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Background: POLARIS is an ongoing, prospective, real world, noninterventional study in patients (pts) with HR+/HER2– ABC receiving PAL. This interim report describes real-world PAL use in preMeno pts. Methods: POLARIS has a targeted enrollment of 1500 pts from ~110 sites in the United States and Canada. Using patient data collected from medical charts and physician surveys, baseline demographics, clinical characteristics, and treatment patterns were analyzed descriptively in self-reported preMeno pts with ABC. Results: At the data cutoff of May 20, 2020, 1208 pts were enrolled; 134 (11.1%) from 61 sites were preMeno, of whom 14.2% completed ≥6 months of PAL treatment. Among 134 preMeno pts (74.6%) who received first-line (1L) therapy, 69.0% received PAL+letrozole (LET) or anastrozole, 28.0% PAL+fulvestrant, and 3.0% PAL+exemestane. Median disease-free interval was 39.3 (range: 0 to 236) months; median treatment-free interval was 14.8 (-3 to 134) months. Of 34 pts (25.4%) who received PAL as second or later line (≥2L), 23.8% previously received hormonal therapy, 28.6% chemotherapy, and 14.3% both. The majority of pts (96.27%) initiated PAL at 125 mg regardless of line of therapy (Table). During the first PAL treatment cycle, 2.9% of all preMeno pts, 1% of 1L pts, and 8.8% of ≥2L pts had a dose reduction; 8.2%, 9%, and 5.9%, respectively, had an interruption. Dose reductions/interruptions peaked in cycle 2 (11.9%/15.7%); 56.67% of these modifications were due to adverse events. Conclusions: PAL is routinely prescribed in clinical practice for preMeno women with HR+/HER2- ABC. The majority of preMeno pts in this real-world dataset received PAL+LET as 1L ABC treatment; PAL was primarily initiated at the recommended dose (125 mg) and was well tolerated with few dose modifications required. Clinical trial identification: Pfizer (NCT03280303) Table.CharacteristicFirst-Line Pre/Perimenopausal Patients (n=100)Second or Later Line Pre/Perimenopausal Patients (n=34)Pre/Perimenopausal Patients (N=134)Age at study enrollment, yMedian (range)44 (22-61)42.5 (27-58)44 (22-61)Distribution, n (%) Citation Format: Meghan S Karuturi, Adnan Garrett, Joanne L Blum, Jay Anderson, Erin Jepsen, Timothy Pluard, Thomas Stanton, Kenneth Manning, Joseph C Cappelleri, Faith Beery, Yao Wang, Debu Tripathy. Pre/perimenopausal (preMeno) women receiving palbociclib (PAL) for hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2–) advanced breast cancer (ABC) in a real-world setting: Treatment patterns from POLARIS [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 PS7-19.

Background: The COVID-19 pandemic is negatively affecting patient enrollment, therapy administration, and patient visits in breast cancer clinical trials worldwide. COVID-19 may have a lasting impact on how clinical trials are conducted, and guidelines are necessary to inform trial design and patient safety. While many groups and journals have recently published guidelines, including NCCN, ESMO, IQVIA, and Lancet Oncology, there is no consensus on how to treat patients in the current environment. Understanding and quantifying the impact of the pandemic on clinical study sites will help inform the rational development of a consensus approach. The goal of this survey was to gather site-level data on the impact of COVID-19 from clinical sites participating in the POLARIS study (NCT03280303), an ongoing, prospective, real-world, noninterventional study in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer receiving palbociclib plus endocrine therapy. Methods: Two rounds of questionnaires were sent to investigators at POLARIS study sites: 1 via email March 26-27, 2020, and 1 via telephone from April 30-May 20, 2020. The questions on COVID-19 impact and management are shown in the Table. Results: Eighty of 122 POLARIS study sites contacted responded to the March questionnaire, and 86 responded to the April-May questionnaire. In March, 33% (26/80) of the surveyed population were working predominantly remotely, 26% (21/80) were working both onsite and remotely, and 31% (25/80) were working onsite. Approximately 24% of sites reported delayed data entry. The option of telemedicine or office visits was offered to subjects at approximately 73% (58/80) of sites, and 11% (9/80) of sites were restricted to telemedicine visits. In April-May, 36% (31/86) of respondents reported an impact on study management and 64% (55/86) reported no impact. Approximately 94% (81/86) of surveyed sites felt they were able to maintain clinical studies despite the challenges due to COVID-19, and 79% (68/86) of sites had the option for telemedicine and/or office visits, while 18% (16/86) had no telemedicine alternative. In April-May, 38% of sites reported an impact on patient visits. Conclusion: Although these findings must be interpreted with caution due to the limitations of survey studies, the results suggest that approximately 1/3 of the study sites will experience an impact on their responsiveness to correspondence, timely data entry, and subject management due to the COVID-19 pandemic. Telemedicine may be used to mitigate the effect of the pandemic on clinical trial execution. Pfizer (NCT03280303) Table. Survey QuestionsMarch Questionnaire (March 26-27, 2020)QuestionResponsesWorking onsite or remotely?26 sites are predominately working remotely21 sites are working a combination of onsite and remotely25 sites are working onsite7 sites provided inconclusive responsesSubject visits in office, by phone, by video, or a combination of 3 options?50 sites are using a combination of onsite and telemedicine8 sites have onsite visits9 sites have telemedicine visits only8 sites provided inconclusive responses4 instances where question was inapplicable due to no active subjectsIs data entry delayed?19 sites responded Yes54 sites responded No6 sites provided inconclusive responsesIs collection of biomarker blood samples impacted?11 sites indicated there will be impact to biomarker collection28 sites indicated there will be no impact to biomarker collection40 instances where question was inapplicable due to no subjects participating in collectionWhat other study areas are impacted?20 sites indicated impact due to financial challenges or limited abilities while working remotelyRemaining sites did not note any additional areas of impactPatient-reported outcome questionnaire issues?Most sites had not experienced any issues, but an overwhelming majority inquired about the ability to do them via phone or mail. Many sites and subjects expressed preference for the paper questionnaire instead of the electronic version.May Questionnaire (April 30-May 20, 2020)QuestionResponsesHas COVID-19 impacted your site’s ability to execute a study?55 sites responded No• Clarify impact on your site31 sites responded Yes• Subject visits impacted (limited onsite visits): 24• Institutional restrictions/limited staff: 7Is there any impact on scheduled onsite standard of care patient visits?53 sites responded No33 sites responded YesPlease indicate which if any of the following apply to your site:67 sites responded that telemedicine is in place for subject visitsProcess in place for remote patient study visits16 sites responded that there is no alternative for telemedicineProcess is used for remote patient study visits1 site noted that they have no active subjectsAlternative methods are available to deliver drug1 site noted that subjects are attending on site visitsOther1 site did not respond to questionHow able are you to maintain ongoing studies at this time?27 sites are extremely able to do so42 sites are very able to do soExtremely able to do so12 sites are moderately able to do soVery able to do so5 sites are able to do so only a littleModerately able to do so• COVID impact is felt more profoundly at 4 sitesA little able to do so• Financial barrier has limited one site’s time on studyNot at all able to do so0 Sites unable to do so at all Citation Format: Debu Tripathy, Joanne L Blum, Gabrielle Rocque, J. Daniel Cuevas, Jennifer Specht, Steven Corso, Jawad E Francis, Stephanie Mendez, Veneta Pope, Joseph Cappelleri, Yao Wang. Impact of COVID-19 on study sites: Survey analysis from the noninterventional POLARIS study [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 SS2-10.

Resume Introduction Le syndrome main-pied-bouche (SMPB) est une dermatose virale connue chez l’enfant ou sa presentation clinique est souvent caracteristique. Sa survenue chez l’adulte est plus rare, de presentation polymorphe et peut representer un vrai defi diagnostique pour le clinicien. Patients et methodes Il s’agit d’une serie de cas retrospective de 2013 a 2018 de SMPB chez l’adulte, tous confirmes par amplification en chaine par polymerase (PCR) positive a enterovirus. Nous avons etudie les caracteristiques cliniques, epidemiologiques, et virologiques de chaque patient. Resultats Nous rapportons les cas de quatre hommes et deux femmes d’âge moyen 42,5 ans. Cinq patients avaient des lesions purpuriques etendues, quatre patients avaient des lesions bulleuses, trois patients avaient une atteinte cutanee pure sans atteinte des muqueuses et quatre patients avaient des lesions etendues sur le tronc. Deux patients ont presente soit des lesions en cocarde et pustuleuses des extremites, soit une plaque eczematiforme etendue avec une atteinte du cuir chevelu. Enfin, un purpura en nappe plantaire a ete observe chez un patient. Discussion Ces differents cas de SMPB chez l’adulte posent la question du diagnostic differentiel avec d’autres eruptions aigues cutaneomuqueuses. La connaissance de ces presentations diverses chez l’adulte est essentielle afin de pouvoir etablir le diagnostic et appliquer les conseils de prevention.

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.

This report describes the rationale, purpose and design of the POLARIS study. POLARIS is an ongoing noninterventional, prospective, multicenter study. Female and male patients in the USA and Canada diagnosed with hormone receptor-positive/HER2-negative metastatic breast cancer were enrolled in the study and treated with the cyclin-dependent kinase 4/6 inhibitor palbociclib when hormone receptor-positive/HER2-negative metastatic breast cancer was deemed to be indicated by their physician. The study will provide real-world data on palbociclib prescribing and treatment patterns in routine clinical practice, associated clinical outcomes, treatment sequencing in the advanced/metastatic setting, patient quality of life and geriatric-specific assessments. The tumor genomic landscape in relation to clinical outcomes will be explored. POLARIS will identify benefits and side effects of palbociclib across multiple lines of therapy and in discrete subsets of patients. Clinical Trial Registration: NCT03280303 ( ClinicalTrials.gov ).

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.

Background: Chemotherapy treatments with robust efficacy that preserve quality of life are needed. Tesetaxel is a novel, oral taxane that has potential advantages over currently available taxanes, including: oral administration with a low pill burden and once every 3 week (Q3W) dosing; no observed hypersensitivity reactions; preclinical evidence of central nervous system (CNS) penetration; and improved activity against chemotherapy-resistant tumors. More than 600 patients have been treated with tesetaxel in clinical studies. Tesetaxel had robust monotherapy activity in a Phase 2 study in 38 patients with HER2-, HR+ MBC, with a confirmed objective response rate (ORR) per RECIST 1.1 of 45%. CONTESSA TRIO investigates tesetaxel plus 3 different PD-(L)1 inhibitors in patients with TNBC and tesetaxel monotherapy in elderly patients with HER2- MBC. Trial design: CONTESSA TRIO is a 2-cohort, multinational, multicenter, Phase 2 study. In Cohort 1, 90 patients (with potential expansion to up to 150 patients) with metastatic TNBC who have not received prior chemotherapy for advanced disease will be randomized 1:1:1 to receive tesetaxel at 27 mg/m2 Q3W plus either: (1) nivolumab at 360 mg Q3W; (2) pembrolizumab at 200 mg Q3W; or (3) atezolizumab at 1,200 mg Q3W. Nivolumab and pembrolizumab (PD-1 inhibitors) and atezolizumab (a PD-L1 inhibitor) are approved for the treatment of multiple types of cancer; atezolizumab, in combination with nab-paclitaxel, was recently approved in the U.S. for the treatment of metastatic TNBC. The dual primary endpoints for Cohort 1 are ORR and progression-free survival (PFS). A sample size of 30 patients in each PD-(L)1 inhibitor treatment group has approximately 70% power to detect an ORR difference of 35% or greater between the treatment group with the highest ORR and the treatment group with the lowest ORR. An increase in the sample size to 50 patients in each treatment group will increase the power to approximately 85%. Secondary endpoints include duration of response (DoR) and overall survival (OS). Efficacy results for each of the 3 PD-(L)1 inhibitor combinations will be assessed for correlation with the results of each of the 3 approved PD-L1 diagnostic assays. CONTESSA TRIO is the first randomized clinical study to compare 3 approved PD-(L)1 inhibitors. In Cohort 2, 40 elderly patients (with potential expansion to up to 60 patients) with HER2- MBC who have not received prior chemotherapy for advanced disease will receive tesetaxel monotherapy at 27 mg/m2 Q3W. The primary endpoint for Cohort 2 is ORR. A sample size of 40 will allow the ORR to be estimated with a maximum standard error of < 8%. An increase in the sample size to 60 patients will decrease the maximum standard error to < 6.5%. Secondary endpoints include PFS, DoR and OS. Patients with CNS metastases are eligible for both cohorts. The Study was initiated in March 2019. For further information on this trial, email joconnell@odonate.com or visit clinicaltrials.gov (NCT03952325). Citation Format: Sara Tolaney, Joanne Blum, Igor Bondarenko, Arlene Chan, Noshir DaCosta, Yin-Hsun Feng, Yann Izarzugaza, Sung-Bae Kim, Mei-Ching Liu, Maria Eva Peréz Lopéz, Mafalda Oliveira, Samuel Guan Wei Ow, Michel Pavic, Hope Rugo, Lee Schwartzberg, Agostina Stradella, Stew Kroll, Joseph O'Connell, Thomas Wei, Elizabeth Mittendorf. CONTESSA TRIO: A multinational, multicenter, phase 2 study of tesetaxel plus 3 different PD-(L)1 inhibitors in patients with metastatic triple-negative breast cancer (TNBC) and tesetaxel monotherapy in elderly patients with HER2- metastatic breast cancer (MBC) [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 OT1-08-08.

Background: Palbociclib in combination with endocrine therapy (ie, an aromatase inhibitor [AI] or fulvestrant) is a current standard of care for patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2−) advanced or metastatic breast cancer (ABC/mBC). Findings from the PALOMA clinical trials have shown that patients receiving palbociclib with AI or fulvestrant maintained stable quality of life (QoL). However, no data are currently available from real-world settings regarding patients’ QoL experiences while receiving palbociclib. Methods: This noninterventional, prospective, multicenter study evaluated female and male patients diagnosed with HR+/HER2- ABC/mBC and treated with palbociclib as indicated by the attending physician in the routine course of care. QoL was assessed using the European Organization for the Research and Treatment of Cancer Quality-of-Life Questionnaire Core 30 (EORTC QLQ-C30). The EORTC QLQ-C30 was collected at enrollment prior to receiving palbociclib (baseline), monthly for the first 3 months of treatment with palbociclib, and then every 3 months until the end of treatment or patient withdrawal or death. The EORTC QLQ-C30 could be completed using an interactive Web response system or a paper questionnaire. Here we report demographic characteristics and interim analysis of QoL assessments as measured by EORTC QLQ-C30 at baseline and at 3 and 6 months postbaseline. Descriptive analyses are presented for subscales of the EORTC QLQ-C30. Results: 522 patients who completed ≥6 months of palbociclib treatment as of May 20, 2019, were included in this interim analysis; 394 were prescribed palbociclib as first-line treatment. The remaining 128 patients initiated palbociclib in second and later lines. Median age at enrollment was 64 years, 98% of patients were female, and 83% were white. More than half of all patients (n=285) received palbociclib in combination with letrozole or anastrozole; of the remaining patients, 218 received palbociclib plus fulvestrant and 19 received palbociclib plus exemestane. Mean (SD) EORTC QLQ-C30 scores remained similar over the first 6 months of treatment: 66.2 (22.6) at baseline, 68.3 (19.7) at 3 months, and 70.2 (21.3) at 6 months. In addition, the mean scores for each functional scale and symptom scale on the EORTC QLQ-C30 also remained stable over the first 6 months (Table). With the exception of pain scores (which declined by 7 points), the change from baseline at 6 months generally was less than 5 points across the different subscales of EORTC QLQ-C30. Conclusions: The 522 patients examined in this interim analysis experienced stable to modestly improved QoL from baseline to 6 months after starting palbociclib. Changes from baseline in EORTC QLQ-C30 scores generally were below the 10-point threshold regarded as clinically meaningful. These early findings indicate that patients enrolled in the study have maintained their baseline QoL while being treated with palbociclib. Funding: Pfizer (NCT03280303) EORTC QLQ-C30Baseline3 Months6 MonthsGlobal Health/Quality of Life*n (missing)474 (48)292 (230)409 (113)Mean (SD) score66.2 (22.6)68.3 (19.7)70.2 (21.3)Functional scales score, mean (SD)*Physical functioning75.6 (23.3)75.8 (21.9)77.2 (21.4)Role functioning72.5 (31.9)76.7 (26.1)77.1 (26.8)Emotional functioning74.8 (22.8)77.7 (22.3)79.7 (20.5)Cognitive functioning78.8 (24.6)82.7 (20.6)80.1 (22.0)Social functioning76.4 (28.3)79.5 (25.5)81.5 (24.7)Symptom scales score, mean (SD)†Fatigue34.3 (25.7)35.0 (23.6)33.7 (22.2)Nausea and vomiting11.3 (20.2)10.4 (16.4)10.6 (19.3)Pain33.5 (30.0)27.3 (27.2)26.5 (26.9)Dyspnea22.2 (28.3)18.7 (22.5)18.8 (24.1)Insomnia29.3 (30.1)27.5 (31.7)27.4 (27.9)Appetite loss21.1 (27.9)19.4 (26.4)17.9 (26.5)Constipation18.4 (26.6)15.2 (23.8)16.0 (23.8)Diarrhea12.3 (22.1)12.0 (20.8)12.6 (22.0)Financial difficulties25.0 (32.4)23.9 (30.4)22.1 (29.5)*Higher scores indicate a better level of functioning. †Higher scores indicate more severe symptoms. Citation Format: Gabrielle Rocque, Joanne L Blum, Aldemar Montero, Ibrahim Nakhoul, Sobha Kurian, Richard C Frank, Bijoy Telivala, Mayank Ajmera, David Coblentz, Joseph C Cappelleri, Yao Wang, Debu Tripathy. Quality of life in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer treated with palbociclib in real-world practice settings [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 PD10-03.

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.

The non-receptor tyrosine kinase Src activation plays a role in the malignant progression of breast cancer, including development of endocrine therapy resistance and survival of bone metastases. This study investigated whether adding Src kinase inhibitor dasatinib to aromatase inhibitor (AI) therapy improved outcomes in estrogen receptor (ER)-positive, HER2-negative metastatic breast cancer (MBC). Postmenopausal patients with ER-positive, HER2-negative MBC (0–1 prior chemotherapies and no prior AI for MBC) were eligible for this non-comparative, parallel group, phase-II study. Patients were randomized to letrozole (2.5 mg/day PO) alone or with dasatinib (100 mg/day PO). Patients with disease progression on letrozole alone could crossover to dasatinib plus continued letrozole. The primary endpoint was clinical-benefit-rate (CBR; complete response + partial response + stable disease ≥6 months). A total of 120 patients were randomized. The CBR of 71% (95% CI 58–83%) was observed with letrozole + dasatinib versus the projected CBR of the combination of 56%. The CBR of 66% (95% CI 52–77%) with letrozole alone also exceeded the projected CBR of 39% with letrozole alone. The CBR was 23% in the crossover arm of letrozole plus dasatinib in patients progressing on letrozole alone. Median progression-free survival with the combination was 20.1 months and 9.9 months with letrozole alone. Letrozole plus dasatinib was well tolerated, although 26% of patients required dasatinib dose reductions. In this non-comparative phase-II trial, the CBR of 71% and the median PFS of 20.1 months with letrozole + dasatinib are encouraging and suggest that dasatinib may inhibit the emergence of acquired resistance to AI therapy.

Maternal exposures during pregnancy affect the onset and progression of adult diseases in the offspring. A prior mouse study indicated that maternal tobacco smoke exposure affects hepatic fibrosis in adult offspring. Gutkha, a broadly used smokeless tobacco (ST) product, is widely used by pregnant woman in many countries. The objective of this murine study was to evaluate whether oral maternal exposure to gutkha during pregnancy alters non-alcoholic fatty liver disease (NAFLD) in adult offspring: risk factors for the progression of NAFLD to cirrhosis in adults remain elusive. Buccal cavity &lsquo, painting&rsquo, of pregnant mice with gutkha began on gestational days (GD) 2&ndash, 4 and continued until parturition. Beginning at 12 weeks of age, a subset of offspring were transitioned to a high-fat diet (HFD). Results demonstrated that prenatal exposure to gutkha followed by an HFD in adulthood significantly increased the histologic evidence of fatty liver disease only in adult male offspring. Changes in hepatic fibrosis-related cytokines (interleukin (IL)-1b and IL-6) and in hepatic collagen mRNA expression were observed when comparing adult male offspring exposed to gutkha in utero to those not exposed. These findings indicate that maternal use of gutkha during pregnancy affects NAFLD in adult offspring in a sex-dependent manner.

A previously healthy 57‐year‐old woman presented with fever (39 °C) lasting for 4 days, and dry cough and rash appeared 2 days before. Diffuse fixed erythematous blanching maculopapular lesions were present, asymptomatic over the limbs and trunk, with burning sensation over the palms (a, b). She denied any drug intake, excepting paracetamol for fever. Thorax computed tomography scan was typical of COVID‐19; nasopharyngeal swab polymerase chain reaction (PCR) confirmed SARS‐CoV‐2. Infectious enquiry was otherwise negative. Skin biopsy specimen showed slight spongiosis, basal cell vacuolation and mild perivascular lymphocytic infiltrate (c).

Background: In an effort to decrease the rates of smoking conventional tobacco cigarettes, electronic cigarettes (e-cigarettes) have been proposed as an effective smoking cessation tool. However, little is known about their toxicological impacts. This is concerning given that e-cigarette use is perceived as less harmful than conventional tobacco cigarettes during pregnancy for both the mother and fetus. Objective: The goal of this study was to test the neurodevelopmental consequences of maternal e-cigarette use on adult offspring behavior and neuroimmune outcomes. Methods: Pregnant female CD-1 mice were randomly assigned to one of three treatment groups (n=8–10 per group) and exposed daily to either filtered air, propylene glycol and vegetable glycerol (50:50 PG/VG vehicle), or to PG/VG with 16mg/mL nicotine (+Nic). Whole-body exposures were carried out for 3 h/d, 7 d/week, from gestational day (GD)0.5 until GD17.5. Adult male and female offspring (8 weeks old) were assessed across a battery of behavioral assessments followed by region-specific quantification of brain cytokines using multiplex immunoassays. Results: Adult offspring of both sexes exposed to +Nic exhibited elevated locomotor activity in the elevated plus maze and altered stress-coping strategies in the forced swim task. Moreover, male and female offspring exposed to PG/VG with and without nicotine had a 5.2% lower object discrimination score in the novel object recognition task. In addition to differences in offspring behavior, maternal e-cigarette exposure with nicotine led to a reduction in interleukin (IL)-4 and interferon-gamma (IFNγ) in the diencephalon, as well as lower levels of hippocampal IFNγ (females only). E-cigarette exposure without nicotine resulted in a 2-fold increase of IL-6 in the cerebellum. Discussion: These findings support previous adverse findings of e-cigarette exposure on neurodevelopment in a mouse model and provide substantial evidence of persistent adverse behavioral and neuroimmunological consequences to adult offspring following maternal e-cigarette exposure during pregnancy. https://doi.org/10.1289/EHP6067

Approximately 1 million women smoke during pregnancy despite evidence demonstrating serious juvenile and/or adult diseases being linked to early-life exposure to cigarette smoke. Susceptibility could be determined by factors in previous generations, i.e. pre-natal or ‘maternal’ exposures to toxins. Pre-natal exposure to airborne pollutants such as mainstream cigarette smoke has been shown to induce early-life insults (i.e. gene changes) in Offspring that serve as biomarkers for disease later in life. In this investigation, we have evaluated genome-wide changes in the lungs of mouse Dams and their juvenile Offspring exposed pre-natally to mainstream cigarette smoke. An additional lung model was tested alongside the murine model, as a means to find an alternative in vitro, human tissue-based replacement for the use of animals in medical research. Our toxicogenomic and bioinformatic results indicated that in utero exposure altered the genetic patterns of the foetus that could put them at greater risk for developing a range of chronic illnesses in later-life. The genes altered in the in vitro, cell culture model were reflected in the murine model of pre-natal exposure to MCS. The use of alternative in vitro models derived from human medical waste tissues could be viable options to achieve human end-point data and to conduct research that meets the remits for scientists to undertake the 3Rs practises.

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.

We aimed to increase pathologic complete response (pCR) in patients with invasive breast cancer by adding preoperative capecitabine to docetaxel following 5‐fluorouracil, epirubicin, cyclophosphamide (FEC) (with trastuzumab for patients with HER2‐positive disease) and to evaluate 5‐year disease‐free survival (DFS) associated with this preoperative regimen. Chemotherapy included four cycles of FEC100 (5‐fluorouracil 500 mg/m2, epirubicin 100 mg/m2, cyclophosphamide 500 mg/m2 IV on Day 1 every 21 days) followed by 4 21‐day cycles of docetaxel (35 mg/m2 days 1 and 8) concurrently with capecitabine (825 mg/m2 orally twice daily for 14 days followed by 7 days off) (wTX). For HER2‐positive patients, treatment was modified by decreasing epirubicin to 75 mg/m2 and adding trastuzumab (H) in standard doses (FEC75‐H →wTX‐H). The study objective was to achieve a pCR rate in the breast and axillary lymph nodes of 37% in patients with HER2‐negative breast cancer and of 67% in patients with HER2‐positive breast cancer treated with preoperative trastuzumab. A total of 186 patients were enrolled on study. In an intent‐to‐treat analysis, the pCR rate was 31% (37/118, 95% CI: 24–40%) in the HER2‐negative patients, 24% (15/62, 95% CI: 14–37%) in ER‐positive/HER2‐negative patients, 39% (22/56, 95% CI: 27–53%) in the ER‐negative/HER2‐negative patients, and 46% (29/63, 95% CI: 34–48%) in the HER2‐positive patients. The pCR rate in the 40 trastuzumab‐treated patients was 53% (21/40, 95% CI: 38–67%). Grade 3 and 4 adverse events included neutropenia, leukopenia, diarrhea, and hand‐foot skin reactions. One trastuzumab‐treated patient developed grade 3 cardiotoxicity, and 4 others experienced grade 1–2 decrements in left ventricular function; all five patients’ cardiac function returned to their baseline upon completion of trastuzumab. At 5 years, disease‐free survival was 70% in the HER2‐negative population (78% in ER‐positive/HER2‐negative and 62% in the ER‐negative/HER2‐negative patients) and 80% in the HER2‐positive patients (87% in the trastuzumab‐treated HER2‐positive patients). At 5 years, overall survival was 80% in the HER2‐negative population (88% in ER‐positive/HER2‐negative and 71% in the ER‐negative/HER2‐negative patients) and 86% in the HER2‐positive patients (94.5% in the trastuzumab‐treated HER2‐positive patients). FEC100 (FEC75 with trastuzumab) followed by weekly docetaxel plus capecitabine, with or without trastuzumab is a safe, effective preoperative cytotoxic regimen. However, the addition of capecitabine to docetaxel following FEC, with or without trastuzumab, did not increase pCR rates nor 5‐year DFS over the rates that have been reported with standard preoperative doxorubicin/cyclophosphamide (AC) followed by paclitaxel, with or without trastuzumab. Therefore, the use of capecitabine as part of preoperative chemotherapy is not recommended.

Exposure to fine ambient particulates (PM(2.5)) during gestation or neonatally has potent neurotoxic effects. While biological and behavioral data indicate a vulnerability to environmental pollutants across distinct neurodevelopmental windows, the behavioral consequences following exposure across the entire developmental period remain unknown. Moreover, several epidemiological studies support a link between developmental exposure to air pollution and an increased risk of later receiving a diagnosis of autism spectrum disorders (ASD), a neurodevelopmental disorder that persists throughout life. In the current study we sought to determine whether perinatal exposure to PM(2.5) would reduce sociability and increase repetitive deficits in mice, two hallmark characteristics of ASD. Pregnant female B(6)C(3) mice were exposed daily to concentrated ambient PM(2.5) (CAPs) (135.8 μg/m(3)) or filtered air (3.1 μg/m(3)) throughout gestation followed by additional exposures to both dams and their litters from days 2-10 postpartum. Adult offspring were subsequently assessed for social and repetitive behaviors at 20 weeks of age. Daily perinatal exposure to CAPs significantly decreased sociability in male and female mice as measured by the social approach task; however, reductions in reciprocal social interaction and increased grooming behavior were only present in male offspring exposed to CAPs. These findings demonstrate that exposure to particulate air pollutants throughout early neurodevelopment induces long lasting behavioral deficits in a sex-dependent manner and may be an underlying cause of neurodevelopmental disorders such as ASD.

PurposeCombining the mTOR inhibitor ridaforolimus and the anti-IGFR antibody dalotuzumab demonstrated antitumor activity, including partial responses, in estrogen receptor (ER)-positive advanced breast cancer, especially in high proliferation tumors (Ki67>15%).MethodsThis randomized, multicenter, international, phase II study enrolled postmenopausal women with advanced ER-positive breast cancer previously treated with a nonsteroidal aromatase inhibitor (NCT01234857). Patients were randomized to either oral ridaforolimus 30mg daily for 5 of 7days (once daily [qd]×5days/week) plus intravenous dalotuzumab 10mg/kg/week or oral exemestane 25mg/day, and stratified by Ki67 status. Due to a high incidence of stomatitis in the ridaforolimus-dalotuzumab group, two sequential, nonrandomized, reduced-dose cohorts were explored with ridaforolimus 20 and 10mg qd×5days/week. The primary endpoint was progression-free survival (PFS).ResultsMedian PFS was 21.4weeks for ridaforolimus 30mg qd×5days/week plus dalotuzumab 10mg/kg (n=29) and 24.3weeks for exemestane (n=33; hazard ratio=1.00; P=0.5). Overall survival and objective response rates were similar between treatment arms. The incidence of drug-related, nonserious, and serious adverse events was higher with ridaforolimus/dalotuzumab (any ridaforolimus dose) than with exemestane. Lowering the ridaforolimus dose reduced the incidence of grade 3 stomatitis, but overall toxicity remained higher than acceptable at all doses without improved efficacy.ConclusionsThe combination of ridaforolimus plus dalotuzumab was no more effective than exemestane in patients with advanced ER-positive breast cancer, and the incidence of adverse events was higher. Therefore, the combination is not being further pursued.

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.

Background POLARIS is an ongoing, prospective, real-world (RW) study of palbociclib (PAL) in patients (pts) with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer (HR+/HER2- ABC). A biomarker goal of this study was to evaluate serial changes in circulating tumor DNA (ctDNA) dynamics among pts with long-term clinical response to PAL plus endocrine therapy (ie, received ≥18 cycles). Methods The data set included pts who received PAL combination therapy, gave consent for blood collection to obtain ctDNA, and had long-term clinical response. The Guardant360 Next-Generation Sequencing platform, which analyzed approximately 73 genes, was used to sequence ctDNA for somatic single-nucleotide variants, including copy number variants. Longitudinal ctDNA changes (at baseline and various time points) and the RW clinical response to PAL are described. Results As of December 17, 2020, 35 pts of 1280 enrolled received ≥18 cycles of PAL combination therapy, with blood samples collected over a minimum of a 24-month period. Pts received PAL plus an aromatase inhibitor (n=16) or fulvestrant (n=19). Median age was 64 years. Thirty pts (85.7%) were white, 29 (82.9%) were postmenopausal, 31 (88.6%) had an Eastern Cooperative Oncology Group score of 0 or 1, 12 (34.3%) had visceral disease, 9 (25.7%) had de novo disease, and 24 (68.6%) had recurrent disease. Six pts (17.1%) had a RW best overall response (BOR) of complete response (CR), 9 (25.7%) had partial response (PR), and 20 (57.1%) had stable disease (SD). Two pts had disease progression resulting in change of therapy at cycles 25 and 38, respectively. Biomarker samples were collected from a median (range) total number of 9 (3-12) visits. The median (range) number of somatic variants detected was 4 (0-11) and included the most prevalent somatic mutations (eg, PIK3CA, TP53, BRCA1/2, FGFR2, GATA3). No ctDNA mutations were detected in 6 pts (17%) post baseline up to 24 months. Among 15 pts who achieved CR/PR, 12 (80%) either had no detectable or sustained very low ctDNA burden or had corresponding ctDNA decrease. Among 16 pts who remained with SD, 12 (75%) either had no detectable or sustained very low ctDNA burden or had ctDNA decrease. Among 8 pts whose disease progressed, 5 (63%) had an increasing trend in ctDNA mutation frequency. Conclusions This study is among the first to provide serial blood-based tumor genotyping data from routine clinical practice. Interim data indicate that even pts with ongoing detectable ctDNA have a BOR of CR, PR, or SD with PAL for HR+/HER2- ABC, suggesting certain mutations might not be drivers of PAL resistance. Dynamic changes of ctDNA mutations may be predictive for treatment response, and may have clinical utility in disease surveillance monitoring. Additional longitudinal data will be presented. Pfizer; NCT03280303 Citation Format: Joanne L. Blum, Aditya Bardia, Sharon Wilks, Steven L. McCune, Carrie L. Dul, John J. Migas, Derrick W. Spell, Zhe Zhang, Yuan Liu, Yao Wang, Debu Tripathy. Longitudinal ctDNA changes in patients with long-term response to palbociclib combination therapy for advanced breast cancer: A preliminary analysis from the real-world POLARIS study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB033.

1071 Background: Racial disparities in breast cancer incidence, mortality, and care are well documented. PAL plus endocrine therapy is indicated for patients (pts) with HR+/HER2− ABC. Findings from the PALOMA clinical trials have shown that pts receiving PAL maintained stable QoL; however, limited QoL data are available from real-world settings for BIPOC receiving PAL. Methods: POLARIS is a noninterventional, prospective, primarily US-based study in pts with HR+/HER2– ABC receiving PAL. QoL was assessed with the European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire Core 30 (EORTC QLQ-C30) at baseline, monthly for the first 3 mo of treatment (Tx) with PAL, and then every 3 mo. In this interim analysis, we report Tx patterns and QoL assessments at baseline and at 6 mo and 12 mo in BIPOC from POLARIS. Results: Of 1280 pts treated with PAL as November 10, 2020, 233 were included in the BIPOC subgroup of whom 159 (68.2%) completed PAL Tx for ≥6 mo and 112 (48.1%) for ≥12 mo. In the BIPOC cohort, 59.2% of pts were black, 35.2% Hispanic, 3.4% American Indian or Alaskan native, 2.1% Pacific Islander. PAL in combination with letrozole/anastrozole was received by 116 pts, 94 received PAL plus fulvestrant, 13 received PAL plus exemestane, and 10 received PAL plus another Tx; 175 pts (75.1%) received PAL as first-line Tx. Mean EORTC QLQ-C30 global health QoL and functional scales scores remained stable over the first 12 mo of PAL Tx, without any changes at or above the 10-point threshold considered clinically meaningful, and were similar to those previously reported in an earlier analysis of the entire POLARIS population (Table and Rocque et al SABCS 2019). Symptom scales scores, including nausea and vomiting, pain, dyspnea, insomnia, appetite loss, constipation, and diarrhea, also remained stable over 12 mo. Conclusions: In this subgroup analysis, PAL had no significant adverse impact on QOL in BIPOC with HR+/HER2– ABC, consistent with previous findings from the total POLARIS study population. Pfizer (NCT03280303). Clinical trial information: NCT03280303 .[Table: see text]

554 Background: TALA is a poly(ADP-ribose) polymerase inhibitor approved as monotherapy for adult pts with g BRCA1/2-mutated HER2-negative locally advanced/metastatic BC. We report biomarker analyses from a phase 2, nonrandomized, single-arm, open-label study (NEOTALA; NCT03499353) evaluating the efficacy and safety of TALA in the neoadjuvant setting for pts with early g BRCA1/2-mutated HER2− BC. Efficacy and safety results are presented separately. Methods: The biomarker analysis population was all pts treated with TALA for whom biomarker results are available. To support molecular eligibility, blood was tested using BRCAnalysis CDx (Myriad Genetics). Baseline tumor tissue was retrospectively tested using FoundationOne CDx, with BRCA1/2 zygosity assessed using somatic-germline-zygosity (SGZ; Sun et al. JCO PO, 2018). Germline mutational status of 14 non- BRCA DNA damage response (DDR) genes was retrospectively assessed in baseline saliva samples using Ambry CustomNext-Cancer. Mutations were defined as known/likely pathogenic/deleterious variants, including copy number alterations (CNAs). Association between mutational status of MYC or RAD21 and primary endpoint pathological complete response (pCR) as per Independent Central Review was investigated with logistic regression. Results: Of 52 evaluable tumor samples from 61 treated pts, 39 (75%) and 13 (25%) pts exhibited BRCA1 and BRCA2 mutations, respectively; 1 (2%) pt exhibited mutations in both genes, and 1 (2%) pt had mutations in neither. BRCA loss of heterozygosity (LOH) was seen in 42/43 (98%) evaluable BRCA-mutant tumors. Of 45 pts evaluable centrally for both germline and tumor, 44/45 (98%) pts exhibited the same BRCA mutation in tumor as originally detected in germline, with the remaining pt exhibiting a g BRCA1 mutation, but lacking a tumor BRCA mutation. None of 49 saliva-evaluable pts exhibited non- BRCA germline DDR mutations. TP53 (51 [98%] pts) was the most frequently mutated gene in tumors. MYC and RAD21 (each 14 [27%] pts) were the most frequent CNAs. No evidence of association between mutational status of MYC or RAD21 and pCR was found (odds ratio=0.39, 95% CI 0.12-2.30). Based on a cutoff of ≥16%, genomic LOH was elevated in 24/27 (89%) tumors evaluable for both gLOH and pCR, precluding assessment of the potential association of gLOH high/low status with pCR. Conclusions: Tumor BRCA mutations were evident in nearly all pts in the biomarker analysis population, with BRCA LOH evident in all but 1 BRCA-mutated tumor. No pts had non- BRCA germline DDR gene mutations; tumor TP53 mutations were near-universal. MYC and RAD21 each exhibited CNAs in 27% of tumors, with no association with pCR. These results support the central role of BRCA mutations in tumor pathobiology in this indication. Clinical trial information: NCT03499353.

1090 Background: In the EMBRACA trial (NCT01945775) of pts with germline BRCA1/2-mutated HER2-negative locally advanced/metastatic breast cancer (ABC), the poly(ADP-ribose) polymerase (PARP) inhibitor TALA significantly improved progression-free survival (PFS) vs PCT (8.6 vs 5.6 mo; HR [95% CI] 0.54 [0.41-0.71]; P < 0.0001). Patient-reported outcomes favored TALA, and most common adverse events included anemia, fatigue, and nausea. Previous subgroup analyses found that pts with a history of CNS metastases had improved PFS for TALA vs PCT (HR [95% CI] 0.32 [0.15-0.68]; P = 0.0016) and improved objective response rate (ORR) 63.2% vs 15.8%, respectively (odds ratio [95% CI] 8.95 [1.86-52.26]; P = 0.0013). This retrospective subgroup analysis further explored the clinical characteristics and outcomes in pts with a history of CNS metastases in EMBRACA. Methods: Pts were randomized 2:1 to TALA or PCT. Pts with adequately treated and stable CNS metastases not requiring corticosteroids were included. This analysis assessed intracranial ORR and best overall response (BOR) based on investigator assessment per RECIST 1.1 in pts with intracranial disease at baseline (data cutoff 15-Sep-17), and overall survival (OS; data cutoff 30-Sep-19). Results: In the intent-to-treat (ITT) population, 63 pts (43/287 [15.0%] TALA and 20/144 [13.9%] PCT) had a history of CNS metastases, of which 33 (11.5%) pts (TALA) and 15 (10.4%) pts (PCT) had intracranial disease at baseline. Additional baseline characteristics are shown in the table. Intracranial ORR in pts with intracranial disease at baseline and unconfirmed complete or partial response was 18.2% (TALA) vs 20.0% (PCT) (odds ratio [95% CI] 0.78 [0.13-5.80]; P = 0.765). In pts with intracranial disease at baseline, an intracranial BOR of stable disease was 69.7% for TALA vs 33.3% for PCT. Median OS in pts with a history of CNS metastases was 12.9 mo (95% CI 9.4-15.6) for TALA and 13.4 mo (95% CI 8.8-17.6) for PCT (HR [95% CI] 0.67 [0.37-1.2]; P = 0.1936 [stratified log-rank test]). In the safety population ([n = 43, TALA]; [n = 19, PCT]), median treatment duration (range) with TALA was 5.0 (0.1-36.0) mo compared with 2.1 (0.4-6.9) mo for PCT. Conclusions: In this subgroup analysis, baseline characteristics between pts with a history of CNS metastases treated with TALA or PCT were comparable. More pts with intracranial disease at baseline treated with TALA vs PCT experienced stable disease. Intracranial ORR in pts with intracranial disease was 18.2% for TALA vs 20.0% for PCT. Treatment options for pts with a history of CNS metastases are limited and further investigation in larger data sets is warranted. Clinical trial information: NCT01945775 .[Table: see text]

505 Background: Talazoparib (TALA) is a poly(ADP-ribose) polymerase inhibitor approved as monotherapy for treating adult patients (pts) with g BRCA1/2-mutated HER2-negative locally advanced or metastatic BC. Methods: This phase 2, non-randomized, single-arm, open-label study (NCT03499353) evaluated the efficacy and safety of TALA in the neoadjuvant setting for pts with early g BRCA1/2-mutated HER2− BC. Primary endpoint was evaluation of pathologic complete response (pCR) as assessed by Independent Central Review (ICR) after completing 24 weeks of neoadjuvant TALA monotherapy 1 mg QD (0.75 mg for moderate renal impairment) followed by surgery. Secondary endpoints included pCR by investigator (INV) and residual cancer burden (RCB) by ICR (RCB: 0 [pCR], I [minimal], II [moderate], III [extensive]). The evaluable population included pts who received at least 80% of the TALA dose prescribed at treatment start and underwent breast surgery and pCR assessment, plus those who progressed before pCR could be assessed. The intent-to-treat (ITT) population included all pts who received at least 1 dose of TALA. Results: Of 61 pts treated with TALA (ITT and safety populations), 48 comprised the evaluable population. All pts had triple-negative BC. 60 pts had adenocarcinoma and 1 had squamous cell histology, with the following staging: I=20, II=27, III=14. Mean age was 44.6 years, mean duration of 4.5 wks since disease onset, mean duration of treatment of 23.3 wks, and mean overall relative dose intensity of 84.5% (ITT population). pCR (assessed by ICR and INV) and RCB (by ICR) for the evaluable and ITT populations are shown in the table below. Ten (16.4%) patients discontinued treatment due to progressive disease. One pt had a disruption of treatment as a result of COVID-19 restrictions, 2 pts for other reasons: to undergo surgery early and consent withdrawal; 9 patients received

This study was conducted to critically evaluate weekly and monthly circulating concentrations of immunoreactive relaxin throughout pregnancies that resulted in live births, stillbirths, and abortions in aquarium-based bottlenose dolphins. A relaxin RIA was used to analyze serum collected during 74 pregnancies involving 41 dolphins and 8 estrous cycles as well as 8 non-pregnant dolphins. Pregnancies resulted in live births (n=60), stillbirths (n=7), or abortions (n=7). Relative to parturition (Month 0), monthly changes (P

Background: P is a novel cyclin-dependent kinase 4/6 inhibitor approved in the United States and Canada in combination with endocrine therapy for HR+/human epidermal growth factor receptor 2–negative (HER2-) advanced breast cancer (ABC). Despite promising trial results, not all patients respond to P. Moreover, despite a median age at diagnosis of 62 years, elderly patients are underrepresented in targeted therapy trials, including the PALOMA studies assessing P. It is important to understand P use in real-world practice settings, including tolerability and outcomes in the vulnerable older population. In addition, understanding the mechanisms of P response or resistance is critical to identify clinical factors and biomarkers that can predict which patients will benefit from P. This multicenter observational and biomarker study will seek to address these and other data gaps. Trial Design: This is a prospective, noninterventional study of 1500 patients treated with P from 100 US and 10 Canadian sites. Study duration will span 2 years of recruitment and 3 years of follow-up after P treatment, until patient withdrawal from the study or death. Study participation is not intended to alter routine treatment; all treatment decisions, including type and timing of disease monitoring, are at the discretion of the treating physician and patient. Eligibility: Eligible patients are aged ≥18 years with a diagnosis of adenocarcinoma of the breast with (1) evidence of advanced or metastatic disease not amenable to treatment with curative intent, (2) documented HR+/HER2- status, and (3) planned treatment with P. Patients with a life expectancy Aims: In a large real-world cohort of HR+/HER2- ABC patients treated with P in routine clinical practice, this study aims to assess the following: prescribing and treatment patterns for ABC before, during, and after P therapy; overall clinical response to P; biomarker assessment investigating potential mechanisms of response and resistance to P based on genomic analyses of blood samples; patient quality of life, as measured by the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30; geriatric assessments in patients aged ≥70 years at enrollment based on the G8 Geriatric Screening Tool and the Activities of Daily Living questionnaire; and sequencing of treatment for metastatic disease. Other outcomes to be assessed include survival and toxicity. Methods: Data will be collected from routine clinical assessments. Patients will have the option to provide blood samples drawn at standard-of-care intervals at baseline, during P treatment, and at the end of treatment for potential biomarker identification. Analyses will be primarily descriptive, with point estimates and confidence intervals as well as Kaplan-Meier methods used to assess time-to-event outcomes. Accrual: Presently, 46 patients from 20 sites are enrolled. Funding: Pfizer Inc. Citation Format: Tripathy D, Bardia A, Blum JL, Rocque G, Wilks S, Lakhanpal S, Migas J, Cappelleri J, Perkins J, Comstock G, Wang Y. POLARIS: Palbociclib (P) in hormone receptor-positive (HR+) advanced breast cancer: A prospective multicenter noninterventional study [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT3-05-03.

Background: TALA significantly prolonged progression-free survival vs physician's choice of chemotherapy (PCT) (hazard ratio [HR] 0.54 [95% CI 0.41-0.71]; P < 0.001) and improved patient-reported outcomes (PRO) in patients (pts) with HER2- ABC (locally advanced/metastatic) with a gBRCA1/2 mutation. We report results of the final OS analysis (secondary endpoint). Methods: Pts randomized 2:1 to TALA or PCT. OS HR was based on stratified Cox regression model (treatment as covariate); P value on stratified log-rank test. Results: 431 pts were randomized (287 TALA/144 PCT), 412 treated (286 TALA/126 PCT). By Sept 30, 2019, 216 deaths (75.3%) occurred for TALA and 108 deaths (75.0%) PCT; median follow-up 44.9 and 36.8 months, respectively. HR for OS was 0.85 (95% CI 0.67-1.07; P = 0.17); survival probability was higher for pts receiving TALA at 24, 36, and 48 months (Table 1). OS results were consistent across subgroups, eg by prior platinum or hormone receptor status. Most pts received post-study therapies; 32.6% of pts in the PCT arm received a PARP inhibitor post-study (4.5% for TALA arm). Grade 3-4 AEs occurred in 69.6% (TALA) and 64.3% (PCT) pts; AEs leading to permanent treatment discontinuation (excluding progressive disease) occurred in 5.9% and 8.7% of pts. Extended follow-up showed statistically significant overall improvements and delays in time to definitive clinically meaningful deterioration in both global health status/QoL and breast symptoms scales favoring TALA vs PCT (P < 0.01 for all), consistent with initial PRO analyses. Table 1.OS and post-study therapy (intent-to-treat)Talazopariboral 1 mg QDN = 287PCTaN = 144Deaths (%)216 (75.3)108 (75.0)HR (95% CI)0.85 (0.67-1.07); P = 0.17Median, mo. (95% CI)b19.3 (16.6-22.5)19.5 (17.4-22.4)Survival probability (95% CI) at Monthc120.71 (0.66-0.76)0.74 (0.66-0.81)240.42 (0.36-0.47)0.38 (0.30-0.47)360.27 (0.22-0.33)0.21 (0.14-0.29)480.19 (0.14-0.25)0.07 (0.02-0.15)Post-study antineoplastic therapy, n (%)233 (81.2)110 (76.4)PARP inhibitor, n (%)13 (4.5)47 (32.6)Platinum-based therapy, n (%)133 (46.3)60 (41.7)CI, confidence interval; HR, hazard ratio; KM, Kaplan-Meier; mo., months; OS, overall survival; PARP, poly(ADP-ribose) polymerase; QD, once daily.aPCT, physician's choice of chemotherapy (capecitabine, eribulin, gemcitabine, vinorelbine).bDuration of OS based on KM estimates.cProbability estimated from the KM curve and CI calculated with product-limit method. Conclusions: In gBRCA1/2-mutated HER2- ABC, TALA did not significantly improve OS over PCT (HR 0.85; 95% CI 0.67-1.07; P = 0.17); analysis not adjusted for subsequent therapies. TALA was generally well-tolerated with no new safety signals. PRO continued to favor TALA. Funding: Pfizer (Medivation) Citation Format: Jennifer K. Litton, Sara A. Hurvitz, Lida A. Mina, Hope S. Rugo, Kyung-Hun Lee, Anthony Gonçalves, Sami Diab, Natasha Woodward, Annabel Goodwin, Rinat Yerushalmi, Henri Roché, Young-Hyuck Im, Wolfgang Eiermann, Ruben G. Quek, Tiziana Usari, Silvana Lanzalone, Akos Czibere, Joanne L. Blum, Miguel Martin, Johannes Ettl. Talazoparib (TALA) in germline BRCA1/2 (gBRCA1/2)-mutated human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer (ABC): Final overall survival (OS) results from randomized Phase 3 EMBRACA trial [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT071.

1018 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). In EMBRACA, the PARPi TALA showed an improvement in progression-free survival (PFS) (HR [95% CI] 0.54 [0.41-0.71], P < 0.001) vs physician's choice of chemotherapy (PCT) in g BRCAm HER2− ABC. Methods: Baseline tumor tissue from 308 pts (71%; intent-to-treat) was sequenced using the FoundationOne CDx panel. Mutations summarized below were known/likely pathogenic single-nucleotide variants, insertions, deletions, or rearrangements. Best tumor response (BOR) was using RECIST 1.1 by Investigator (confirmation of CR or PR not required). Results: 296/308 (96%) of evaluable pts exhibited ≥1 tumor BRCA mutation, with 7 of the remaining 12 exhibiting BRCA copy number alterations deemed pathogenic. Mutations in other genes implicated in DDR and/or potential sensitization to PARPi were rare, with mutations detected in BARD1, CDK12, FANCG, STAG2 (each 0.3%), ATR, BRD4, FANCC, PALB2, RAD51B (0.6%), ATM, BRIP1 (1.0%), NBN (1.3%), CHEK2, FANCA (1.6%), and ARID1A (2.3%). No association was observed between total number of DDR mutations, including BRCA1/2, and best tumor response (BOR) [odds ratio of 1 vs ≥2 DDR mutations (95% CI): TALA, 0.76 (0.31-1.87), P = 0.55; PCT, 0.98 (0.27-3.51), P = 0.97]. TP53 and PIK3CA were the most commonly mutated non- BRCA genes in BRCAm tumors (52.0 and 10.8%, respectively). TP53 mutations were more prevalent in BRCA1m vs BRCA2m tumors (85.2 vs 24.8%). PIK3CA mutations were more prevalent in BRCA2m vs BRCA1m tumors (15.9 vs 5.2%). With TALA, PFS was significantly shorter in pts with TP53 mutations than without [HR (95% CI) 1.693 (1.186-2.418), P = 0.0033]. A similar, non-significant, trend was evident with PCT [HR (95% CI) 1.439 (0.859-2.411), P = 0.1614]. PIK3CA mutational status had no impact on PFS in either arm. Conclusions: Selection based on g BRCA mutational status is appropriate to identify HER2─ ABC pts with potential for clinical benefit from TALA, with the total number of tumor mutations in BRCA1/2 and other DDR genes not impacting response (within the g BRCAm subset). TP53 mutations were associated with shorter PFS, likely reflecting the worse outcomes observed in g BRCA1m patients. Additional correlative analyses are ongoing. Clinical trial information: NCT01945775 .

A heritable condition is the identified cause of cancer in 5% to 10% of women with breast cancer and in 25% of women with ovarian cancer. It is critical to identify patients at risk for inherited genetic mutations to implement risk-reducing screening and interventions; however, reports in the medical literature indicate that an alarming number of patients with inherited genetic mutations do not receive recommended genetic counseling, testing, or interventions. In order to improve outcomes for these high-risk patients, barriers to genetic testing and counseling must be identified. We analyzed approximately 200 patients seen at our institution with breast or ovarian cancer who met criteria of the National Comprehensive Cancer Network for genetic counseling and testing. Of these patients, almost 70% had appropriate genetic testing and counseling. Review of the remaining 30% revealed that the largest obstacle to receiving genetic testing and/or counseling was lack of referral from the treating oncologist. Of the patients diagnosed with a pathogenic heritable mutation, most underwent appropriate risk-reducing procedures and surveillance. Thus, the initial referral to genetic counseling is the most significant barrier for at-risk patients at our institution and likely in this population at large. Additional study is needed to identify ways to improve appropriate use of genetic testing and counseling.

Accumulating evidence indicates the developing central nervous system (CNS) is a target of air pollution toxicity. Epidemiological reports increasingly demonstrate that exposure to the particulate matter (PM) fraction of air pollution during neurodevelopment is associated with an increased risk of neurodevelopmental disorders (NDDs) such as autism spectrum disorder (ASD). These observations are supported by animal studies demonstrating prenatal exposure to concentrated ambient PM induces neuropathologies characteristic of ASD, including ventriculomegaly and aberrant corpus callosum (CC) myelination. Given the role of the CC and cerebellum in ASD etiology, this study tested whether prenatal exposure to concentrated ambient particles (CAPs) produced pathological features in offspring CC and cerebella consistent with ASD. Analysis of cerebellar myelin density revealed male-specific hypermyelination in CAPs-exposed offspring at postnatal days (PNDs) 11–15 without alteration of cerebellar area. Atomic absorption spectroscopy (AAS) revealed elevated iron (Fe) in the cerebellum of CAPs-exposed female offspring at PNDs 11–15, which connects with previously observed elevated Fe in the female CC. The presence of Fe inclusions, along with aluminum (Al) and silicon (Si) inclusions, were confirmed at nanoscale resolution in the CC along with ultrastructural myelin sheath damage. Furthermore, RNAseq and gene ontology (GO) enrichment analyses revealed cerebellar gene expression was significantly affected by sex and prenatal CAPs exposure with significant enrichment in inflammation and transmembrane transport processes that could underlie observed myelin and metal pathologies. Overall, this study highlights the ability of PM exposure to disrupt myelinogenesis and elucidates novel molecular targets of PM-induced developmental neurotoxicity.

The poly(adenosine diphosphate-ribose) inhibitor talazoparib has shown antitumor activity in patients with advanced breast cancer and germline mutations in BRCA1 and BRCA2 ( BRCA1/2).We conducted a randomized, open-label, phase 3 trial in which patients with advanced breast cancer and a germline BRCA1/2 mutation were assigned, in a 2:1 ratio, to receive talazoparib (1 mg once daily) or standard single-agent therapy of the physician's choice (capecitabine, eribulin, gemcitabine, or vinorelbine in continuous 21-day cycles). The primary end point was progression-free survival, which was assessed by blinded independent central review.Of the 431 patients who underwent randomization, 287 were assigned to receive talazoparib and 144 were assigned to receive standard therapy. Median progression-free survival was significantly longer in the talazoparib group than in the standard-therapy group (8.6 months vs. 5.6 months; hazard ratio for disease progression or death, 0.54; 95% confidence interval [CI], 0.41 to 0.71; P0.001). The interim median hazard ratio for death was 0.76 (95% CI, 0.55 to 1.06; P=0.11 [57% of projected events]). The objective response rate was higher in the talazoparib group than in the standard-therapy group (62.6% vs. 27.2%; odds ratio, 5.0; 95% CI, 2.9 to 8.8; P0.001). Hematologic grade 3-4 adverse events (primarily anemia) occurred in 55% of the patients who received talazoparib and in 38% of the patients who received standard therapy; nonhematologic grade 3 adverse events occurred in 32% and 38% of the patients, respectively. Patient-reported outcomes favored talazoparib; significant overall improvements and significant delays in the time to clinically meaningful deterioration according to both the global health status-quality-of-life and breast symptoms scales were observed.Among patients with advanced breast cancer and a germline BRCA1/2 mutation, single-agent talazoparib provided a significant benefit over standard chemotherapy with respect to progression-free survival. Patient-reported outcomes were superior with talazoparib. (Funded by Medivation [Pfizer]; EMBRACA ClinicalTrials.gov number, NCT01945775 .).

Myoepithelial cells play key roles in normal mammary gland development and in limiting pre-invasive to invasive breast tumor progression, yet their differentiation and perturbation in ductal carcinoma in situ (DCIS) are poorly understood. Here, we investigated myoepithelial cells in normal breast tissues of BRCA1 and BRCA2 germline mutation carriers and in non-carrier controls, and in sporadic DCIS. We found that in the normal breast of non-carriers, myoepithelial cells frequently co-express the p63 and TCF7 transcription factors and that p63 and TCF7 show overlapping chromatin peaks associated with differentiated myoepithelium-specific genes. In contrast, in normal breast tissues of BRCA1 mutation carriers the frequency of p63+TCF7+ myoepithelial cells is significantly decreased and p63 and TCF7 chromatin peaks do not overlap. These myoepithelial perturbations in normal breast tissues of BRCA1 germline mutation carriers may play a role in their higher risk of breast cancer. The fraction of p63+TCF7+ myoepithelial cells is also significantly decreased in DCIS, which may be associated with invasive progression., Myoepithelial cells prevent tumour growth and invasion in DCIS. Here, the authors show that p63 and TCF7 cooperate to regulate a transcription factor network for the maintenance of normal myoepithelial function and altered expression of these genes perturb myoepithelial function in DCIS to promote invasive progression.

Edward C Jauch,1 David Y Huang,2 Allison J Gardner,3 Julie L Blum3 1Department of Emergency Medicine, Medical University of South Carolina, Charleston, SC, USA; 2Department of Neurology, Division of Stroke and Vascular Neurology, University of North Carolina School of Medicine, Chapel Hill, NC, USA; 3QI Institute, Med-IQ, Baltimore, MD, USA Background: The timely evaluation and initiation of treatment for acute ischemic stroke (AIS) is critical to optimal patient outcomes. However, clinical practice often falls short of guideline-established goals. Hospitals in rural regions of the USA, and notably those in the Stroke Belt, are particularly challenged to meet timing goals since the vast majority of primary stroke centers (PSCs) are concentrated in urban academic institutions. Methods: Between May 2015 and May 2017, emergency department (ED) teams from 5 non-PSC hospitals in the Stroke Belt participated in a quality improvement (QI) initiative. The intervention included a baseline practice assessment survey, repeat audit-and-feedback cycles with patient data on AIS treatment timing, personalized Continuing Medical Education/Continuing Education-certified grand rounds sessions at each participating site with expert study faculty, targeted reinforcement of best practices, and follow-up to evaluate the benefits and limitations of the intervention. Results: At the start of the initiative, clinical staff from participating EDs overestimated the proportion of patients with AIS who received alteplase within the guideline-recommended 60-minute door-to-needle window at their facility. At the end of the 6-month intervention period, significantly more patients were treated with alteplase within 60 minutes of ED arrival compared to baseline across the entire sample (1.9% of patients at baseline vs. 5.2% at 6 months; P < 0.01). Similarly, there was a trend toward a decrease in the percentage of patients whose alteplase treatment was initiated more than 60 minutes after their arrival at the ED (67.3% at baseline vs. 22.2% at 6 months). Conclusion: Structured QI interventions that engage ED care teams to reflect on processes related to AIS diagnosis and treatment and deploy repeat audit-and-feedback cycles with real-time patient data have the potential to support an increase in the number of patients who receive alteplase within the guideline-recommended timeframe of 60 minutes from hospital arrival. Keywords: AIS, neurology, CME, quality improvement, alteplase

Trabectedin is an alkylating agent that binds to the minor groove of DNA. Early studies with trabectedin suggested efficacy in triple-negative and HER2-overexpressing metastatic breast cancer (MBC). The efficacy and safety of trabectedin in pretreated patients with these tumors were evaluated in this parallel-cohort phase II trial. Patients received a 3-h infusion of trabectedin 1.3 mg/m(2) intravenously every 3 weeks until progression or unmanageable/unacceptable toxicity. The primary objective was to evaluate the efficacy using the objective response rate (ORR) as per Response Evaluation Criteria In Solid Tumors (RECIST). Secondary objectives comprised time-to-event endpoints and safety assessed with the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v.3.0. Patients with heavily pretreated triple-negative (n = 50) or HER2-overexpressing (n = 37) MBC were enrolled. No confirmed responses were found in triple-negative MBC patients, with median progression-free survival (PFS) of 2.2 months (95 % CI 1.3-2.7 months). Confirmed partial responses occurred in 4 of 34 evaluable HER2-overexpressing MBC patients (ORR = 12 %; 95 % CI 3-27 %) and lasted a median of 12.5 months (95 % CI, 6.2-14.7 months); median PFS was 3.8 months (95 % CI, 1.8-5.5 months). Most trabectedin-related adverse events were mild or moderate, and the most frequent were fatigue, nausea, vomiting, constipation, and anorexia. Severe neutropenia and transaminase increases were non-cumulative and transient and were mostly managed by infusion delays or dose reductions. Single-agent trabectedin is well tolerated in aggressive MBC and has moderate activity in HER2-overexpressing tumors. Further studies are warranted to evaluate trabectedin combined with HER2-targeted treatments in this subtype.

Purpose: We conducted a randomized phase III study to determine whether patients with early breast cancer would benefit from the addition of capecitabine (X) to a standard regimen of doxorubicin (A) plus cyclophosphamide (C) followed by docetaxel (T). Experimental Design: Treatment comprised eight cycles of AC→T (T dose: 100 mg/m2 on day 1) or AC→XT (X dose: 825 mg/m2 twice daily, days 1–14; T dose: 75 mg/m2 on day 1). The primary endpoint was 5-year disease-free survival (DFS). Results: Of 2,611 women, 1,304 were randomly assigned to receive AC→T and 1,307 to receive AC→XT. After a median follow-up of 5 years, the study failed to meet its primary endpoint [HR, 0.84; 95% confidence interval (CI), 0.67–1.05; P = 0.125]. A significant improvement in overall survival, a secondary endpoint, was seen with AC→XT versus AC→T (HR, 0.68; 95% CI, 0.51–0.92; P = 0.011). There were no unexpected adverse events. Of patients with estrogen receptor (ER)–positive/HER2-negative disease, 70% of whom were node-positive, 26% and 59% had tumors with a centrally assessed Ki-67 score of Conclusions: The very low event rate in patients with ER-positive, low Ki-67 cancers, regardless of nodal status, strongly suggests that these patients should not be enrolled in adjuvant trials that assess 5-year DFS rates and that central Ki-67 analyses can identify these patients. Clin Cancer Res; 21(19); 4305–11. ©2015 AACR.

Background: Next-generation sequencing (NGS) allows for broader germline genetic testing for hereditary cancers. Since the Supreme Court decision of AMP v. Myriad on June 13, 2013, hereditary cancer multi-gene panels can now include BRCA1 and BRCA2, making these panels an option for first-tier testing. However, questions have been raised about the clinical utility and implications of extended panels for medical management given the inclusion of unknown to moderate penetrant genes. Methods: We reviewed all patients who underwent multi-gene panel testing from July 1, 2013 through May 23, 2014. The indications for testing included personal and/or family history of breast or ovarian cancer. The panels were ordered in a single genetic counseling clinic within a large community-based cancer center. Results: A total of 136 patients underwent panel testing via a single commercial laboratory. We identified 12 (8.8%) patients who were positive for a pathogenic or likely pathogenic mutation in a cancer susceptibility gene; 4 had prior negative BRCA1 and BRCA2 sequencing and deletion/duplication testing. These positive results included 4 BRCA2 mutations, 2 TP53 mutations, 1 CDH1 mutation, 2 ATM mutations, and 1 patient each with a CHEK2, NBN, or PALB2 mutation. Of the patients found to have a positive test result, 100% met the National Comprehensive Cancer Network (NCCN) guidelines for Hereditary Breast and Ovarian Cancer (HBOC) genetic testing. The CDH1 mutation carrier did not meet NCCN guidelines for hereditary diffuse gastric cancer testing and only one of the TP53 mutation carriers met NCCN guidelines for Li-Fraumeni syndrome. Within our cohort (136), 21 (15.4%) patients had a total of 25 variants of uncertain significance (VUS) and 103 (75.7%) patients had negative test results. Conclusion: Testing through NGS panels identified 7/12 (58%) patients with a mutation which led to changes in current medical management and 3/7 (43%) had a mutation in a gene other than BRCA1 or BRCA2. Our findings suggest that there is clinical utility of NGS panels for use in this patient population despite the inclusion of unknown to moderate penetrant genes and a higher rate of VUS than single gene testing. Citation Format: J L Blum, C A Garby, A E Simmons, S A Walker, L E Panos. Results of next-generation sequencing panels in a large community-based hereditary cancer risk program [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-12-06.

The circulating pattern of immunoreactive relaxin and progestagens based on monthly and gestational stage (early, mid, late) profiles were determined during pregnancies that resulted in live calves (LIVE, n = 30), stillbirths (STILLB, n = 3), abortions (ABORT, n = 5) and presumptive false pregnancies (FALSE, n = 8), and during the follicular (n = 34) and luteal phase (n = 58). Monthly LIVE relaxin concentrations steadily increased during gestation, but values did not significantly exceed those of the luteal phase until 9 months prior to parturition, peaking during the final month at 2356 ng/ml. Relaxin surged (P < 0.05) during the final week of gestation (36,397 ng/ml), undergoing a 3 and 9-fold increase compared with concentrations in the preceding two weeks, respectively. Monthly relaxin production did not differ among each reproductive state with the exception of months-13-16 where concentrations were higher (P < 0.001) for STILLB than LIVE. Relaxin concentration was reduced (P < 0.0001) by 849% in placental versus maternal serum collected within 1 day of labor. Mid- and late-pregnancy progestagen concentrations were lower for FALSE (P < 0.001) compared with STILLB and LIVE. Late pregnancy progestagen concentrations were reduced for FALSE (P < 0.05) and ABORT (P < 0.02) compared with LIVE and STILLB. Monthly progestagen production in ABORT tended to be lower than LIVE across a range of gestational months (Months 2, 7, 8, 11) but this difference only became significant during months 14 and 15. Results indicate that relaxin is primarily produced by the CL during pregnancy, and that concentrations could not be used to differentiate from non-pregnant females until the final 6 months of gestation. In addition, as would be expected from a primarily CL product, relaxin cannot be used to detect abnormal pregnancies. Conversely, progestagens, which are produced by both the placenta and CL can be used to differentiate FALSE from normal pregnancy and may be useful indicators of fetal health in the killer whale.

Accumulating studies indicate that the brain is a direct target of air pollution exposure during the fetal period. We have previously demonstrated that exposure to concentrated ambient particles (CAPs) during gestation produces ventriculomegaly, periventricular hypermyelination, and enlargement of the corpus callosum (CC) during postnatal development in mice. This study aimed to further characterize the cellular basis of the observed hypermyelination and determine if this outcome, among other effects, persisted as the brain matured. Analysis of CC-1(+) mature oligodendrocytes in the CC at postnatal days (PNDs) 11–15 suggest a premature maturational shift in number and proportion of total cells in prenatally CAPs-exposed males and females, with no overall change in total CC cellularity. The overall number of Olig2(+) lineage cells in the CC was not affected in either sex at the same postnatal timepoint. Assessment of myelin status at early brain maturity (PNDs 57–61) revealed persistent hypermyelination in CAPs-exposed animals of both sexes. In addition, ventriculomegaly was persistent in CAPs-treated females, with possible amelioration of ventriculomegaly in CAPs-exposed males. When oligodendrocyte precursor cell (OPC) pool status was analyzed at PNDs 57–61, there were significant CAPs-induced alterations in cycling Ki67(+)/Olig2(+) cell number and proportion of total cells in the female CC. Total CC cellularity was slightly elevated in CAPs-exposed males at PNDs 57–61. Overall, these data support a growing body of evidence that demonstrate the vulnerability of the developing brain to environmental insults such as ambient particulate matter. The sensitivity of oligodendrocytes and myelin, in particular, to such an insult warrants further investigation into the mechanistic underpinnings of OPC and myelin disruption by constituent air pollutants.

Purpose Docetaxel and cyclophosphamide (TC) was superior to doxorubicin and cyclophosphamide (AC) in a trial in early breast cancer. However, activity of TC relative to AC regimens with a taxane (TaxAC) is unknown. Methods In a series of three adjuvant trials, women were randomly assigned to TC for six cycles (TC6) or to a standard TaxAC regimen. US Oncology Research (USOR) 06-090 compared TC6 with docetaxel, doxorubicin, and cyclophosphamide (TAC6). National Surgical Adjuvant Breast and Bowel Project (NSABP) B-46-I/USOR 07132 compared TC6, TAC6, or TC6 plus bevacizumab. NSABP B-49 compared TC6 with several standard AC and taxane combination regimens. Before any analysis of individual trials, a joint efficacy analysis of TC versus the TaxAC regimens was planned, with invasive disease-free survival (IDFS) as the primary end point. Patients who received TC6 plus bevacizumab on NSABP B-46-I/USOR 07132 were not included. A hazard ratio (HR) from a stratified Cox model that exceeded 1.18 for TC6 versus TaxAC was predefined as inferiority for TC6. The prespecified interim monitoring plan was to report for futility if the HR was > 1.18 when 334 IDFS events were observed (50% of 668 events required for definitive analysis). Results A total of 2,125 patients were randomly assigned to receive TC6 regimens and 2,117 patients were randomly assigned to receive TaxAC regimens. The median follow-up time was 3.3 years. There were 334 IDFS events, and the HR for TC6 versus TaxAC was 1.202 (95% CI, 0.97 to 1.49), which triggered early reporting for futility. The 4-year IDFS was 88.2% for TC6 and was 90.7% for TaxAC ( P = .04). Tests for treatment interaction by protocol, hormone receptor status, and nodal status were negative. Conclusion The TaxAC regimens improved IDFS in patients with high-risk human epidermal growth factor receptor 2–negative breast cancer compared with the TC6 regimen.

PurposeTo evaluate whether adding humanized monoclonal insulin growth factor-1 receptor (IGF-1R) antibody (dalotuzumab) to mammalian target of rapamycin (mTOR) inhibitor (ridaforolimus) plus aromatase inhibitor (exemestane) improves outcomes in patients with estrogen receptor (ER)-positive advanced/metastatic breast cancer.MethodsThis randomized, open-label, phase II trial enrolled 80 postmenopausal women with high-proliferation (Ki67 index staining≥15%), ER-positive breast cancer that progressed after a non-steroidal aromatase inhibitor (NCT01605396). Randomly assigned patients were given oral ridaforolimus 10mg QD 5×/week, intravenous dalotuzumab 10mg/kg/week, and oral exemestane 25mg/day (R/D/E, n=40), or ridaforolimus 30mg QD 5×/week and exemestane 25mg/day (R/E; n=40). Primary end point was progression-free survival (PFS).ResultsMedian PFS was 23.3weeks for R/D/E versus 31.9weeks for R/E (hazard ratio 1.18; 80% CI 0.81-1.72; P=0.565). Grade 3-5 adverse events were reported in 67.5% of patients in the R/E arm and 59.0% in the R/D/E arm. Stomatitis (95.0 vs. 76.9%; P=0.021) and pneumonitis (22.5 vs. 5.1%; P=0.027) occurred more frequently in the R/E than the R/D/E arm; hyperglycemia (27.5 vs. 28.2%) occurred at a similar rate.ConclusionsR/D/E did not improve PFS compared with R/E. Because the PFS reported for R/E was similar to that reported for everolimus plus exemestane in patients with advanced breast cancer, it is possible that lower-dose ridaforolimus in the R/D/E arm (from overlapping toxicities with IGF1R inhibitor) contributed to lack of improved PFS.

Women with a mutation in BRCA1 or BRCA2 face a lifetime risk of breast cancer of approximately 80 %. Tamoxifen treatment of the first cancer has been associated with a reduction in the risk of a subsequent contralateral cancer. We studied 1,504 women with a known BRCA1 or BRCA2 mutation, 411 women with bilateral breast cancer (cases) and 1,093 women with unilateral breast cancer (controls) in a matched case-control study. Control women were of similar age and had a similar age of diagnosis of first breast cancer as the cases. For each woman who used tamoxifen, the starting and stopping dates were abstracted and the duration of tamoxifen use was calculated. Three hundred and thirty-one women had used tamoxifen (22 %); of these 84 (25 %) had completed four or more years of tamoxifen, the remainder stopped prematurely or were current users. For women with up to 1 year of tamoxifen use, the odds ratio for contralateral breast cancer was 0.37 (95 % CI 0.20-0.69; p = 0.001) compared to women with no tamoxifen use. Among women with 1-4 years of tamoxifen use the odds ratio was 0.53 (95 % CI 0.32-0.87; p = 0.01). Among women with four or more years of tamoxifen use the odds ratio was 0.83 (95 % CI 0.44-1.55; p = 0.55). Short-term use of tamoxifen for chemoprevention in BRCA1 and BRCA2 mutation carriers may be as effective as a conventional 5-year course of treatment.

Background: Cancer cells with deleterious mutations in breast cancer susceptibility genes 1 and 2 (BRCA1/2) are deficient in the DNA double-strand break repair mechanism, rendering them highly dependent on the single-strand break repair pathway, which is initiated by poly-(ADP-ribose) polymerase (PARP) [1-3]. In cells with deleterious BRCA1/2 mutations, PARP inhibition is synthetically lethal because of accumulation of irreparable DNA damage [1-3]. Talazoparib (BMN 673) exhibits a novel two-pronged approach in treating BRCA1/2-mutant tumors: 1) potent catalytic inhibition of the PARP enzyme; and 2) trapping of PARP at sites of DNA damage [4-7]. The capacity to trap PARP-DNA complexes varies widely across PARP inhibitors and is not correlated with catalytic inhibition potency [4-7]. In preclinical models, trapping PARP on DNA is more potent at inducing cancer cell death than enzymatic inhibition of PARP alone [4,7]. Talazoparib is the most potent clinical-stage PARP inhibitor tested to date with the highest efficacy at trapping PARP-DNA complexes [7]. Talazoparib has shown single-agent antitumor efficacy in several solid tumor types and was generally well tolerated in a phase 1/2 clinical study [8]. Methods: This open-label, randomized, parallel, 2-arm, phase 3 international trial (EMBRACA) compares the safety and efficacy of talazoparib with physician's choice (capecitabine, eribulin, gemcitabine, or vinorelbine) in patients with advanced breast cancer. The primary objective is progression free survival (PFS). Secondary objectives include objective response rate (ORR), overall survival (OS), and safety. Exploratory objectives include duration of response (DOR) for objective responders and health-related quality of life measurements. Subject eligibility includes age ≥18 years with histologically/cytologically confirmed breast carcinoma, locally advanced and/or metastatic disease, germline BRCA1/2 mutations, ≤2 prior chemotherapy-inclusive regimens for locally advanced and/or metastatic disease, prior treatment with a taxane and/or anthracycline, and Eastern Cooperative Oncology Group (ECOG) performance status ≤1. Subjects (n=429) will be randomized 2:1 to receive either talazoparib oral capsules (1 mg/day, 21-day cycles) or physician's choice treatment. This trial is currently enrolling patients from the United States, Asia/Pacific, Europe, Israel, and South America (NCT01945775). This study is funded by BioMarin Pharmaceutical Inc. References: 1. Ashworth A. J Clin Oncol. 2008;26:3785-3790; 2. Jalve M, Curtin NJ. Ther Adv Med Oncol. 2011;3:257-267; 3. Helleday T. Mol Oncol. 2011;5:387-393; 4. Murai J et al. Cancer Res. 2012;72:5588-5599; 5. Rouleau M et al. Nat Rev Cancer. 2010;10:293-301; 6. Shen Y et al. Clin Cancer Res. 2013;19:5003-5015; 7. Murai J et al. Mol Cancer Ther. 2014;13:433-443; 8. Wainberg ZA et al. J Clin Oncol. 2014;32(suppl):5. Abstract 7522. Citation Format: Litton JK, Blum JL, Im Y-H, Martin M, Mina L, Roché H, Visco F, Yang X, Lokker NA, Lounsbury DL, Eiermann W. EMBRACA: A phase 3, open-label, randomized, parallel, 2-arm international study of the oral PARP inhibitor talazoparib (BMN 673) versus physician's choice in BRCA mutation subjects with locally advanced and/or metastatic breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT1-03-16.

Introduction Dasatinib inhibits the protein tyrosine kinase, Src, which can support the development of bone metastases in patients with ER+ breast cancer. The primary objective of this study is to determine if letrozole plus dasatinib increases the clinical benefit rate (CBR) (CR+PR+SD ≥6mo) in first-line MBC patients compared with letrozole alone. Secondary objectives include overall response; progression-free survival; time to treatment failure (TTF); and toxicity. Methods This is a Phase II randomized, noncomparative study of postmenopausal women with locally recurrent or metastatic, measurable or nonmeasurable BC, ER+, HER2-. Patients are allowed to have had prior non-AI endocrine therapy for MBC; prior adjuvant AI therapy if completed at least 1 year prior to study entry; and up to 1 prior chemotherapy regimen for MBC. Patients are stratified by ≤2 yrs vs >2 years disease-free interval (DFI) from initial breast cancer diagnosis (date of definitive surgery) to first locally recurrent or MBC and by prior tamoxifen for MBC. Patients were randomly assigned to Arm 1 (letrozole 2.5mg PO QD + dasatinib 100mg PO QD) or Arm 2 (single-agent letrozole 2.5mg PO QD) on 28-day cycles. Arm 1 patients who experienced intolerable toxicity related to dasatinib discontinued dasatinib and continued single-agent letrozole. Arm 2 patients who developed progressive disease (PD) on letrozole had the option to receive dasatinib plus letrozole. The primary endpoint of CBR was assessed when patients developed progressive disease on their randomly assigned therapies before any crossover therapy. Results Patients with prior adjuvant AI/tamoxifen were 39%/32% Arm 1 and 44%/37% Arm 2; prior metastatic endocrine therapy Arm 1/Arm 2 was 9%/5%; and prior metastatic chemotherapy Arm 1/Arm 2 was 11%/6%. Median DFI Arm 1/Arm 2 was 27.5/21.2 months; patients presenting with de novo MBC Arm 1/Arm 2 was 42%/32%, respectively; measureable disease by RECIST Arm 1/Arm 2 was 58%/75%. The ITT population comprised 120 patients; 57 in Arm 1 and 63 in Arm 2. Clinical benefit rate (CBR) in 116 evaluable patients in Arm 1(55)/Arm 2(61), respectively, was 64% (95% CI, 50-76) and 61% (95% CI, 47-73). Median PFS time was 22 months with letrozole/dasatinib and 11 months with letrozole alone, p = .05. PFS at 6 and 12 months for Arms 1 and 2, respectively, was 78%/66% and 66%/43%. The most common toxicities observed with dasatinib on Arm 1 were fatigue (38%), nausea (38%), anemia (25%), rash (23%), pleural effusion (16%), and edema (13%). 27% of patients required dasatinib dose reduction. Conclusion The addition of dasatinib to letrozole in MBC patients receiving their first AI therapy for metastatic disease did not improve CBR compared with letrozole alone. Median PFS improved from 11 to 22 months (p = .05) with the addition of dasatinib, suggesting dasatinib improved duration of disease control combined with letrozole. Most patients tolerated full dose dasatinib until PD. 25% of patients remain on study therapy; final results will be available at SABCS 2013. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr S3-07.

Background: Preclinical studies indicate that the dual inhibition of IGFR and mTOR may be additive or synergistic and abrogates the feedback activation of AKT due to rapamycin analog mTOR inhibitors. A phase 1 study of the mTOR inhibitor RIDA and the anti-IGFR antibody DALO demonstrated that the combination was feasible and well-tolerated at doses that were nearly those used for the two single agents. The dose limiting toxicity was stomatitis, similar to RIDA monotherapy. Preliminary signals of anti-tumor activity, including partial responses and prolonged progression free survival (PFS), were observed in ER+ advanced breast cancer (ABC), especially in high proliferation tumors (Ki67 ≥15%). Methods: The trial was a multi-center, international randomized study with PFS as the primary endpoint. Key eligibility included ABC with prior treatment with a non-steroidal aromatase inhibitor. The original phase 2 study design was a two-part, adaptive design intended to first test the combination of RIDA (30 mg by mouth daily for 5 out of every 7 days), -DALO (10 mg/kg IV weekly) against a standard agent, exemestane in Part A. Patients were stratified into high and low proliferation strata based on baseline Ki67. Following a demonstration of PFS benefit of the combination in Part A, Part B was intended to show the PFS benefit of the combination over each single agents by comparing RIDA-DALO to RIDA and DALO. Results: The study was initiated in October 2011. Accrual was suspended after the first 66 patients were randomized due to a higher than expected rate of stomatitis in the RIDA-DALO arm. Preliminary data indicated an overall incidence of any grade stomatitis was 68% (22/33 pts), and of grade 3 stomatitis was 35% (11/33 pts). In an effort to identify a more tolerable regimen, the study was amended to eliminate Part B and to evaluate two sequential reduced dose RIDA-DALO cohorts in a non-randomized design: 20mg and 10mg for 5 out of every 7 days. The dose of DALO was unchanged. Preliminary safety results of overall and grade 3 stomatitis in the 20 mg were 81.5% (22/27 pts) and 37% (10/27 pts), respectively. Although the incidence of overall stomatitis in the 10 mg cohort remained high, 88% (22/25 pts), grade 3 stomatitis was dramatically reduced to 8% (2/25 pts). Conclusion: Preliminary evaluation of safety from this phase 2 study demonstrates that the previously recommended phase 2 dose of RIDA-DALO was not tolerable. However lower doses of RIDA (10 mg) in combination with DALO appeared to be tolerable with markedly reduced rates of grade 3 stomatitis. Final results of efficacy, safety and RNA profiling analysis from the two RIDA-DALO dose cohorts as well as from the randomized portion of the study will be available at the time of the meeting. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-16-04.