor talazoparib demonstrated encouraging efficacy in gBRCA-mutated ABC, both in pts whose cancer responded to prior platinum therapy (cohort 1) and in pts who had received ≥3 prior nonplatinum chemotherapy regimens for ABC (cohort 2). Methods Baseline tumor tissue (primary or metastatic sites) from enrolled pts was sequenced using the FoundationOne CDx NGS panel. 60/84 pts (71%) in the intent-to-treat population had available tumor tissue, which could be sequenced. Mutations summarized below were known or likely pathogenic single-nucleotide variants, insertions, deletions, or rearrangements. Additional exploratory computational analyses pertinent to HR deficiency were performed, including genomic loss of heterozygosity (gLOH) and somatic-germline-zygosity assessments. Results Tumor mutations in BRCA1 and BRCA2 were detected in 29 (48%) and 28 (47%) of 60 evaluable pts (no pts exhibited mutations in both BRCA1 and BRCA2). These mutations were most commonly single-nucleotide variants (BRCA1: 12 [20%] and BRCA2: 10 [17%]) or deletions (BRCA1: 11 [18%] and BRCA2: 12 [20%]). Mutations in other genes implicated in HR were comparatively rare, with mutations in CHEK2 (2 pts), ARID1A, ATR, BARD1, BRD4, BRIP1, FANCC, and STAG2 (each in single pts) detected. In addition to BRCA1/2, genes where mutations were detected in ≥ 10% of evaluable pts included TP53 (45%) and PIK3CA (12%). TP53 mutations were more commonly observed in BRCA1-mutated than in BRCA2-mutated tumors (22/29 [76%] compared with 4/28 [14%]). Associations of genetic/genomic events with progression-free survival will be presented. Conclusions NGS of tumors from the ABRAZO study of talazoparib in patients with gBRCA-mutated ABC revealed a complex mutational landscape. Exploratory correlative analyses are ongoing and will be reported. Clinical trial identification NCT02034916. Legal entity responsible for the study Pfizer Inc. Funding Pfizer Inc. Disclosure N.C. Turner: Advisory / Consultancy, Research grant / Funding (institution): Pfizer Inc.; Advisory / Consultancy, Research grant / Funding (institution): BioMarin. A..D. Laird: Full / Part-time employment: Pfizer Inc. M.L. Telli: Advisory / Consultancy, Research grant / Funding (institution): Pfizer Inc.; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Tesaro; Advisory / Consultancy, Research grant / Funding (institution): PharmaMar; Advisory / Consultancy, Research grant / Funding (institution): Vertex; Research grant / Funding (institution): AbbVie; Research grant / Funding (institution): Biothera; Research grant / Funding (institution): Calithera Biosciences; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Medivation; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): OncoSec; Research grant / Funding (institution): Sanofi. H.S. Rugo: Research grant / Funding (institution): Eisai; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): GSK; Research grant / Funding (institution), Travel / Accommodation / Expenses: Lilly; Research grant / Funding (institution): MacroGenics; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): OBI Pharma; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Plexxikon; Travel / Accommodation / Expenses: Mylan; Travel / Accommodation / Expenses: Puma; Research grant / Funding (institution): Eisai; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (institution), Travel / Accommodation / Expenses: Lilly; Research grant / Funding (institution): MacroGenics; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): OBI Pharma; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Plexxikon; Travel / Accommodation / Expenses: Mylan; Travel / Accommodation / Expenses: Puma. A. Mailliez: Honoraria (self), Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Tesaro; Advisory / Consultancy, Research grant / Funding (institution): PharmaMar; Advisory / Consultancy: Vertex; Research grant / Funding (institution): AbbVie; Research grant / Funding (institution): Biothera; Research grant / Funding (institution): Calithera Biosciences; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Medivation; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): OncoSec; Research grant / Funding (institution): Pfizer Inc. J. Ettl: Honoraria (institution), Advisory / Consultancy: Lilly; Advisory / Consultancy, Travel / Accommodation / Expenses: Novartis; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; Honoraria (institution), Advisory / Consultancy: Roche; Advisory / Consultancy: Tesaro; Advisory / Consultancy: Eisai; Research grant / Funding (institution), Travel / Accommodation / Expenses: Celgene; Honoraria (self): TEVA; Honoraria (self): AstraZeneca. J. Balmana: Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZenca; Advisory / Consultancy: Clovis; Advisory / Consultancy: Tesaro; Advisory / Consultancy: BMS; Research grant / Funding (institution), Travel / Accommodation / Expenses: PharMar. P.A. Fasching: Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Novartis; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: Celgene; Honoraria (self), Advisory / Consultancy: Puma; Honoraria (self), Advisory / Consultancy: Daiichi Sankyo; Honoraria (self), Advisory / Consultancy: Eisai; Honoraria (self), Advisory / Consultancy: Merck; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Teva; Honoraria (self), Advisory / Consultancy: Hexal; Honoraria (institution), Speaker Bureau / Expert testimony: Myelo; Research grant / Funding (institution): BioNTech. S.A. Hurvitz: Research grant / Funding (institution): Ambryx; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): BI Pharma; Research grant / Funding (institution): Biomarin; Research grant / Funding (institution): Cascadian; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): Dignitana; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): GSK; Research grant / Funding (institution), Travel / Accommodation / Expenses: Lilly; Research grant / Funding (institution): Macrogenics; Research grant / Funding (institution): Medivation; Research grant / Funding (institution): Merrimack; Research grant / Funding (institution), Travel / Accommodation / Expenses: Novartis; Research grant / Funding (institution), Travel / Accommodation / Expenses: OBI Pharma; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Pieris; Research grant / Funding (institution): PUMA; Research grant / Funding (institution): Roche. L.A. Albacker: Full / Part-time employment: Foundation Medicine Inc. G.M. Frampton: Full / Part-time employment: Foundation Medicine Inc. J. Chelliserry: Shareholder / Stockholder / Stock options, Full / Part-time employment: Pfizer Inc. P. Bycott: Research grant / Funding (self), Shareholder / Stockholder / Stock options, Full / Part-time employment: Pfizer Inc. U. Conte: Shareholder / Stockholder / Stock options, Full / Part-time employment: Pfizer Inc. A.M. Wardley: Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Lilly; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Roche. M.E. Robson: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy: McKesson; Research grant / Funding (institution): AbbVie; Research grant / Funding (institution): BioMarin; Research grant / Funding (institution): Medivation; Research grant / Funding (institution): Myriad Genetics; Research grant / Funding (institution): Tesaro. All other authors have declared no conflicts of interest.

Background BRAWO is a German non-interventional study of 3000 patients (pts) with advanced/metastatic, hormone-receptor-positive and HER2-negative breast cancer treated with everolimus and exemestane (EVE+EXE). The pivotal BOLERO-2 trial demonstrated that adding EVE to EXE improved PFS over EXE and was generally well tolerated in elderly patients with HR+ advanced breast cancer (>65 years as well as >70 years). Here we describe data of elderly patients treated with EVE+EXE in daily clinical routine. Methods We report data of the 3rd preplanned interim analysis (IA) of the first 1300 pts documented in BRAWO. Patient and disease characteristics in elderly patients (≥ 70 years, n=485) and patients Results At time of data cut-off, 71% pts had discontinued the study, 29% were still ongoing. Patient and disease characteristics were comparable in both groups except for: median age (60y (range: 20-69y) vs. 75y (range 70-93y)), median time since 1st diagnosis (6.4y More patients in the older group received fulvestrant (20.6% vs. 16.2%), in the younger group more patients received chemotherapy (20.3% vs. 14.2%) as last antineoplastic therapy. In general, more patients in the older subgroup did not receive any chemotherapy as pretreatment (53.6% vs 40.2%). More patients in the subgroup ≥70y received 5mg EVE as starting dose (30.3% vs. 20.8%) and had 5mg as end dose (37.9% vs. 26.9%). Median PFS was 7.1 months in the overall population, 7.0 months (6.5, 8.0; 95%CI) for pts Table 1: Incidence and severity of stomatitis Patient Characteristics< 70 years (n=813)≥ 70 years (n=485)Stomatitis Number of patients with at least one Stomatitis Event (based on stomatitis questionnaires)339 (41.7%)200 (41.2%)Grade 1181 (22.3%)95 (19.6%)Grade 2119 (14.6%)79 (16.3%)Grade 319 (2.3%)11 (2.3%)unknown20 (2.5%)15 (3.1%)Number of Stomatitis Events431 (100.0%)252 (100%)Grade 1237 (55.0%)125 (49.6%)Grade 2136 (31.6%)87 (34.5%)Grade 319 (4.4%)13 (5.2%) Discussion The data described here show that EVE+EXE treatment is effective and safe for elderly patients in daily clinical routine. This is consistent with data from an exploratory analysis of the pivotal BOLERO-2 trial, where the same differences in baseline characteristics were observed for elderly pts compared to younger pts as in BRAWO. Efficacy was also comparable to elderly pts in BOLERO-2 (mPFS 6.8 months for EVE+EXE in pts ≥70 years). Citation Format: Tesch H, Grischke E-M, Fasching PA, Decker T, Uleer C, Schneeweiss A, Salat C, Wimberger P, Mundhenke C, Förster F, Kluth-Pepper B, Schubert J, Bloch W, Jackisch C, Schütz F, Lüftner D. Results of the 3rd interim analysis of the non-interventional trial BRAWO – Subanalysis of patients

Background: GAIN-2 compares the effectiveness and safety of a predefined intense dose-dense regimen (EnPC) vs. a dose-dense regimen with modification of single doses depending on individual hematological and non-hematological toxicities (dtEC-dtD) (NCT01690702). Moreover, the Trastuzumab substudy compares the subcutaneous administration of the drug to the abdominal wall vs. thigh. Methods: The primary objective of the GAIN-2 trial is to compare the invasive disease-free survival (iDFS) in patients with high-risk primary breast cancer (luminal A ≥4 N+; luminal B N+; HER2+ and TNBC N0/N+). Patients are randomized between EnPC (epirubicin 150 mg/m2 q2w x 3, nab-Paclitaxel 330 mg/m2 q2w x 3, cyclophosphamide 2000 mg/m2 q2w x 3) or dtEC-dtD (dd/tailored epirubicin/cyclophosphamide q2w x 4 followed by dd/tailored docetaxel q2w x 4) Two safety interim analyses after 200 (Noeding et al. Ann Oncol 2014) and 900 patients who have completed chemotherapy were planned. We present the results of the second safety analysis. In addition to the standard analyses for hematological and non-hematological toxicities, any affections of the cranial nerves as well as the rate of macula degenerations and anaphylactic reactions are of special interest. Results: Between 09/2012 and 05/2015 a total of 1473 patients have been randomized (EnPC n=734; dtEC-dtD n=739). Among those, 84 patients have been included in the trastuzumab substudy. No safety data are currently available for the substudy. Median age was 52 years and median body-mass-index 26. In terms of hematological adverse events, the rate of febrile neutropenia grade 3-4 (12% vs. 8%) and thrombopenia grade 3-4 (12% vs. 5%) was significantly increased in the EnPC arm. As for non-hematological side effects, there were significantly more patients developing an increase in alkaline phosphatase (59% vs. 40%), ALAT (69% vs. 59%), peripheral sensory neuropathy (83% vs. 68%), arthralgia (63% vs. 49%), myalgia (48% vs. 41%) and bone pain (25% vs. 17%) in the EnPC arm, whereas nosebleed (10% vs. 25%), edema (13% vs. 26%) and hand-foot syndrome (12% vs. 28%) were more common in the dtEC-dtD arm. We observed two treatment related deaths, both in the dtEC-dtD arm (cause of death: acute respiratory distress syndrome and pneumonia). There were no differences between the treatment arms for the toxicities of special interest. In the EnPC arm, overall 30% of the patients required dose-reductions due to hematological toxicities compared with only 10% in the dtEC-dtD arm (p Conclusion: This interim safety analysis from a prospectively randomized trial investigating iddEnPC with predefined doses and a toxicity adapted idd/tailored strategy (dtEC-dtD) showed no additional or unexpected safety signals in the iddEnPC or dtEC-dtD arm. Therefore, no modifications in the conduction of the study are necessary and the study continues as expected. Citation Format: Möbus V, Lück H-J, Forstbauer H, Wachsmann G, Ober A, Schneeweiss A, Christensen B, von Abel E, Grischke E-M, Höffkes H-G, Klare P, Yon-Dschun K, Schmatloch S, Furlanetto J, Burchardi N, von Minckwitz G, Loibl S. GAIN-2: Adjuvant phase III trial to compare intense dose-dense (idd) treatment with EnPC to tailored dose-dense (dt) therapy with dtEC-dtD for patients with high-risk early breast cancer: Results of the second safety interim analyses. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-13-05.

Background BRAWO is a German non-interventional study of 3000 patients (pts) with advanced/metastatic, hormone receptor positive and HER2 negative breast cancer treated with everolimus and exemestane (EVE+EXE). One of the objectives was the documentation of how stomatitis was managed and prevented in clinical routine. We report data of the 3rd preplanned interim analysis (IA) focusing on prophylaxis and management of stomatitis in daily clinical routine. Methods Here we report data of the first 1300 documented pts on efficacy and safety with focus on the adverse event stomatitis. Patient and treatment characteristics were associated with the occurrence of stomatitis. Furthermore chosen treatments for the management of stomatitis are described. Results At time of data cut-off 71% pts had discontinued the study, 29% were still under therapy. Patient and tumor characteristics were reported previously. The most commonly reported AEs of any grade were stomatitis (41.5%), fatigue (14.6%), nausea (12.2%), diarrhea (12.1%), dyspnea (11.3%). 75.2% of stomatitis events occurred during the first 5 weeks of treatment, regardless of the chosen starting dose 5 mg or 10 mg EVE per day. Median duration of a stomatitis episode was 28 days for 5 mg EVE start dose and 23 days for 10mg. However, there was a numerically lower stomatitis incidence and less severe intensity of stomatitis for a start dose of 5 mg vs 10 mg (Table 1). Table 1: Stomatitis incidence and severity by EVE start dose: Worst intensitiy of stomatitisTotal (n=1300)Start dose 5mg (n=316)Start dose 10mg (n=975)Other* (n=9)Number (%) of pts with at least one stomatitis event (any grade)513 (41.5)115 (36.4)421 (43.2)3 (33.3)Grade 1276 (21.2)73 (23.1)202 (20.7)1 (11.1)Grade 2198 (15.2)31 (9.8)165 (16.9)2 (22.2)Grade 330 (2.3)3 (0.9)27 (2.8)0Unknown35 (2.7)8 (2.5)27 (2.8)0*Other includes 2.5mg (n=3), 7.5mg (n=2), 15mg (n=1), 20mg(n=2), 30mg (n=1) 86.5% of pts received recommendations regarding stomatitis prophylaxis. The most frequent recommendations were: mild dental hygiene (e.g. soft toothbrush) (74.8%), avoidance of hot, sour or salty food (70.9%), rinsing with tea (61.7%), and cooling (e.g. sucking ice or frozen pineapple) (56,6%). At least one therapeutic measure was documented for 85.5% of stomatitis events. The most common therapeutic measures were non-drug mouthwash solution (58.3%), cooling (34.7%) or drug intervention (31.9%). Temporary EVE dose adjustments due to stomatitis were done in 11.6% of stomatitis events, temporary dose interruptions in 21.8%, respectively. Efficacy of EVE+EXE seemed to be independent of stomatitis occurrence within 8 weeks after therapy start: mPFS 6.9 months (95%CI, 6.4-8.0) without stomatitis, mPFS 7.4 months (95%CI, 6.3-8.6) with stomatitis. Discussion The percentage of patients with any grade stomatitis was lower in BRAWO (41.5%) than in the pivotal BOLERO-2 trial (59%), which might be explained by increased awareness and experience of treating physicians for prophylaxis and management of this type of adverse event under treatment with EVE+EXE. Most stomatitis events occurred during the first 5 weeks of treatment, which is consistent with data from BOLERO-2. Citation Format: Schütz F, Grischke E-M, Decker T, Uleer C, Schneeweiss A, Salat C, Wimberger P, Mundhenke C, Förster F, Kluth-Pepper B, Schubert J, Bloch W, Tesch H, Jackisch C, Lüftner D, Fasching PA. Stomatitis in patients treated with everolimus and exemestane - Results of the 3rd interim analysis of the non-interventional trial BRAWO. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-13-08.

Introduction BRAWO is a non-interventional study collecting data of 3000 breast cancer patients treated with everolimus and exemestane (advanced or metastatic, hormone-receptor-positive, HER2-negative breast cancer). We introduce results of the 3rd preplanned interim analysis with data cut-off 08/01/ 2015, including 1300 patients. Since physical activity/exercise was reported to influence side effects as well as quality of life (QoL) of various cancer types and therapies, this analysis focuses on the impact of the physical activity/exercise history, development on adverse effects (AE) of the medical treatment and QoL. Methods Patients were asked to complete the EORTC QLQ-C30 QoL questionnaire and visual analogue scales (VAS-KAS) measuring their present-, past ten year- and lifetime physical activity/exercise level. To differentiate between activity/exercise levels, VAS were divided in three equal components (inactive, somewhat active, very active). Questionnaires and information about AE (e. g. stomatitis, fatigue, nausea, diarrhea, etc.) were collected before starting the medical treatment and were repeated each three months. Logistic regression model was used to estimate the impact of baseline physical activity/exercise on AE at any time point of the therapy. ANOVA models were used to calculate the impact of the baseline activity/exercise level on QoL at the last completed data set of each patient. Results Median age of patients was 66 years, median weight was 70 kg, median BMI was 25.9, median time since primary diagnosis was 6.2 years, and 54.4% had visceral metastases at baseline. The median PFS for the first 1300 patients was 7.1 months (95% CI, 6.5-8.0). Patients who reported to be very active (exercise) at the week prior to baseline (4.4%) showed significant lower numbers of AE compared to patients who indicate to be somewhat (14.8%) or inactive (80.8%). In contrast to the exercise level, physical activity in everyday life did not affect the AE incidence. Neither lifetime nor past ten year activity/exercise level is associated with the occurrence of AE. Regarding QoL, very active as well as somewhat active women (measured at baseline for almost each time period) showed significant higher QoL values compared to inactive women during the last assessment before death/progress. Conclusion Exercise prior to medical treatment with Everolimus and Exemestane may impact AE during therapy. Since physical activity did not show such a relation, this analysis highlights the importance of specific guidelines for preventive/rehabilitative exercise programs. More knowledge about dose-response relationships is needed. Furthermore a livelong healthy, "active" lifestyle may increase QoL, even in patients with advanced and terminal breast cancer disease. Citation Format: Bloch W, Baumann F, Zimmer P, Grischke E-M, Fasching PA, Decker T, Uleer C, Schneeweiss A, Salat C, Wimberger P, Mundhenke C, Förster F, Kluth-Pepper B, Schubert J, Tesch H, Schütz F, Lüftner D, Jackisch C. Impact of physical activity/exercise on adverse events and quality of life during treatment with everolimus and exemestane for ER+ women - Results of the 3rd interim analysis of BRAWO. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-13-07.

The incidence of isolated loco-regional recurrence of breast cancer is between 2–20 %. It constitutes the most common type of breast cancer recurrence. In contrast to distant metastasis, a number of curative therapies are available to treat isolated loco-regional recurrence of breast cancer. Screening for early detection and regular examinations as part of a recommended follow-up programme is important. If distant metastasis has been excluded, therapy for recurrence ideally consists of surgery with R0 resection margins. Radiotherapy is indicated after non-curative surgery (R1/R2) for local tumour control to improve the chances of curative surgery and as a palliative therapy for local control of symptoms in inoperable cancer, also in combination with hyperthermia and systemic therapy. There was previously some uncertainty concerning the benefit of systemic therapy after R0 resection and breast-conserving therapy and after previous mastectomy. If the recurrence is hormone-receptor positive, (repeat) endocrine systemic therapy is indicated for both constellations. If the hormone-receptor status is negative, the question whether repeat chemotherapy is indicated as an adjuvant therapy and whether it offers a benefit to patients was still controversially discussed. However, data from the CALOR trial presented at the San Antonio Breast Cancer Symposium in 2012 has now answered this question in favour of chemotherapy. These new findings will not merely have an impact on future therapy recommendations but also on the entire clinical management of isolated loco-regional recurrence.

Die klassische Schwangerenvorsorge in Deutschland, sowie in den meisten westlichen Landern, zeigt in ihrer Untersuchungsfrequenz eine pyramidenartige Struktur. Sind anfangs nur wenige Untersuchungstermine in der Schwangerschaft vorgesehen, nimmt die Haufigkeit der Kontrollen mit zunehmendem Gestationsalter zu. Seit einigen Jahren lassen sich immer mehr Risiken fur verschiedene Schwangerschaftskomplikationen im Ersttrimester-Screening vorhersagen. Ist es an der Zeit, die „Pyramide der Schwangerenvorsorge“ umzudrehen?

Purpose The prognosis is poor for patients with recurrent, platinum-resistant epithelial ovarian cancer (EOC). Evidence suggests that antiangiogenic treatment modalities could play a major role in EOC. A combined therapy consisting of the investigational oral antiangiogenic agent pazopanib and metronomic oral cyclophosphamide may offer a well-tolerable treatment option to patients with recurrent, previously treated EOC. Patients and methods This study was designed as a multicenter phase I trial evaluating the optimal dose as well as activity and tolerability of pazopanib with metronomic cyclophosphamide in the treatment of patients with recurrent, platinum-resistant, previously treated ovarian, peritoneal, or fallopian tube cancer. Here, 50mg cyclophosphamide were combined with 400 to 800mg pazopanib daily. Results Sixteen patients were treated; mean age was 66years. At dose levels (DL) I and II, one instance of dose-limiting toxicity (DLT) was seen in one of 6 patients. At DL III, two of four patients showed a DLT, leading to a maximum tolerated dose (MTD) of 600mg pazopanib daily. Median number of administered cycles was 6 (2−13), with three patients being treated for at least 13months. Median progression-free survival (PFS) and overall survival (OS) were 8.35months and 24.95months, respectively. 155 adverse events (AE) occurred, most frequently elevation of liver enzymes, leukopenia, diarrhea and fatigue. Altogether, five serious adverse events (SAE) developed in four patients. Conclusion Pazopanib 600mg daily p.o. and metronomic cyclophosphamide 50mg daily p.o. is a feasible regimen for patients with recurrent platinum-resistant EOC and showed promising activity in this previously treated patient population. Trial registration Clin.trial.gov registry no.: NCT01238770.

Introduction: The EvaluateTM study (Evaluation of therapy management and patient compliance in postmenopausal hormone receptor-positive breast cancer patients receiving letrozole treatment) is a prospective, non-interventional study for the assessment of therapy management and compliance in the routine care of postmenopausal women with invasive hormone receptor-positive breast cancer receiving letrozole. The parameters for inclusion in the study are presented and discussed here. Material and Methods: Between January 2008 and December 2009 a total of 5045 patients in 310 study centers were recruited to the EvaluateTM study. Inclusion criteria were hormone receptor-positive breast cancer and adjuvant treatment or metastasis. 373 patients were excluded from the analysis for various reasons. Results: A total of 4420 patients receiving adjuvant treatment and 252 patients with metastasis receiving palliative treatment were included in the study. For 4181 patients receiving adjuvant treatment, treatment with the aromatase inhibitor letrozole commenced immediately after surgery (upfront). Two hundred patients had initially received tamoxifen and started aromatase inhibitor treatment with letrozole at 1–5 years after diagnosis (switch), und 39 patients only commenced letrozole treatment 5–10 years after diagnosis (extended endocrine therapy). Patient and tumor characteristics were within expected ranges, as were comorbidities and concurrent medication. Conclusion: The data from the EvaluateTM study will offer a good overview of therapy management in the routine care of postmenopausal women with hormone receptor-positive breast cancer. Planned analyses will look at therapy compliance and patient satisfaction with how information is conveyed and the contents of the conveyed information.