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Purpose Assessment of HER2 overexpression using immunohistochemistry (IHC) and/or in situ hybridisation (ISH) for the detection of HER2 amplifications is standard to identify patients for established HER2-directed treatments. Patients with lower HER2 expression levels have recently also become candidates for novel therapies targeting HER2. This study aimed to assess tumour and patient characteristics and prognosis in patients with advanced breast cancer (aBC), relative to low HER2 expression levels. Methods PRAEGNANT is a prospective aBC registry (NCT02338167), focusing on molecular biomarkers. Patients in all therapy lines receiving any kind of treatment are eligible. This analysis includes patients with conventionally HER2-negative aBC. Clinical outcome was compared in the groups with no (IHC score 0) or with low HER2 expression (IHC 1+, or IHC 2+/ISH negative). Results Low HER2 expression levels in triple-negative aBC patients did not influence progression-free survival. Overall survival appeared poorer in patients with IHC 2+ compared with patients with no HER2 expression in the unadjusted analysis (hazard ratio 2.24, 95% confidence interval 0.1.12–4.47). However, this effect was not maintained in the adjusted analysis. In HER2-negative, hormone receptor–positive patients, low HER2 expression appeared to have no effect on prognosis, neither progression-free survival nor overall survival. Conclusions We could not demonstrate that HER2 expression at a low level and assessed in clinical routine can differentiate patients into prognostic groups. However, the prevalence of patients with a low expression makes this population interesting for clinical trials with potentially active treatments using HER2 as a target.

Substances with good effectiveness that intervene in specific signalling pathways have been used increasingly in recent years in the treatment of patients with advanced breast cancer, and new therapies and approaches have now been added, which actually relate to quite specific changes, such as the treatment of patients with HR+/HER2 tumours with a PIK3CA mutation. The treatment of patients with a BRCA1 or BRCA2 mutation has also been improved by the introduction of PARP inhibitors. Attempts are now being made increasingly to extend treatment indications based on molecular patterns, to identify other patients who could benefit from a treatment and to integrate the newly established treatment methods in existing therapy sequences. This review articles summarises the latest information in this connection.

Background In EMBRACA, talazoparib prolonged progression-free survival versus chemotherapy (hazard ratio [HR] 0.542 [95% confidence interval (CI) 0.413-0.711]; P Patients and methods This randomized phase III trial enrolled patients with gBRCA1/2-mutated HER2-negative ABC. Patients received talazoparib or physician's choice of chemotherapy. OS was analyzed using stratified HR and log-rank test and prespecified rank-preserving structural failure time model to account for subsequent treatments. Results A total of 431 patients were entered in a randomized study (287 talazoparib/144 chemotherapy) with 412 patients treated (286 talazoparib/126 chemotherapy). By 30 September 2019, 216 deaths (75.3%) occurred for talazoparib and 108 (75.0%) chemotherapy; median follow-up was 44.9 and 36.8 months, respectively. HR for OS with talazoparib versus chemotherapy was 0.848 (95% CI 0.670-1.073; P = 0.17); median (95% CI) 19.3 months (16.6-22.5 months) versus 19.5 months (17.4-22.4 months). Kaplan–Meier survival percentages (95% CI) for talazoparib versus chemotherapy: month 12, 71% (66% to 76%)/74% (66% to 81%); month 24, 42% (36% to 47%)/38% (30% to 47%); month 36, 27% (22% to 33%)/21% (14% to 29%). Most patients received subsequent treatments: for talazoparib and chemotherapy, 46.3%/41.7% received platinum and 4.5%/32.6% received a poly(ADP-ribose) polymerase (PARP) inhibitor, respectively. Adjusting for subsequent PARP and/or platinum use, HR for OS was 0.756 (95% bootstrap CI 0.503-1.029). Grade 3-4 adverse events occurred in 69.6% (talazoparib) and 64.3% (chemotherapy) patients, consistent with previous reports. Extended follow-up showed significant overall improvement and delay in time to definitive clinically meaningful deterioration in global health status/quality of life and breast symptoms favoring talazoparib versus chemotherapy (P Conclusions In gBRCA1/2-mutated HER2-negative ABC, talazoparib did not significantly improve OS over chemotherapy; subsequent treatments may have impacted analysis. Safety was consistent with previous observations. PRO continued to favor talazoparib.

The treatment of patients with early breast cancer has always been characterised by escalation by new therapies and de-escalation through identification of better treatment regimens or introduction of better tools to estimate prognosis. Efforts in some of these areas in the last few years have led to solid data. The results of the large studies of de-escalation through use of multi-gene tests are available, as are the results of some studies that investigated the new anti-HER2 substances T-DM1 and pertuzumab in the early treatment situation. Several large-scale studies examining the role of CDK4/6 inhibitors will soon be concluded so innovations can be anticipated in this area also. This review article will summarise and classify the results of the latest publications.

Purpose The treatment of advanced stages of medication-related osteonecrosis of the jaw (MRONJ) remains challenging. In order to improve decision making concerning the therapy, we examined the change of patients’ quality of life (QoL) after surgical treatment of MRONJ stage III. Method The primary outcome variable was patients’ QoL. It was preoperative (T0), 6 weeks postoperative (T1) and 6 months postoperative (T2) assessed by the European Organisation for Research and Treatment of Cancer QoL-H&N35 (EORTC QoL-H&N35) and the Oral Health Impact Factor-G14 (OHIP-G14) questionnaire in a prospective cohort study. Other variables included location, age, sex, risk factors, and recurrence. Descriptive statistics and general multivariate regression models were calculated. Results Forty-three patients with stage III MRONJ underwent surgery. OHIP-G14 scores decreased (improvement) statistically significant (p = .001) by 52.02% (T0-T1) and 56.45% (T1–T2). EORTC QoL-H&N35 showed statistical improvement for “swallowing” (p = .007), “opening mouth” (p = .045), “painkiller” (.005), “weight loss” (.004), “pain” (p = .001), “trouble with social eating” (p = .001), “trouble with social contact” (p = .001), and “teeth” (p = .001). Patients who developed a recurrence did not show any significant higher (worse) scores in OHIP G14 or EORTC QoL-H&N35 scores compared with patients without recurrence. Twenty-nine out of 36 patients showed full mucosal healing (T2). For patients with no full mucosal healing, a downgrade to stage I was achieved. Conclusion In terms of QoL patients with stage III MRONJ do benefit from surgical treatment. The incident of a recurrence seems to have no significant impact on patients QoL.

The aim of the study was to evaluate the surgical outcome of patients with advanced medication-related osteonecrosis of the jaw (MRONJ) treated with different flaps for soft tissue closure. Only MRONJ stage III patients with a minimum follow-up of 6 months were included in our prospective study. The soft tissue closure techniques were: Mylohyoid Muscle Flap, Buccal Fat Flap and mucoperiosteal flap alone. Potential risk factors and surgical side effects were analyzed. Relapses occurred in 12 of 44 included cases and 38 reached mucosal integrity within the follow-up. Cases treated with the muscle or fat flap showed better results regarding the recurrence rate (p < 0.001) and soft tissue healing (p = 0.002): only 3 of 33 developed a relapse, and 31 of 33 reached mucosal integrity. The outcome was worse if MRONJ occurred at the front areas of the jaw (p = 0.025). Postoperative, the pain level was reduced significantly (p < 0.001). Partial hypoesthesia of the lip arose in 18 cases. An impairment of the long-term prosthetic rehabilitation has not been seen.Patients with MRONJ stage III undergoing surgery benefit from extensive soft tissue closure.

PurposePalbociclib is a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor, approved in combination with endocrine therapy for the treatment of women and men with hormone receptor–positive, human epidermal growth factor receptor 2–negative advanced breast cancer (HR+/HER2− ABC). In the phase 2, open-label, PALOMA-1 trial, palbociclib plus letrozole significantly prolonged progression-free survival (PFS) versus letrozole alone (hazard ratio, 0.488; 95% CI 0.319‒0.748;P = 0.0004; median PFS, 20.2 vs 10.2 months, respectively) in postmenopausal women with estrogen receptor–positive (ER+)/HER2− ABC. Here, we present the final overall survival (OS) and updated safety results.MethodsPostmenopausal women with ER+/HER2− ABC were randomized 1:1 to receive either palbociclib (125 mg/day, 3/1 schedule) plus letrozole (2.5 mg/day, continuous) or letrozole alone (2.5 mg/day, continuous). The primary endpoint was investigator-assessed PFS; secondary endpoints included OS and safety.ResultsA total of 165 patients were randomized. At the data cutoff date of December 30, 2016 (median duration of follow-up, 64.7 months), the stratified hazard ratio for OS was 0.897 (95% CI 0.623–1.294;P = 0.281); median OS in the palbociclib plus letrozole and letrozole alone arms was 37.5 and 34.5 months, respectively. The median time from randomization to first subsequent chemotherapy use was longer with palbociclib plus letrozole than letrozole alone (26.7 and 17.7 months, respectively). The most frequently reported adverse event in the palbociclib plus letrozole arm was neutropenia (any grade, 75%; grade 3 or 4, 59%).ConclusionsPalbociclib plus letrozole treatment led to a numerical but not statistically significant improvement in median OS.Pfizer Inc (NCT00721409)

The Advanced Breast Cancer Fifth International Consensus Conference (ABC5) which focuses on the diagnosis and treatment of advanced breast cancer was held in Lisbon on November 14 – 16, 2019. The aim of the conference is to standardize the treatment of advanced breast cancer worldwide using evidence-based data and to ensure that patients with advanced breast disease anywhere in the world are treated appropriately and have access to the latest therapies. This year, the emphasis was on new developments and study results from patients with advanced breast cancer as well as precision medicine. The collaboration with patient advocates from all over the globe is also an important goal of the ABC Conference, which is why the international ABC panel also included a number of patient advocates. We present a commentary on the voting results of the ABC5 panelists in Lisbon by a working group of German breast cancer specialists together with the implications for routine clinical care in Germany. The commentary is based on the recommendations of the Breast Commission of the German Gynecological Oncology Working Group (AGO). This commentary is useful, it includes country-specific features for the ABC consensus.

Background: Talazoparib is a potent oral inhibitor of poly(ADP-ribose) polymerase (PARP) 1 and 2, which significantly improved progression-free survival versus standard-of-care chemotherapy in patients with HER2-negative advanced breast cancer (ABC; locally advanced/metastatic breast cancer) and a germline BRCA1/2 mutation (gBRCA1/2mut) in the Phase 3 EMBRACA trial (Litton J, et al. N Engl J Med. 2018;379:753-763). An integrated analysis of five clinical trials (Phase 1-3) in multiple tumor types was performed to evaluate the safety of talazoparib administered at 1 mg/day (d). Methods: Data were pooled from the ongoing Phase 3 randomized EMBRACA trial in HER2-negative gBRCA1/2mut ABC (NCT01945775), the Phase 2 non-randomized ABRAZO trial in gBRCA1/2mut ABC (NCT02034916), the Phase 1 trial in advanced/recurrent solid tumors (NCT01286987), the Phase 1 cardiac repolarization trial in advanced solid tumors (NCT03042910), and an ongoing open-label extension trial (NCT02921919). Results: 494 patients who received talazoparib 1 mg/d were included (Table). The most common all-grade adverse drug reactions (≥20%) with talazoparib were ANEMIA (includes preferred terms: anemia, decreased hemoglobin, decreased hematocrit; 49.6%), fatigue (47.6%), nausea (44.3%), NEUTROPENIA (neutropenia, decreased neutrophil count; 30.2%), THROMBOCYTOPENIA (thrombocytopenia, decreased platelet count; 29.6%), headache (26.5%), diarrhea (22.7%), alopecia (22.3%; Grade 1, 20.6%; Grade 2, 1.6%), vomiting (22.3%), and decreased appetite (20.2%). Grade 3/4 toxicities (≥10%) with talazoparib were ANEMIA (35.2%), NEUTROPENIA (17.4%), and THROMBOCYTOPENIA (16.8%). Overall 24 patients (4.9%) died within 30 days after the last dose of study drug; the most common cause of death was disease progression (13 patients; 2.6%). Other causes of death were reported in 1 patient each (cerebral hemorrhage, dyspnea, lung infection, lung metastases, respiratory failure, suspected veno-occlusive liver disease, and worsening of neurological symptoms); cause of death was not reported for 4 patients. The most common treatment-related serious adverse event was anemia (4.3%). Median duration of talazoparib exposure was 5.4 months (range, 0.0-61.1). Median relative dose intensity (defined as actual-dose intensity/planned-dose intensity) was 92.8%. Dosing interruptions due to TEAEs were reported for 48.6% of patients receiving talazoparib; median duration of dosing interruption due to TEAEs was 8.0 days (range, 1.0-121.0). Hematologic TEAEs (≥5%) associated with dose modification (interruption or reduction) included anemia (33.0%), neutropenia (15.8%), thrombocytopenia (13.4%), and decreased platelet count (5.9%); non-hematologic TEAEs (≥2%) associated with dose modification included fatigue (4.3%), vomiting (2.6%), and nausea (2.0%). Only 18 patients (3.6%) permanently discontinued due to a TEAE (anemia, 3 patients [0.6%]; other events, 1 patient each [0.2%]). Conclusions: Talazoparib monotherapy at 1 mg/d was generally well tolerated with few patients permanently discontinuing talazoparib due to AEs. Common toxicities were primarily hematologic and were manageable through dosing modifications and/or standard supportive care. Funding: Pfizer Inc. Table Summary of TEAEsPhase 3 EMBRACA trialOpen-label trialsTalazoparibTalazoparib mg/dTalazoparib 1 mg/d1 mg/d populationbTalazoparibPCTABRAZONCT01286987NCT03042910OLEaTotalN=286N=126N=83N=77N=37N=46N=494Any TEAE282 (98.6)123 (97.6)81 (97.6)75 (97.4)28 (75.7)39 (84.8)484 (98.0)Grade 3 or 4 TEAE193 (67.5)80 (63.5)54 (65.1)52 (67.5)9 (24.3)21 (45.7)326 (66.0)Treatment-related Grade 3 or 4 TEAE159 (55.6)61 (48.4)48 (57.8)36 (46.8)3 (8.1)14 (30.4)260 (52.6)SAE91 (31.8)37 (29.4)23 (27.7)27 (35.1)3 (8.1)14 (30.4)156 (31.6)Treatment-related SAE26 (9.1)11 (8.7)11 (13.3)3 (3.9)1 (2.7)1 (2.2)42 (8.5)TEAE primary reason for permanent discontinuation13 (4.5)7 (5.6)3 (3.6)002 (4.3)18 (3.6)TEAE associated with dose modification190 (66.4)75 (59.5)55 (66.3)46 (59.7)4 (10.8)15 (32.6)308 (62.3)All data are number (%) of patients; d, day; OLE, open-label extension; PCT, physician’s choice of chemotherapy; SAE, serious adverse event; TEAE, treatment-emergent adverse event;aInitiated treatment with talazoparib; monotherapy (1 mg/d) in either the originating or the extension trial;b35 patients who initiated talazoparib 1 mg/d in two of the trials and continued in the OLE are counted only once in the total number of patients Citation Format: Joannes Ettl, Jennifer Litton, Hope S. Rugo, Lida Mina, Miguel Martin, Nicholas Turner, Henri Roché, Zev Wainberg, Johann de Bono, Tiziana Usari, Mohamed Elmeliegy, Silvana Lanzalone, Akos Czibere, Liza DeAnnuntis, Sara A. Hurvitz. An integrated safety analysis of talazoparib monotherapy from five clinical trials (phase 1-3) in advanced cancers [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 P1-19-29.

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 To evaluate predictive clinico-pathological characteristics on outcome in head and neck melanoma (HNM) in a population-based study with particular emphasis on the prognostic effect of sentinel lymph node biopsy (SLNB), Charlson comorbidity index (CCI) and distinct tumor localisations. Methods Here we primarily describe a retrospective multicenter population-based cohort study with 402 patients having undergone resection with curative intent of HNM between 2010 and 2017. SLNB was used in the diagnosis of 79 HNM patients. Outcome was analyzed, focusing on SLNB, CCI as well as tumor localisation. Overall survival (OAS) und recurrence free survival (RFS) was examined by uni- and multivariate analysis. Results Histopathologically verified lymph node metastasis according to SLNB was associated with impaired RFS in HNM patients (p = 0.004). Especially in higher tumor stages, the sole implementation of SLNB improved survival significantly in the present cohort (p = 0.042). With most of the HNM being located in the face, melanoma of the scalp and neck could be linked to deteriorated patient’s outcome in uni- as well as multivariate analysis (p = 0.021, p = 0.004). Conclusions SLNB is a useful tool in predicting development of distant metastasis after HNM resection with curative intent. Especially in higher tumor stages, performing a SLNB ameliorated survival of HNM patients. Additionally, CCI as well as a distinct tumor localisations in HNM were identified as important risk factors in our population-based cohort study.

Introduction/Background* Due to the improved prognosis of patients with breast cancer, health-related quality of life has become increasingly important. The aim of the study is to evaluate the potential impact of different epidemiological, oncological and treatment parameters on the quality of life at different stages of diagnosis, treatment and follow-up in order to help improve and individualize the support for patients with breast cancer. Methodology Between January 2019 and January 2021, 189 breast cancer patients were included. The quality of life was assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-C30) and a German questionnaire quantifying psychological distress (FBK-R10) at three distinct time points: At initial diagnosis as well as after six and 12 months. Sociodemographic and clinical data were also included. Result(s)* Both the subjective quality of life and the perceived health condition differed significantly between the three time points (p Conclusion* The quality of life decreased significantly during the first six months after diagnosis, identifying this time as a period of particular need for a multidisciplinary support system. In addition, patients undergoing treatment should receive special attention given their lower quality of life, greater psychological distress and substantially more sexual dysfunction. A significant improvement in quality of life can be observed 12 months after the initial diagnosis. Future studies should focus on how to regain an improved quality of life earlier and how to implement support systems based on the patients’ different needs at different times during the course of the disease.

Background: Loss-of-function mutations in genes encoding components of the homologous recombination DNA damage response (DDR) machinery, notably BRCA1/2, are associated with tumor sensitivity to poly(ADP-ribose) polymerase inhibitors (PARPi). Little is known about the potential contribution of tumor alterations in non-DDR genes to modulating sensitivity to PARP inhibitors in the clinic. In EMBRACA, the PARPi TALA improved progression-free survival (PFS) (HR [95% CI] 0.54 [0.41-0.71], P Methods: Baseline tumor tissue from 308 pts (71%; intent-to-treat) was tested by FoundationOne®. To support exploratory identification of tumor gene alterations associated with best vs worst outcomes, pts were mapped into 2 groups: [1] BEST: Pts in TALA arm with OS ≥ 30 mo and duration of treatment ≥ 24 mo, Pts in CT arm with OS ≥ 30 mo; [2] WORST: Pts in TALA or CT arm with a PFS event (PD by Independent Radiological Facility or death) ≤ 12 wks. 2 pts had short PFS but long OS and were initially mapped to both groups but then assigned to BEST and excluded from WORST. Results: Exploratory heat map visualizations of known/likely pathogenic genetic alterations defined by the FoundationOne® gene panel were used to assess differences in genetic alterations between BEST and WORST in TNBC and non-TNBC subpopulations, leading to the identification of MYC and RAD21 as commonly altered genes of high interest. Based on these results showing imbalances in tumor amplification events between BEST and WORST outcome pts, Cox regression analysis was used to explore potential associations of MYC or RAD21 amplification with OS across the evaluable ITT population. In TNBC pts receiving TALA, OS was shorter with MYC amplification than without [HR (95% CI) 1.877 (1.102, 3.196)]. No such association was evident in TNBC pts receiving CT [HR (95% CI) 0.706 (0.303, 1.643)]. In contrast, for non-TNBC pts receiving TALA, no association with OS was evident for MYC amplification versus without [HR (95% CI) 0.603 (0.310, 1.173)], while for pts receiving CT OS was shorter with MYC amplification than without [HR (95% CI) 1.917 (1.037, 3.544)]. RAD21 amplification status was not associated with OS in either TNBC or non-TNBC patients for either treatment arm, although it should be noted that two RAD21 subgroups were very small (n=7 and 11; others had n ≥ 21). Conclusions: Based on these exploratory, retrospective analyses MYC amplification was associated with shorter OS in TNBC pts receiving TALA. This may reflect the role of MYC in positive regulation of genes involved in homologous recombination such as RAD51 (Carey et al, Cancer Res 2018;78(3):742-757). MYC and RAD21 are both located at 8q24 and frequently coamplified in breast cancer (eg, Annunziato et al, Nat Commun. 2019;10(1):397), hence the lack of association of RAD21 amplification with outcome in TNBC suggests that the association of MYC amplification with shorter OS seen in pts receiving TALA may be gene-specific. Further investigation is warranted. Funding: Pfizer TNBCNon-TNBCTALACTTALACTGene AlterationBest n=10Worst n=15Best n=7Worst n=16Best n=17Worst n=11Best n=20Worst n=11MYC amplification0 (0%)7 (47%)2 (29%)6 (38%)5 (29%)1 (9%)3 (15%)5 (46%)RAD21 amplification1 (10%)2 (13%)3 (43%)5 (31%)5 (29%)1 (9%)7 (35%)4 (36%) Citation Format: Johannes Ettl, A. Douglas Laird, Joanne L. Blum, Hope S. Rugo, Sara A. Hurvitz, Miguel Martín, Henri Roché, Young-Hyuck Im, Annabel Goodwin, Rinat Yerushalmi, Tiziana Usari, Silvana Lanzalone, Akos Czibere, Julia Hopkins, Lee A. Albacker, Lida A. Mina, Jennifer K. Litton. A retrospective analysis of association of MYC and RAD21 amplification with final overall survival (OS) data in the phase 3 EMBRACA study with talazoparib [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 PS5-07.

Purpose To illustrate the influence of different socioeconomic factors on the treatment and outcome of patients in Germany with oral cancer. Methods In this retrospective single-center study, 400 patients of our department of oral and maxillofacial surgery with primary cases of oral cancer were included. Preoperative diagnostics, occupational groups, and marital and health insurance status were evaluated. Overall and disease-specific survival were analyzed. Occupations were distinguished in 5 groups (unemployed, physically light workers, physically hard worker, university graduate, and freelancer). Data were adjusted to covariables like tumor size, positive lymph nodes, age, alcohol, or tobacco abuse. Results There was no differences between private and statutory insured patients concerning overall (p = 0.858) or disease-specific survival (p = 0.431). Private insured patients received more preoperative PET-CT (p = 0.046) and had a better dental status (p = 0.006). The occupational groups showed also no differences in survival (p = 0.963). The hospitalization of freelancers was in average 2 days shorter. Physically hard workers were diagnosed with bigger tumors (p = 0.018) and consumed more tobacco and alcohol. The 5-year survival rate of married patients was approximately 20% points better than not married patients, without showing a significant difference over the entire observation time (p = 0.084). Conclusion In our cohort, socioeconomic factors have just a limited influence on the survival or treatment of patients with oral cancer. A sufficient statutory health insurance system is a reasonable explanation for this.

Background In the EMBRACA phase III study (NCT01945775), talazoparib was associated with a significantly prolonged progression‐free survival (PFS) compared with physician's choice of chemotherapy (PCT) in germline BRCA1/2‐mutated HER2‐negative advanced breast cancer (ABC). Herein, the safety profile of talazoparib is explored in detail. Materials and Methods Overall, 412 patients received ≥1 dose of talazoparib (n = 286) or PCT (n = 126). Adverse events (AEs) were evaluated, including timing, duration, and potential overlap of selected AEs. The relationship between talazoparib plasma exposure and grade ≥3 anemia was analyzed. Time‐varying Cox proportional hazard models assessed the impact of dose reductions on PFS. Patient‐reported outcomes (PROs) in patients with common AEs and health resource utilization (HRU) were assessed in both treatment arms. Results The most common AEs with talazoparib were hematologic (195 [68.2%] patients) and typically occurred within the first 3–4 months of receiving talazoparib. Grade 3‐4 anemia lasted approximately 7 days for both arms. Overlapping grade 3‐4 hematologic AEs were infrequent with talazoparib. Higher talazoparib exposure was associated with grade ≥3 anemia. Permanent discontinuation of talazoparib due to hematologic AEs was low (, Talazoparib is a viable option for patients with germline BRCA‐mutated advanced breast cancer. This article presents detailed safety analyses for talazoparib, as a follow‐up to reported results from the EMBRACA trial, to highlight patterns of toxicity compared with chemotherapy and to outline guidelines for management of talazoparib toxicity in clinical practice via dose modifications and/or standard supportive care.

Objectives The aim of this retrospective study was to analyze the early postoperative swallowing outcome in oral cancer patients considering risk factors and localization. Materials and methods Four hundred patients with primary cases of oral cancer were included. Tumors’ locations were categorized into four main groups (central, lateral, anterior and posterior). Swallowing function was evaluated at day 7 after surgery. Results Ninety-eight percent (393/400) of the patients had a swallowing impairment including 41 (10.2%) patients who were unable to swallow. Strong risk factors with p values of 0.001 were tumor size, nodal stage, tracheotomy, insufficient dental status and reconstruction with a flap. The inability to swallow was increased at T1 und T2 patients, if they were reconstructed with a flap compared to patients who had a primary wound closure (p = 0.04). Decreased swallowing function was determined if the tumor was located central (OR = 1.8; p = 0.141) and additionally posterior (OR = 5.8; p = 0.110). Inability to swallow, even at that early point in time, (p = 0.001) was as significant as tumor size (p = 0.009) and nodal stage (p = 0.020), referring to overall survival. Conclusion The impact of early dysphagia should not be underestimated. By considering swallowing impairment at the primary therapy patients can profit concerning survival and comorbidity.

The treatment of breast cancer patients in a curative situation is special in many ways. The local therapy with surgery and radiation therapy is a central aspect of the treatment. The complete elimination of tumour cells at the site of the primary disease must be ensured while simultaneously striving to keep the long-term effects as minor as possible. There is still focus on the continued reduction of the invasiveness of local therapy. With regard to systemic therapy, chemotherapies with taxanes, anthracyclines and, in some cases, platinum-based chemotherapies have become established in the past couple of decades. The context for use is being continually further defined. Likewise, there are questions in the case of antihormonal therapy which also still need to be further defined following the introduction of aromatase inhibitors, such as the length of therapy or ovarian suppression in premenopausal patients. Finally, personalisation of the treatment of early breast cancer patients is also being increasingly used. Prognostic tests could potentially support therapeutic decisions. It must also be considered how the possible use of new therapies, such as checkpoint inhibitors and CDK4/6 inhibitors could look in practice once study results in this regard are available. This overview addresses the backgrounds on the current votes taken by the international St. Gallen panel of experts in Vienna in 2019 for current questions in the treatment of breast cancer patients in a curative situation.

Purpose: To assess talazoparib activity in germline BRCA1/2 mutation carriers with advanced breast cancer. Patients and Methods: ABRAZO (NCT02034916) was a two-cohort, two-stage, phase II study of talazoparib (1 mg/day) in germline BRCA mutation carriers with a response to prior platinum with no progression on or within 8 weeks of the last platinum dose (cohort 1) or ≥3 platinum-free cytotoxic regimens (cohort 2) for advanced breast cancer. Primary endpoint was confirmed objective response rate (ORR) by independent radiological assessment. Results: We enrolled 84 patients (cohort 1, n = 49; cohort 2, n = 35) from May 2014 to February 2016. Median age was 50 (range, 31–75) years. Triple-negative breast cancer (TNBC) incidence was 59% (cohort 1) and 17% (cohort 2). Median number of prior cytotoxic regimens for advanced breast cancer was two and four, respectively. Confirmed ORR was 21% [95% confidence interval (CI), 10–35; cohort 1] and 37% [95% CI, 22–55; cohort 2]. Median duration of response was 5.8 and 3.8 months, respectively. Confirmed ORR was 23% (BRCA1), 33% (BRCA2), 26% (TNBC), and 29% (hormone receptor–positive). The most common all-grade adverse events (AE) included anemia (52%), fatigue (45%), and nausea (42%). Talazoparib-related AEs led to drug discontinuation in 3 (4%) patients. In an exploratory analysis, longer platinum-free interval was associated with higher response rate in cohort 1 (0% ORR with interval 6 months). Conclusions: Talazoparib exhibited promising antitumor activity in patients with advanced breast cancer and germline BRCA mutation.

Background Studies leading to the approval of trastuzumab emtansine (T-DM1) have been conducted without pertuzumab as previous therapy. Therefore data about patient characteristics and the efficacy of T-DM1 after a treatment with pertuzumab is scarce. Aim of this study was to analyze a real world patient cohort of advanced breast cancer (aBC) patients, who were treated with T-DM1 after a treatment containing pertuzumab in the metastatic setting with regard to patient characteristics and progression free survival (PFS). Methods The PRAEGNANT metastatic breast cancer registry (NCT02338167) is a prospective registry for metastatic breast cancer patients with focus on molecular biomarkers. Patients of all therapy lines with any kind of treatment are eligible for this registry. Collected data comprises all relevant patient and tumor characteristics, therapies, adverse events, quality of life, patient reported outcomes, response and survival (PFS/OS). Here we report on the patient characteristics and PFS data for HER2 positive patients treated with T-DM1 after a treatment with pertuzumab. Patients had to be included before or at the beginning of the T-DM1 therapy. Results A total of 58 patients could be identified, who were suitable for the analysis. Of those 34 were treated in the second line, 14 in the third line and 10 in the fourth line or higher. Most of the pertuzumab therapies before T-DM1 were conducted in first line (n=46; 79.3%). Median PFS for all patients was 4.8 months (95% CI: 3.0-7.8 months). Median PFS for patients treated in the 3rdline and 4thline or higher was 4.2 months(95%CI: 2.3 - NA) and 4.0 months (95%CI: 1.8-N.A.), respectively. In patients treated 2ndline with T-DM1 PFS was 7.7 months (95%CI: 2.8 – 12.2). Conclusion T-DM1 is effective as 2ndand further line therapy following pretreatment with pertuzumab. Overall PFS was about 5 months with 7.7 months as 2nd-line therapy. The PFS in higher therapy lines might be shorter. As the sample size of this real world cohort was rather low and analyses have to be considered exploratory, this data need to be confirmed in studies with a larger sample size. Citation Format: Schneeweiss A, Lux MP, Hartkopf AD, Volz B, Kolberg H-C, Hadji P, Tesch H, Haeberle L, Ettl J, Lüftner DI, Wallwiener M, Müller V, Beckmann MW, Belleville E, Wimberger P, Hielscher C, Geberth M, Lermann J, Abenhardt W, Kurbacher C, Wuerstlein R, Thomssen C, Untch M, Overkamp F, Huober J, Taran F-A, Janni W, Wallwiener D, Brucker SY, Fasching PA, Fehm TN. Progression free survival (PFS) and overall survival (OS) of patients treated with trastuzumab emtansine (T-DM1) after previous treatment with pertuzumab in patients with advanced breast cancer (NCT02338167) [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 P6-17-22.

Purpose: This analysis describes comprehensive real-world data concerning the use of anti-HER2 therapies in HER2 positive metastatic breast cancer (MBC). Specifically, it describes the therapy patterns of treatments with trastuzumab (TZM), pertuzumab+trastuzumab (PTZ/TZM), lapatinib (LAP) and trastuzumab emtansine (T-DM1). Methods: The PRAEGNANT study is a real-time, real-world registry for patients with MBC. Patients can be registered for PRAEGNANT at any time during the course of their metastatic disease and are followed up until death. All therapy lines are documented. This analysis presents the utilization of anti-HER2 therapies as well as therapy sequences. Results: Of 1936 patients within PRAEGNANT at the time of database closure 451 were HER2 positive (23.3%). Within the analysis set (417 patients after an unilateral breast cancer diagnosis), of which 53% were included in PRAEGNANT in the 1stline setting, 241 were treated with TZM (58%), 237 with PTZ (57%), 85 with LAP (20%) and 125 with T-DM1 (30%) during the course of their therapies. The sequence PTZ/TZMàT-DM1 was given to 51 patients (12%). Worse ECOG, negative hormone receptor status, and visceral or brain metastases were associated with a more frequent use of this therapy sequence. Most patients received T-DM1 after a therapy with pertuzumab. Conclusions: Both novel therapies (PTZ/TZM and T-DM1) are utilized in a high proportion of HER2 positive breast cancer patients. As most patients receive T-DM1 after pertuzumab real world data might help to understand whether this sequence has similar efficacy like in the approval study. Citation Format: Lux MP, Hartkopf AD, Huober J, Volz B, Taran F-A, Overkamp F, Hadji P, Tesch H, Haeberle L, Ettl J, Lueftner DI, Wallwiener M, Müller V, Beckmann MW, Belleville E, Wimberger P, Hielscher C, Geberth M, Lermann J, Abenhardt W, Kurbacher C, Wuerstlein R, Thomssen C, Untch M, Fasching PA, Janni W, Fehm TN, Wallwiener D, Brucker SY, Schneeweiss A, Kolberg H-C. Therapy landscape of patients with metastatic, HER2 positive breast cancer - Data from the real world breast cancer registry PRAEGNANT (NCT02338167) [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 P6-17-37.

Background: In node negative and 1-3 positive nodes breast cancer patients with hormone receptor positive (HR+), HER2-negative (HER2-) early-stage breast cancer the indication for chemotherapy is based on clinical and pathologic risk stratification (tumor size, nodal status, grading, quantitative ER, progesterone receptor and Ki67). For further decision-making, the EndoPredict test, which combines a molecular signature with the clinical risk factors tumor size and nodal status, stratifies patients into “low risk" or “high risk” groups. Level I-B- evidence demonstrates, that EndoPredict predicts the 10 year cumulative risk of relapse and metastases in patients with HR+/HER2- primary breast cancer with endocrine treatment. Aim: In the RESCUE-Trial we document distant metastasis-free survival (DMFS), disease free survival (DFS) and overall survival (OS) events in patients who had an EndoPredict test. The primary objective is to show that 10-year DMFS of patients tested as “low risk” by EndoPredict and treated with adjuvant endocrine therapy alone is >90 %. Secondary endpoints among others include DMFS, DFS, OS in patients with EPclin “low risk” versus “high risk”. Also the proportion of patients whose treatment was concordant and non-concordant with EndoPredict test results, will be analyzed for survival. The prognostic performance of classical prognostic factors (like tumor size, nodal status, grading, quantitative ER, progesterone receptor and Ki67 level) with respect to survival will also be assessed. Eligibility: Patient with HR+/HER2- primary invasive breast cancer stage I/II and T1 to T3 with 0 to 3 positive lymph nodes will be eligible, if they had an EndoPredict test within three months before inclusion. Methods: The EndoPredict test results, tumor board decision and anti-tumor therapy will be assessed. After one year, annually (for 10 years), patients will be evaluated for treatment compliance, recurrence, metastases, and survival. The primary endpoint will be analyzed by a Kaplan-Meyer estimate for which a one-sided lower 95 % confidence interval will be given. Several secondary endpoints will be assessed in three interim analyses after completion of the 1st, 3rd, 5th year and then finally after 10 years. Accrual: Start of accrual is planned for July 2018. At least 26 sites in Germany and one site in Switzerland will be active. Sponsor: The study is sponsored by the North-Eastern-German Society of Gynecological Oncology (NOGGO) e.V. Contact Information: For further information, contact NOGGO via studies@noggo.de or the leading physician Dr. Johannes Ettl via johannes.ettl@tum.de. Citation Format: Ettl J, Blohmer J-U, Denkert C, Keller M, Klein E, Kronenwett R, Neuser P, Paepke S, Schade-Brittinger C, Schnuppe K, Untch M, Wittenberg M, Kiechle M. RESCUE: Reaching for Evidence-baSed Chemotherapy Use in Endocrine sensitive breast cancer - A prospective health care study on risk assessment by the clinicomolecular test EndoPredict® and long-term patient outcome in early luminal 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 OT1-12-03.

Background: Every seventh to eighth woman is diagnosed with breast cancer in her life. Next to surgery and radiotherapy most of them receive (neo)adjuvant chemotherapy, which comes along with adverse effects. Complementary and alternative medicine (CAM) like Reiki can reduce these effects. Reiki is a Far Eastern method that promotes healing on a physical, mental and emotional level and activates self-healing powers. REASSURE examines the effects of Reiki on quality of life and taxane-induced polyneuropathy during chemotherapy. Methods: REASSURE is a prospective, randomized, controlled, two-armed clinical trial, in which patients with breast cancer receive chemotherapy and Reiki (18 times) or chemotherapy and sport (18 times). During chemotherapy and before and after every Reiki- or sport-session the patients fill out standardized questionnaires (e.g. FACT/GOG-NTX Version 4). Primary endpoint is the comparison of quality of life at the end of chemotherapy between Reiki and sport based on the FACT/GOG-NTX score by T-Test. Secondary endpoint is the comparison of the taxane-induced polyneuropathy at the end of chemotherapy between the two groups. Also short-term effects before and after the Reiki- and sport-session will be examined. A power of 1-β = 0.8, a bilateral probability of error of α = 0.05, a minimum relevant difference deltaθ = 4 and a pooled standard deviation of 11 for the two-sided T-Test result in case numbers of 2 x 120 = 240 patients. Conclusion: REASSURE is the most comprehensive prospective study to the effects and the feasibility of Reiki on breast cancer patients during chemotherapy so far. Since July 2015, 138 patients have been enrolled at three different centers. Currently 63 patients in total (39 patients of the Reiki-group and 24 patients of the sport-group) have completed the study. 24 Reiki-patients and 36 sport-patients are counted as dropouts because of reasons like incomplete data records, discontinuation of chemotherapy, not enough time or energy for Reiki- or sport-sessions or other reasons. Sponsor: This is a collaborative study of the Department of Obstetrics and Gynecology, Klinikum rechts der Isar, Technische Universität München (TUM), Munich, Germany, Rotkreuzklinikum München, Frauenklinik, Munich, Germany, Department of Gynaecology, Städtisches Klinikum München Harlaching, Munich, Germany and the ProReiki – der Berufsverband e.V., Berlin, Germany. Contact Information: For further information contact Sophie Katzendobler via sophie.katzendobler@gmail.com or the leading physician Dr. Johannes Ettl via johannes.ettl@tum.de. Citation Format: Katzendobler S, Haunreiter L, Zander L, Schmidt R, Andrulat A, Münch K, Hanusch C, Napieralski R, Petri I, Ettl J. REASSURE- Effects of Reiki as supportive treatment during chemotherapy of breast cancer: A prospective, randomized, controlled clinical trial [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 OT1-05-05.

Background During the last decades the treatment of advanced breast cancer (ABC) patients has improved due to a variety of new treatment strategies. Nevertheless, many ABC patients are faced with limited prognosis, and their treatment remains a challenge. New targeted therapies complement the well-established treatment options for ABC (CDK4/6 inhibition, anti-endocrine, chemotherapy, antibody based and bone related therapies), leading to improved treatment regimens tailored to the needs of special patient sub-populations. SPECIFIC AIMS/TRIAL DESIGN The PRAEGNANT network study is conducted as an academic, prospective registry and diagnostic translational study, accompanied by biomaterial collection. The pilot phase in more than 60 centers aims at including 3500 ABC patients. The primary objective is to discover biomarkers, which predict progression free survival (PFS). Secondary objectives include overall survival (OS), breast cancer specific survival, objective response rate, patient reported outcomes (PRO), description of therapies used in the metastatic setting, therapy adherence, health economics for patients with ABC, incidence of (serious) adverse events and big data/ machine learning algorithms. The exploratory objectives comprise correlations of gene alterations and their influence on OS, PFS, side effects and PRO. Exploratory biomarkers are assessed at baseline and at every change of therapy. These biomarkers include gene expression profiling of the primary tumor and corresponding metastasis, somatic mutations (measured in the tumor and in circulating tumor DNA), germline genetic variations, epigenetic changes and miRNA variations. Furthermore, plasma and serum markers are assessed. If actionable molecular alterations are detected patients are informed and recruited into suitable studies if available. ELIGIBILITY CRITERIA: Any adult patient (>18 years) with the diagnosis of ABC and who is willing and able to sign the informed consent can be enrolled. STATISTICAL METHODS/TARGET ACCRUAL: The PRAEGNANT study as a prospective real world registry and diagnostic translational study aims to identify biomarkers in ABC patients, which may predict PFS. Target accrual for the pilot phase is 3500 patients. Each patient will be documented for up to 36 months with an estimated median PFS for all patients of 11 months across all treatment lines. Citation Format: Müller V, Huober J, Volz B, Overkamp F, Kolberg H-C, Hadji P, Haeberle L, Ettl J, Hartkopf AD, Lux MP, Lüftner DI, Wallwiener M, Taran F-A, Beckmann MW, Belleville E, Wimberger P, Hielscher C, Geberth M, Lermann J, Abenhardt A, Kurbacher C, Wuerstlein R, Thomssen C, Untch M, Janni W, Fehm TN, Brucker SY, Wallwiener D, Schneeweiss A, Fasching PA, Tesch H. PRAEGNANT - Real world evidence, translational research, big and smart data: A prospective academic translational research network for the optimization of the oncological health care quality in the adjuvant and advanced/ metastatic setting (NCT02338167) [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 OT1-11-02.

Background: Talazoparib (TAL) prevents DNA damage repair by inhibiting poly (ADP-ribose) polymerase (PARP) enzymes and trapping PARP on DNA, resulting in cell death in BRCA1/2-mutated cells. Methods: EMBRACA is an open-label, randomized, 2-arm phase 3 trial in which efficacy and safety of TAL (1 mg/d) were compared with physician's choice of therapy (PCT; capecitabine, eribulin, gemcitabine, vinorelbine) in patients (pts) with locally advanced or metastatic breast cancer (ABC) and a germline BRCA mutation (gBRCAm). Outcomes were assessed by region of the world (North America [NA]; Europe [EU]; rest of world [ROW]). Progression-free survival (PFS), objective response rate (ORR), and clinical benefit rate (CBR) at 24 wks were assessed; safety was also assessed. Results: 431 pts were randomized 2:1. Pt characteristics were well balanced, although a higher percentage of pts in ROW had more severe disease (eg, triple-negative breast cancer [TNBC], Disease-free interval [DFI] Table 1CategoryNA* (N=156)EU* (N=190)ROW* (N=85)Mean age, years49.049.244.2Race, % White76.971.152.9Black5.8-3.5Asian5.8-42.4Not reported-27.4-TNBC, %424447BRCA1**, %414748BRCA2**, %595352DFI Conclusions: In pts with gBRCAm ABC, TAL demonstrated significant improvements in clinical outcomes compared with PCT regardless of the region of the world in which they lived. However, slight differences among the regions in baseline characteristics were noted, possibly due to regional variation in diagnosis and detection of gBRCAm ABC as well as different treatment paradigms for metastatic breast cancer. Funding: Medivation LLC, acquired by Pfizer. Citation Format: Mina L, Lee K-H, Gonçalves A, Woodward N, Hurvitz SA, Diab S, Yerushalmi R, Goodwin A, Moreira Costa Zorzetto M, Kim S-B, Czibere A, Tudor IC, Gauthier E, Litton JK, Ettl J. EMBRACA: Efficacy and safety of talazoparib or physician's choice of therapy in patients with advanced breast cancer and a germline BRCA1/2 mutation: A regional analysis [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 P6-18-12.

Background: The EndoPredict test is a clinico-molecular test that has been validated to predict the likelihood of distant metastases and late relapse inpatients (pts) with hormone receptor positive (HR+), HER2-negative (HER2-) early breast cancer and up to three positive lymph nodes. However, so far prospective outcome results of pts in whom decision on use of adjuvant chemotherapy (CTX) was based on Endopredict has not been available. Here we present three year outcome data of pts, whose adjuvant systemic therapy recommendation was based on EndoPredict test result. Methods: Pts with HR+, HER2- early breast cancer with 0-3 positive lymph nodes were enrolled at a single institution (Interdisciplinary Breast Center of Klinikum rechts der Isar, Munich, Germany). The Endopredict test was carried out on all tumor samples. Demographic, clinical and pathological data as well as EPclin risk class were assessed for each patient at baseline. Therapy recommendations were given during an interdisciplinary tumor board. Pts were evaluated for treatment compliance, local recurrence, distant metastases and survival (cut-off date of last follow up: July 31st 2017). Censored time-to-event outcomes were analysed by cox proportional hazards models. Additional estimates of the event-free-survival were given by the Kaplan-Meier method. Hypothesis testing was conducted on two-sided exploratory 5% significance levels. Results: A total of 373 consecutive pts were enrolled between March 2012 and March 2015. Median age was 59.9 (range: 29.1-88.9) years. In 39% of pts tumorsize was >2cm, 24% of pts were node positive, 16% had G3 tumors, in 21% of pts ki67 was ≥25% and in 13% progesterone receptor was Conclusion: These first prospective outcome results show, that EPclin in clinical routine is a valid clinico-molecular marker to predict DFS and guide decision of adjuvant CTX use in HR+, HER2- early breast cancer pts with 0-3 positive lymph nodes. Citation Format: Ettl J, Anders S, Hapfelmeier A, Noske A, Paepke S, Weichert W, Klein E, Kiechle M. First prospective outcome data for the clinico-molecular test Endopredict® in hormone receptor positive, HER2-negative early breast cancer in clinical routine [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 P4-08-11.

Purpose of review Over the last decades the time which is needed to translate a preclinical finding or idea in the clinic has reduced continuously. Especially but not only for breast cancer the number of tested drugs and targeted pathways have increased immensely. In addition, the introduction of immune-oncological treatments has further advanced the possibilities for future treatments. This review focuses on recent developments in the prevention and treatment of breast cancer including results from major clinical trials and recent conferences. Recent findings Many pathways involved in the progression or treatment of breast cancer have been also identified in the cause and pathogenesis of breast cancer. Therefore, breast cancer risk can be described in much more detail, possibly leading to new prevention strategies. In breast cancer treatment the introduction of PARP inhibitors has begun. Recent trials will lead to a better understanding whether PI3K inhibitors can be developed for application in the clinic and first large randomized trials show the superiority of anti PD-1/PD-L1 treatments. Summary Treatment strategies which were developed over the last decade are moving rapidly into the clinical use. The understanding of treatment targets and involved side effects will be important for the safe implementation of these treatments into routine practice.

// Daniela Schulz 1 , Irene Stancev 1 , Antonio Sorrentino 2 , Ayse-Nur Menevse 2 , Philipp Beckhove 2 , Gero Brockhoff 3 , Matthias Gunther Hautmann 4 , Torsten Erich Reichert 1 , Richard Josef Bauer 1, 5 and Tobias Ettl 1 1 Department of Oral and Maxillofacial Surgery, University Hospital Regensburg, Regensburg, Germany 2 Regensburg Center for Interventional Immunology, University Regensburg and Department of Hematology-Oncology, Internal Medicine III, University Hospital Regensburg, Regensburg, Germany 3 Department of Gynecology and Obstetrics, University Medical Center Regensburg, Regensburg, Germany 4 Department of Radiotherapy, University of Regensburg, Regensburg, Germany 5 Center for Medical Biotechnology, Department of Oral and Maxillofacial Surgery, University Hospital Regensburg, Regensburg, Germany Correspondence to: Richard Josef Bauer, email: richard.bauer@ukr.de Keywords: PD-L1; immune checkpoint; head and neck cancer; irradiation; GSK-3beta Received: November 15, 2018 Accepted: December 13, 2018 Published: January 15, 2019 ABSTRACT At present, targeting PD-1/PD-L1 axis for immune checkpoint inhibition has improved treatment of various tumor entities, including head and neck squamous cell carcinoma (HNSCC). However, one part of the patient cohort still shows little improvement or even hyperprogression. We established three radioresistant (RR) and three radiosensitive (RS) HNSCC cell lines. RR cells showed prolonged survival as well as delayed and diminished apoptosis after irradiation with vimentin expression but no E-cadherin expression, whereas RS cell lines died early and exhibited early apoptosis after irradiation and high vimentin expression. Here, we present results demonstrating differential basal PD-L1 gene and protein expression in RR and RS HNSCC cell lines. Moreover, we observed a radiation dose dependent increase of total PD-L1 protein expression in RR cell lines up to 96h after irradiation compared to non-irradiated (non-IRR) cells. We found a significant GSK-3beta phosphorylation, resulting in an inactivation, after irradiation of RR cell lines. Co-immunoprecipitation experiments revealed decreased interaction of GSK-3beta with PD-L1 in non-IRR compared to irradiated (IRR) RR cells leading to PD-L1 stabilization in RR cells. PD-L1 knockdown in RR cells showed a strong decrease in cell survival. In summary, our results suggest an irradiation dependent increase in basal PD-L1 expression in RR HNSCC cell lines via GSK-3beta inactivation.

PURPOSE Among patients with metastatic breast cancer (mBC), the frequency of germline mutations in cancer susceptibility genes and the clinical relevance of these mutations are unclear. In this study, a prospective cohort of patients with mBC was used to determine mutation rates for breast cancer (BC) predisposition genes, to evaluate the clinical characteristics of patients with mutations, and to assess the influence of mutations on patient outcome. PATIENTS AND METHODS Germline DNA from 2,595 patients with mBC enrolled in the prospective PRAEGNANT registry was evaluated for mutations in cancer predisposition genes. The frequencies of mutations in known BC predisposition genes were compared with results from a prospective registry of patients with nonmetastatic BC sequenced using the same QIAseq method and with public reference controls. Associations between mutation status and tumor characteristics, progression-free survival, and overall survival were assessed. RESULTS Germline mutations in 12 established BC predisposition genes (including BRCA1 and BRCA2) were detected in 271 (10.4%) patients. A mutation in BRCA1 or BRCA2 was seen in 129 patients (5.0%). BRCA1 mutation carriers had a higher proportion of brain metastasis (27.1%) compared with nonmutation carriers (12.8%). Mutations were significantly enriched in PRAEGNANT patients with mBC compared with patients with nonmetastatic BC (10.4% v 6.6%, P < .01). Mutations did not significantly modify progression-free survival or overall survival for patients with mBC. CONCLUSION Multigene panel testing may be considered in all patients with mBC because of the high frequency of germline mutations in BRCA1/2 and other BC predisposition genes. Although the prognosis of mutation carriers and nonmutation carriers with mBC was similar, differences observed in tumor characteristics have implications for treatment and for future studies of targeted therapies.

Background: The therapeutic armamentarium for patients with metastatic breast cancer is becoming more and more specific. Recommendations from clinical trials are not available for all treatment situations and patient subgroups, and it is therefore important to collect real-world data. Summary: To develop recommendations for up-to-date treatments and participation in clinical trials for patients with metastatic breast cancer, the Prospective Academic Translational Research PRAEGNANT Network was established to optimize the quality of oncological care in the advanced therapeutic setting. The main aim of PRAEGNANT is to systematically record medical care for patients with metastatic breast cancer in the real-life setting, including the outcome and side effects of different treatment strategies, to monitor quality-of-life changes during therapy, to identify patients eligible for participation in clinical studies, and to allow targeted therapies based on the molecular structures of breast carcinomas. Key Messages: This article describes the PRAEGNANT network and sheds light on the question of whether the various end points from clinical trials can be transferred to the real-world treatment situation.

The aim of this study was to identify risk factors for surgical (SSI) and remote site (RSI) infections, pathogens and antibiotic resistances in patients after pedicled and free flap reconstruction in the head and neck area. SSI criteria implicated infections affecting superficial or deep tissue in the flap area with purulent discharge, fistula, abscess formation and local infections signs. RSI criteria were defined as infections remote from the surgical site presenting with systemic symptoms like fever, leucocytosis, increase in C-reactive protein, purulent tracheobronchial secretion or deterioration of blood gases. Focus adequate specimen sampling and aerobic and anaerobic incubation and cultivation was performed. Epidemiological data, factors directly related to surgery or reconstruction, perioperative antibiotic regimen, length of stay, autologous blood transfusion and microbiological aspects were retrospectively analysed in 157 patients. 10.8% of patients presented SSI, 12.7% RSI. Cultivated bacteria were sampled from flap sites, blood cultures, central catheters and sputum including mainly gram-negative bacteria (70.3%) being frequently resistant against penicillin (85%) and third generation cephalosporine derivates (48%). Autologous blood transfusion (p = 0.018) and perioperative clindamycin use (p = 0.002) were independent risk factors for overall (SSI and RSI combined) infections. Prior radiation (p = 0.05), autologous blood transfusion (p = 0.034) and perioperative clindamycin use (p = 0.004) were predictors for SSIs. ASA >2 (p = 0.05) was a risk factor for remote site infections and prolonged ICU stay (p = 0.002) was associated with overall infections, especially in irradiated patients. Efforts need to be made in improving patient blood management, antibiotic stewardship and accurate postoperative care to avoid postoperative infections after head and neck reconstructive surgery.

Background Microvascular tissue transfer (MTT) has been established as the gold standard in oral- and maxillofacial reconstruction. However, free flap surgery may be critical in multimorbid elderly patients and after surgery or radiotherapy, which aggravate microsurgery. This study evaluates indications and outcome of the submental island flap (SMIF) and the pectoralis major myocutaneous flap (PMMF) as alternatives to the free radial forearm flap (RFF). Methods This retrospective study included 134 patients who had undergone resection and reconstruction with SMIF, PMMF, or RFF at our department between 2005 and 2020. The level of comorbidity was measured with the Age-adjusted Charlson comorbidity index (ACCI). Primary outcome variables were flap success, complications, wound dehiscence, surgery duration, as well as time at the ICU and the ward (hospitalization). Chi-square tests, t-tests, and ANOVA were performed for statistics. Results 24 SMIFs, 52 RFFs, and 58 PMMFs were included in this study. The flap types did not significantly differ in terms of flap success, complications, and healing disorders. The SMIF presented a success rate of 95.8% and was significantly more often used in elderly patients (mean age = 70.2 years; p p p p p = 0.009) and the ward (p p p p p Conclusions The pedicled SMIF represents a valuable reconstructive option for elderly patients with increased comorbidity because of the shorter duration of surgery and hospitalization. On the other hand, the PMMF serves as a solid backup solution after head and neck surgery or radiotherapy. The rates of flap success, complications, and healing disorders of both pedicled flaps are comparable to those of free flap reconstruction.

Background Radiotherapy aggravates implant‐based prosthetic rehabilitation in patients with head and neck cancer. Purpose To evaluate the impact of radiation dose at implant and parotid gland site for prosthetic rehabilitation. Material and methods The retrospective study includes 121 irradiated head and neck cancer patients with 751 inserted implants. Radiation doses on implant bed and parotid gland site were recorded by 3‐dimensional modulated radiation plans. Implant success was clinically and radiographically evaluated according to modified Albrektsson criteria and compared to treatment‐ and patient‐specific data. Results Implant overall survival after 5 years was 92.4% with an implant success rate of 74.9%. Main reasons for implant failure were marginal bone resorption (20.9%), implant not in situ or unloaded (9.6%) and peri‐implantitis (7.5%). A mean radiation dose of 62.6 Gy was applied with a mean parotid dose of 35 Gy. Modulating radiation techniques went along with lower grades of xerostomia (p < 0.001). At implant site mean doses of 57.5, 42.0, and 32.3 Gy were recorded for oral, oropharyngeal, and hypopharyngeal/laryngeal carcinoma, respectively. Implant success inversely correlated to radiation dose at implant site. Strong predictors for implant failure in uni‐ and multivariate analysis were implant‐specific dose >50 Gy (HR 7.9), parotid dose >30 Gy (HR 2.3), bone (HR 14.5) and soft tissue (HR 4.5) transplants, bad oral hygiene (HR 3.8), nonmodulated radiation treatment planning (HR 14.5), and nontelescopic prosthetics (HR 5.2). Conclusion Radiotherapy impedes implant success in a dose‐dependent manner at implant site. Modern radiation techniques effectively reduce xerostomia favoring implant‐based prosthetic rehabilitation. Implantation in bone grafts is more critical and telescopic‐retained overdentures should be preferred.

Background In the phase III OlympiAD trial, olaparib significantly increased progression-free survival (PFS) compared with chemotherapy of physician's choice in patients with germline BRCA-mutated (gBRCAm), human epidermal growth factor 2 (HER2)-negative metastatic breast cancer (mBC). The phase IIIb LUCY trial assessed the clinical effectiveness of olaparib in similar patients, in a setting reflecting clinical practice. Methods This open-label, single-arm trial of olaparib (300 mg, twice daily) enrolled patients with BRCAm, HER2-negative mBC who had received taxane and/or anthracycline in the (neo)adjuvant/metastatic setting and not more than two lines of prior chemotherapy for mBC. Patients with hormone receptor–positive mBC had progressed on at least one line of endocrine therapy in an adjuvant/metastatic setting and were unsuitable for further endocrine treatment. This interim analysis was planned after 160 PFS events. Results Of 563 patients screened, 252 patients with gBRCAm were enrolled and received at least one dose of olaparib. The median investigator-assessed PFS was 8.11 months (95% confidence interval [CI], 6.93–8.67; 166/252 events [65.9% maturity]). The investigator-assessed clinical response rate was 48.6%, and median time to first subsequent treatment or death was 9.66 months (95% CI, 8.67–11.14). The most common treatment-emergent adverse events (TEAEs; >20% patients) were nausea, anaemia, asthenia, vomiting and fatigue. Eleven patients (4.4%) discontinued treatment because of a TEAE. Grade 3 or higher TEAEs occurred in 64 patients (25.4%), including anaemia (33 patients; 13.1%). Conclusion Olaparib was clinically effective in patients with gBRCAm, HER2-negative mBC with safety outcomes consistent with previous findings. ClinicalTrials.gov identifier: NCT03286842 .

Introduction/Background Breast cancer is the most common cancer of the female, and the second most common cancer overall. While chemotherapy is standard of care for many patients with this type of cancer, it is associated with various side effects that require supportive care. In addition to standard medical therapies, patients may benefit from complementary treatments, such as sport therapy or Reiki. Reiki is a far eastern method that promotes healing on a physical, mental and emotional level and activates self-healing powers. Aim of this study was to compare the efficacy of Reiki versus Sport as supportive care during primary systemic therapy of early breast cancer within the REASSURE study. Methodology REASSURE was a prospective, randomized, controlled, two-armed clinical trial, in which patients with breast cancer received chemotherapy and Reiki (18 times) or chemotherapy and sport (18 times). This evaluation specifically focused on patients who received neoadjuvant chemotherapy with four cycles of Epirubicin and Cyclophosphamide followed by 12 cycles of a Taxane. All patients were enrolled in the REASSURE-study and randomized before their first chemotherapy cycle. While sport therapy was delivered as conventional physiotherapy, Reiki was delivered by a trained Reiki practitioner. We conducted a statistical analysis using Wilcoxon Rank sum tests to compare incidence of adverse events (febrile neutropenia (FNP), fever, infection, blood count variation, hospitalization), dose modifications (therapy discontinuation, dose interruption, dose reduction) and use of conventional medical supportive care treatments (G-CSF, antibiotics, blood transfusion, platelet transfusion). Results A total of 48 subjects were included, of which 27 received Reiki and 21 received sport treatment. When comparing FNP events between both groups, we found 3 events in the sport group, whereas there were none in the Reiki group (p = 0.047). The median number of GCSF-application was 4 (range 0 to 8) in the sport group versus 0 (range 0 to 8) in the Reiki group (p = 0.006). For all other parameters, calculation of 95 percent confidence intervals showed no clinically significant difference between the two groups. Conclusion Reiki may pose a viable alternative medical treatment option to sport as a supportive therapy option to combat side effects of neoadjuvant Epirubicin, Cyclophosphamide and Taxane chemotherapy for breast cancer treatment. To better understand the beneficial influence of this therapy, further research is needed to compare Reiki with a control group receiving no additional therapy. Disclosures REASSURE Studie - This study is a collaborative study between Frauenklinik Rechts der Isar, Frauenklinik des Rotkreuzklinikums, Frauenklinik der Munchen Klinik Harlaching, and ProReiki – Berufsverband e.V.. There was no funding. There are no conflicts of interest.

Introduction: Extracorporeal Cardiopulmonary Resuscitation (ECPR) may achieve ROSC after prolonged CA when conventional cardiopulmonary resuscitation fails. We investigated the impact of ECPR on cardiac hemodynamic recovery and hypothesized, that left ventricular hemodynamic function is impaired in resuscitated hearts. Methods: Adult male Sprague-Dawley rats (500 g, n=36) were subjected to 6 or 8 min of ventricular fibrillation CA, thereafter resuscitated with ECPR (open reservoir, roller pump, membrane oxygenator, draining catheter in the right jugular vein, inflow catheter in the right femoral artery; custom made bypass system), mechanical ventilation and drugs (epinephrine, bicarbonate, heparin). After defibrillation and ROSC, rats survived for 14 days and were compared to 7 sham animals. The hearts were isolated and mounted onto an erythrocyte-perfused, isolated working heart (WH) system. Cardiac output, left ventricular systolic pressure (LVSP), coronary flow and pressure-volume (P-V) relationships (by increasing the afterload in 10 mmHg increments) were measured. Myocardium of all rats was evaluated pathohistological in hematoxylin-eosin staining. Results: ROSC was achieved in 18 animals after 6 min of CA, of which 10 survived 14 d and 7 were investigated in WH, in 8 min CA group 15 achieved ROSC of which 5 survived to 14 d and 2 were investigated in WH and compared to the hearts of 7 sham animals. At defined afterload (60 mm Hg; baseline) there was no difference in cardiac hemodynamics between sham and 6 min CA group. In contrast, 8 min CA rats showed a tendency towards decrease in cardiac output and LVSP compared to sham animals. Notably, both CA groups showed impaired P-V loop relationship and subsequently less tolerance to hemodynamic stress. Histologically all 8 min CA rats showed multiple foci of myocardial scarring. Conclusions: CA led to impaired left ventricular hemodynamics in 8 min CA rats resuscitated with ECPR. In addition, hearts were more vulnerable to hemodynamic stress after successful resuscitation. For investigating the effects of future therapy approaches during and after resuscitation from CA on the heart function, isolated WH might be a promising approach in resuscitation research.

A version of the Institute for Safe Medication Practices (ISMP) questionnaire adapted to the Austrian inpatient setting was used to sample the estimates of a group of experts regarding the level of medication safety in a level II hospital. To synthesize expert opinions on a group level reproducibly, classical Delphi method elements were combined with an item weight and performance weight decision-maker. This newly developed information synthesis method was applied to the sample dataset to examine method applicability. Method descriptions and flow diagrams were generated. Applicability was then tested by creating a synthesis of individual questionnaires. An estimate of the level of medication safety in an Austrian level II hospital was, thus, generated. Over the past two decades, initiatives regarding patient safety, in general, and medication safety, in particular, have been gaining momentum. Questionnaires are state of the art for assessing medication practice in healthcare facilities. Acquiring consistent data about medication in the complex setting of a hospital, however, has not been standardized. There are no publicly available benchmark datasets and, in particular, there is no published method to reliably synthesize expertise regarding medication safety on an expert group level. The group-level information synthesis method developed in this study has the potential to synthesize information about the level of medication safety in a hospital setting more reliably than unstructured approaches. A medication safety level estimate for a representative Austrian level II hospital was generated. Further studies are needed to establish convergence characteristics and benchmarks for medication safety on a larger scale.

Simple Summary In the last decades, tremendous advances have been made in understanding HER2-positive breast cancer biology, with a progressive improvement in survival rates of patients with this breast cancer subtype. However, a not negligible proportion of patient with HER2-positive breast cancer will eventually relapse, and metastatic HER2-positive disease is still to be considered an incurable condition, thus highlighting the imperative need to further improve our understanding in this regard. In this context, there is growing knowledge that HER2-overexpressing breast tumors are highly heterogeneous, and the co-expression of hormone-receptors may account, at least in part, for this heterogeneity. The aim of the present work is to review preclinical and clinical evidence on HER2-positive/hormone-receptor positive breast cancer, focusing on studies investigating both activity and efficacy of various combination of treatment strategies, including anti-HER2 drugs, hormonal treatments and other targeted agents, such as CDK inhibitors, both in the early and advanced setting. Abstract Enormous advances have been made in the understanding and treatment of human epidermal growth factor receptor 2-positive breast cancer (HER2+ BC) in the last 30 years that have resulted in survival gains for affected patients. A growing body of evidence suggests that hormone receptor-positive (HR+)/HER2+ BC and HR-negative (HR−)/HER2+ BC are biologically different, with complex molecular bidirectional crosstalk between the estrogen receptor and HER2 pathway potentially affecting sensitivity to both HER2-targeted and endocrine therapy in patients with HR+/HER2+ BC. Subgroup analyses from trials enrolling patients with HER2+ BC and the results of clinical trials specifically designed to evaluate therapy in patients with HR+/HER2+ BC are helping to guide treatment decisions. In this context, encouraging results with strategies aimed at delaying or reversing drug resistance, including extended adjuvant therapy and the addition of drugs targeting alternative pathways, such as cyclin-dependent kinase (CDK) 4 and 6 inhibitors, have recently emerged. We have reached the point where tailoring the treatment according to risk and biology has become the paradigm in early BC. However, further clinical trials are needed that integrate translational research principles and identify and consider specific patient subgroups and biomarkers.

PURPOSE The cornu ammonis 1 (CA1) region of the hippocampus is specifically vulnerable to global ischemia. We hypothesized that histopathological outcome in a ventricular fibrillation cardiac arrest (VFCA) rat model depends on the time point of the examination. METHODS Male Sprague-Dawley rats were put into VFCA for 8 min, received chest compressions for 2 min, and were defibrillated to achieve return of spontaneous circulation. Animals surviving for 80 min, 14 days and 140 days were compared with controls. Viable neurons were counted in a 500 μm sector of the CA1 region and layer thickness measured. Microglia cells and astrocytes were counted in a 250×300 μm aspect. RESULTS Control and 80 min surviving animals had similar numbers of pyramidal neurons in the CA1 region. In 14 days and 140 days survivors neuron numbers and layer thickness were severely diminished compared with controls (P

Heme oxygenase (HO) and biliverdin reductase (BVR) activities are important for neuronal function and redox homeostasis. Resuscitation from cardiac arrest (CA) frequently results in neuronal injury and delayed neurodegeneration that typically affect vulnerable brain regions, primarily hippocampus (Hc) and motor cortex (mC), but occasionally also striatum and cerebellum. We questioned whether these delayed effects are associated with changes of the HO/BVR system. We therefore analyzed the activities of HO and BVR in the brain regions Hc, mC, striatum and cerebellum of rats subjected to ventricular fibrillation CA (6 min or 8 min) after 2 weeks following resuscitation, or sham operation. From all investigated regions, only Hc and mC showed significantly decreased HO activities, while BVR activity was not affected. In order to find an explanation for the changed HO activity, we analyzed protein abundance and mRNA expression levels of HO-1, the inducible, and HO-2, the constitutively expressed isoform, in the affected regions. In both regions we found a tendency for a decreased immunoreactivity of HO-2 using immunoblots and immunohistochemistry. Additionally, we investigated the histological appearance and the expression of markers indicative for activation of microglia [tumor necrosis factor receptor type I (TNFR1) mRNA and immunoreactivity for ionized calcium-binding adapter molecule 1 (Iba1])], and activation of astrocytes [immunoreactivity for glial fibrillary acidic protein (GFAP)] in Hc and mC. Morphological changes were detected only in Hc displaying loss of neurons in the cornu ammonis 1 (CA1) region, which was most pronounced in the 8 min CA group. In this region also markers indicating inflammation and activation of pro-death pathways (expression of HO-1 and TNFR1 mRNA, as well as Iba1 and GFAP immunoreactivity) were upregulated. Since HO products are relevant for maintaining neuronal function, our data suggest that neurodegenerative processes following CA may be associated with a decreased capacity to convert heme into HO products in particularly vulnerable brain regions.

Background: The purpose of the study was to categorize the vitality and inflammation of resected bone of patients with medication-related osteonecrosis of the jaw (MRONJ) and to correlate the grade of inflammation with the surgical success. Methods: This prospective study includes 44 patients with stage III MRONJ. Necrotic bone was resected in a block fashioned way. After demineralization and staining, histological analyses were performed by measuring the areas of necrotic, vital, and regenerative bone. Areas of chronic and acute inflammation were categorized as non, mild, moderate, and severe and were correlated with surgical success and parameters of inflammation in blood plasma (C-reactive protein and leukocytes). Results: An average area of 59.0% was necrotic in the examined specimen. Vital bone was measured with an average area of 40.9%. The stage of chronic inflammation correlated with the amount of vital bone (P < .001) and the success of surgery (P = .002). If acute inflammation was dominant, chronic inflammation areas were found less while necrotic areas were observed more (P < .001). Also, the risk of relapses, wound healing disorders, and the level of C-reactive protein were elevated if acute inflammation was severe or moderate (P = .031). Areas of bone regeneration were seen only in 11.3% of vital bone areas and occurred independently of infection stages. Conclusion: If possible, surgery should be delayed in patients with signs of severe acute inflammation. Patients may profit from prolonged pre-operative antibiotic therapy to reduce the level of acute inflammation.

BackgroundPalbociclib improves outcomes for women with hormone receptor–positive/human epidermal growth factor receptor 2–negative advanced breast cancer (HR+/HER2− ABC). Dose reductions are recommended for the management of hematologic toxicities. A previous pooled analysis from the PALOMA clinical trials showed that 36.9% of patients required dose reduction, predominantly during the first 6 months of treatment and with decreasing frequency during subsequent 28-day treatment cycles (C). Previous data have shown that palbociclib dose reductions do not affect efficacy. This pooled, post hoc analysis evaluated the frequency of hematologic adverse events (AEs) before and after palbociclib dose reduction in PALOMA-1, PALOMA-2, and PALOMA-3.MethodsThis analysis evaluated the frequency of hematologic AEs 30 days before dose reduction and during each subsequent treatment from C1 to C6 among patients who required palbociclib dose reduction. Data were pooled from 3 randomized studies. PALOMA-1 was a phase 2, open-label study of postmenopausal patients untreated for ABC receiving palbociclib plus letrozole or letrozole alone. PALOMA-2 was a phase 3, double-blind study of postmenopausal patients untreated for ABC receiving palbociclib plus letrozole or placebo plus letrozole. PALOMA-3 was a phase 3, double-blind study of pre/perimenopausal or postmenopausal patients, whose disease progressed on prior endocrine therapy, receiving palbociclib plus fulvestrant or placebo plus fulvestrant.ResultsA total of 311 (35.5%) patients with HR+/HER2− ABC required a palbociclib dose reduction (93.6% due to AEs) from 125 to 100 mg. Mean patient age was 59.9 years, and 46.9% of patients had visceral disease. Median time to dose reduction was 70 days. The majority of dose reductions occurred within 3 months of starting palbociclib treatment. Incidences of all-grade and grades 3/4 hematologic AEs were lower following dose reduction.ConclusionsA decrease in frequency and severity of hematologic AEs, including febrile neutropenia, following palbociclib dose reduction was observed, supporting the recommended use of dose reduction in AE management.Trial registrationThese studies were sponsored by Pfizer. ClinicalTrials.gov:NCT00721409; registration date July 24, 2008. ClinicalTrials.gov:NCT01740427; registration date December 4, 2012. ClinicalTrials.gov:NCT01942135; registration date September 13, 2013.

Background Talazoparib is a poly(adenosine diphosphate-ribose) polymerase inhibitor that causes death in cells with breast cancer susceptibility gene 1 or 2 (BRCA1/2) mutations. Methods EMBRACA (NCT01945775) was a randomized phase III study comparing efficacy, safety, and patient-reported outcomes (PROs) of talazoparib (1 mg) with physician’s choice of chemotherapy (PCT: capecitabine, eribulin, gemcitabine, vinorelbine) in locally advanced or metastatic breast cancer with a germline BRCA1/2 (gBRCA1/2) mutation. Prespecified patient subgroups were analyzed for progression-free survival, objective response, clinical benefit, duration of response, and safety. PROs were evaluated in hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2−) or triple-negative breast cancer (TNBC) subgroups. Results Of 431 patients, 287 were randomly assigned to talazoparib and 144 to PCT. Prespecified subgroup analyses showed prolonged progression-free survival with talazoparib (HR+/HER2−: hazard ratio = 0.47, 95% confidence interval = 0.32 to 0.71; TNBC: hazard ratio = 0.60, 95% confidence interval = 0.41 to 0.87) and greater objective response rate (odds ratio = 1.97 to 11.89), clinical benefit rate (odds ratio = 2.05 to 7.77), and duration of response with talazoparib in all subgroups. PROs in HR+/HER2− and TNBC subgroups showed consistent overall improvement and delay in time to definitive clinically meaningful deterioration with talazoparib vs PCT. Across subgroups, common adverse events included anemia, fatigue, and nausea with talazoparib and neutropenia, fatigue, and nausea with PCT. Seven patients (2.4%) receiving talazoparib had grade II alopecia and 22.7% had grade I alopecia. Conclusions Across all patient subgroups with gBRCA-mutated advanced breast cancer, talazoparib demonstrated clinically significant superiority in outcomes compared with PCT.

New therapeutic developments aimed at treating women with advanced breast cancer currently focus both on identifying patients eligible for targeted therapeutic concepts and on the continuing development of immune therapies. The data on CDK4/6 inhibitors are now complete and consistent in this class of substances (palbociclib, ribociclib and abemaciclib). Further pathways under investigation are PI3K and AKT signalling pathways along with diverse approaches to their inhibition. Initial study results were also presented recently on both mechanisms of action. Insights into the PARP inhibitors, moreover, are increasing; studies in this respect are also examining in which population they can be used most effectively. This review offers a summary of the recent studies and an outline of the latest developments.Neue Therapieentwicklungen zur Behandlung von Patientinnen mit fortgeschrittenem Mammakarzinom konzentrieren sich zurzeit sowohl auf die Identifikation von Patientinnen für zielgerichtete Therapieansätze als auch auf die Weiterentwicklung von immuntherapeutischen Ansätzen. Die Datenlage zu den CDK4/6-Inhibitoren konnte vervollständigt werden und ist konsistent in dieser Klasse von Substanzen (Palbociclib, Ribociclib und Abemaciclib). Weitere Signalwege, die untersucht werden, sind der PI3K-und der AKT-Signalweg sowie verschiedene Ansatzpunkte zu deren Hemmung. Für beide Wirkmechanismen liegen auch erste Studienergebnisse vor, die vor Kurzem vorgestellt wurden. Außerdem wachsen die Erkenntnisse zu den PARP-Inhibitoren, für die auch untersucht wird, in welcher Population sie am effektivsten eingesetzt werden können. Dieser Review-Artikel soll die aktuellen Studien zusammenfassen und einen Ausblick der neuesten Entwicklungen geben.

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.

In the EMBRACA phase III trial, talazoparib (1 mg daily, orally) demonstrated a statistically significant improvement in PFS versus physician's choice of chemotherapy (PCT; capecitabine, eribulin, gemcitabine, or vinorelbine) in patients with HER2-negative advanced breast cancer carrying a germline BRCA1/2 mutation; we evaluated patient-reported outcomes (PROs).Patients were randomized 2 : 1 to receive talazoparib or PCT. PROs were assessed at day 1 (baseline), the start of each treatment cycle (every 3 weeks), and at the end of treatment, using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-30) and its breast cancer module, QLQ-BR23. Prespecified exploratory analyses included a longitudinal mixed-effect model comparing treatment arms and a time to definitive clinically meaningful deterioration (TTD) analysis carried out in the global health status/quality of life (GHS/QoL), and all functional and symptom scales from the EORTC QLQ-C30 and -BR23 questionnaires. Between-arm TTD comparisons were made using a stratified log-rank test and a Cox proportional hazards model.Baseline scores were similar between arms. Statistically significant estimated overall improvement from baseline in GHS/QoL was seen for talazoparib compared with statistically significant deterioration for PCT {3.0 [95% confidence interval (CI) 1.2, 4.8] versus -5.4 [95% CI -8.8, -2.0]; between arms, P 0.0001}. A statistically significant greater delay was observed in TTD in GHS/QoL, favoring talazoparib over PCT [hazard ratio, 0.38 (95% CI 0.26, 0.55; median, 24.3 versus 6.3 months, respectively; P 0.0001)]. A statistically significant overall change and a statistically significant delay in TTD, all favoring talazoparib, were also observed in multiple functions and symptoms.Patients who received talazoparib had significant overall improvements and significant delay in TTD in multiple cancer-related and breast cancer-specific symptoms, functions, and GHS/QoL.NCT01945775.

Background CXCR4 is a chemokine receptor frequently overexpressed in invasive breast cancer that has been shown to play a major role in signaling pathways involved in metastasis. The aim of this retrospective analysis was to assess the diagnostic performance of CXCR4-directed PET imaging in patients with breast cancer using the recently introduced CXCR4-targeted PET probe 68Ga-Pentixafor. Results Thirteen patients with first diagnosis of breast cancer, four patients with recurrent disease after primary breast cancer, and one patient with axillary lymph node metastasis of unknown primary underwent CXCR4-targeted PET imaging using 68Ga-Pentixafor. Maximum standardized uptake values (SUVmax) and tumor-to-background (T/B) ratios of tumor lesions were measured and compared with pathological prognostic factors and molecular subtypes. 18F-FDG PET/CT images were available in 8/18 cases and were compared semi-quantitatively. Comparison with CXCR4 expression determined by immunohistochemistry was performed in 7/18 patients. Nine of 13 primary breast cancers were visually detectable on 68Ga-Pentixafor PET images (mean SUVmax of 3.0). The visually undetectable lesions included both cases of invasive lobular carcinoma (ILC) and two cases of invasive carcinoma of no special type (NST) without any hormone receptor and HER2 expression (triple negative). Metastases of recurrent breast cancer and unknown primary cancer were visually detectable in all five cases, exhibiting a mean SUVmax of 3.5. 18F-FDG PET demonstrated higher SUVmax in all patients compared to 68Ga-Pentixafor PET. A correlation between SUVmax obtained from 68Ga-Pentixafor PET and prognostic factors including estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) status, proliferation index, tumor grade, or molecular subtypes was not observed. Conclusions CXCR4-directed PET imaging in patients with primary and recurrent breast cancer is feasible; however, tumor detectability is significantly lower compared to 18F-FDG PET. Moreover, we did not find any correlation between aforementioned prognostic factors of breast cancer and CXCR4-targeted tracer accumulation. Based on these results in a small patient cohort, CXCR4-targeted PET imaging does not seem to be suitable as a general diagnostic tool for imaging of breast cancer. Future CXCR4 imaging studies should investigate whether this modality might be useful in more specific applications, e.g., in therapeutic approaches especially under the view of current developments in targeted immune cell and immune checkpoint inhibitory therapy.