bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dose-escalation study of SAR439859, an oral selective estrogen receptor (ER) degrader (SERD), in postmenopausal women with ER+/HER2- metastatic breast cancer (mBC).
Authors: Bardia Aditya , Linden Hannah M. , Ulaner Gary A. , Chandarlapaty Sarat , Gosselin Alice , Doroumian Séverine , Celanovic Marina , Campone Mario 
Published: May 2019

1054 Background: SERDs result in ER competitive antagonism and degradation and can block signaling in ER-dependent tumors resistant to other endocrine therapies. This study investigates SAR439859, a potent oral SERD, +/- palbociclib in ER+/HER2- mBC. Here are preliminary results, as of 28 Nov 2018, for single-agent SAR439859 dose escalation. Methods: Part A of this Phase 1/2 study (NCT03284957; TED14856) assessed SAR439859 dose escalation (dose range: 20–600 mg once daily [QD]; 3 + 3 design) in postmenopausal women with ER+/HER2- mBC treated for ≥ 6 months with prior endocrine therapy and ≤ 3 chemotherapies in the advanced setting. Endpoints: dose-limiting toxicities (DLTs); maximum tolerated dose (MTD); safety; pharmacokinetics (PK); tumor response (RECIST 1.1); pharmacodynamic (PD) inhibition of ER occupancy (18FES-PET scan). Results: Patients (pts; n = 16) had a median age of 59.5 years (range 40–79), ECOG performance status of 0 (62.5%) or 1 (37.5%) and a median of three prior anticancer therapies (range 1–8) in the advanced setting (endocrine therapy n = 16; chemo/targeted therapy n = 13). All pts had ≥ 1 treatment emergent adverse event (mostly grade 1–2); most frequent were asthenia/fatigue (43.8%), hot flushes (37.5%), nausea (37.5%), diarrhea (31.3%), constipation (31.3%), and decreased appetite (31.3%). There were no DLTs at any of the five dose levels (maximum administered dose: 600 mg QD); MTD was not reached. In 18FES-PET scans, signal inhibition > 87% occurred with plasma concentrations > 100 ng/mL. There was a dose proportional increase of exposure up to 400 mg after repeated QD doses. Average Ctrough was reached after repeated 400 mg QD allowing 90% of 18FES-PET signal inhibition. One pt (6.3%) had confirmed partial response (150 mg QD); eight (50%) had stable disease (SD) including three (18.8%) long-term SD (≥ 24 weeks); seven (43.8%) had progressive disease. Conclusions: SAR439859 had a favorable safety profile, high ER occupancy and encouraging antitumor activity (to be confirmed in dose expansion) in pretreated pts with ER+/HER2- mBC. With no DLTs and MTD, 400 mg QD was selected for expansion cohorts based on safety, PD and PK data. Funding: Sanofi. Clinical trial information: NCT03284957.
RIBECCA: A phase IIIb, multicenter, open label study for women with estrogen receptor-positive locally advanced or metastatic breast cancer treated with ribociclib (LEE011) in combination with letrozole—Results of the second interim analysis.
Authors: Nusch Arnd , Decker Thomas , Reinisch Mattea , Hartkopf Andreas D. , Heinrich Bernhard , Kurbacher Christian M. , Fuchs Roswitha Dorothea , Tesch Hans , Krabisch Petra , Brucker Sara , Fehm Tanja N. , Janni Wolfgang , Kümmel Sherko , Luftner Diana , Schneeweiss Andreas , Schuler Martin H. , Voges Claudia , Schubert Joerg , Fasching Peter A. 
Published: May 2019

1061 Background: RIBECCA is a national, multi-center, open-label, single-arm phase IIIb trial assessing the efficacy and safety of ribociclib in combination with letrozole in a patient population similar to the populations of MONALEESA-2, -3 and -7. Here we present the results of the second preplanned interim analysis. Methods: Main inclusion criteria allowed enrollment of men or women with metastatic or locally advanced breast cancer not amenable to curative treatment by surgery or radiotherapy, and histological or cytological confirmation of ER+, HER2- breast cancer, irrespective of their menopausal status. The primary objective is to assess the clinical benefit rate (CBR) after 6 months. Secondary objectives include: progression free survival (PFS), overall survival (OS), safety and changes in quality of life. Results: The cut-off date for this second interim analysis was 12 months after the last patient was enrolled in the pretreated and premenopausal cohort. Here we report a preliminary analysis on safety, efficacy and quality of life. We describe the baseline characteristics, safety data and the clinical benefit rate (CBR) at 24 weeks, of patients (pts) with at least 24 weeks follow up (n = 411). The median observation time for all patients in this analysis was 8.1 months. Baseline characteristics: of 411 pts, 409 were female and 2 male. Median age: 64 yrs; 46 pts pre-or perimenopausal, 363 postmenopausal; ECOG 0-1: 97.0%; median time since first recurrence: 1.6 months; 72.5 % pts had bone metastases (40.6% bone only), 30.7% liver, 27.3% lung and 29.2% other metastases. Median relative dose intensity was 0.905 for ribociclib and 1 for letrozole. The most common treatment emergent AEs (all grades) were neutropenia and/or neutrophil count decreased (54.5%), nausea (40.6%), fatigue (36.5%), alopecia (32.6%), leukopenia or WBC decreased (29%), nasopharyngitis (23.1%), diarrhea (21.4%), ALT increased (20.7%), AST increased (19%). The CBR by week 24 was 67.6%. Preliminary information on quality of life will be provided. Conclusions: The results of the second interim analysis in this additional patient population are in line with data published from the pivotal phase III studies MONALEESA-2, MONALEESA-3 and MONALEESA-7. Clinical trial information: NCT03096847.
IMpassion130: Expanded safety analysis from a P3 study of atezolizumab (A) + nab-paclitaxel (nP) in patients (pts) with treatment (tx)-naïve, locally advanced or metastatic triple-negative breast cancer (mTNBC).
Authors: Schneeweiss Andreas , Rugo Hope S. , Winer Eric P. , Barrios Carlos H. , Iwata Hiroji , Dieras Veronique , Loi Sherene , Maiya Vidya , Bond John , Lei Guiyuan , Chui Stephen Y. , Adams Sylvia , Emens Leisha A. , Schmid Peter 
Published: May 2019

1068 Background: IMpassion130 showed PFS benefit with A + nP vs placebo (P) + nP as 1L tx for mTNBC in the ITT and PD-L1 IC+ pts. We report expanded safety data with 4.5-mo longer follow-up (FU), focusing on adverse events of special interest (AESI), potentially immune related. Methods: Pts with unresectable locally advanced or mTNBC received nP 100 mg/m2 IV (d1, 8 and 15 of a 28-d cycle) + A 840 mg IV q2w or P until PD or toxicity. Safety was a secondary endpoint. Results: With 15.6 mo of median FU, of 453 pts with A+nP and 437 pts with P+nP, 49% and 43% had Gr 3/4, 1% and <1% had Gr 5, 23% and 19% had serious AEs, and 58% and 42% had AESI, respectively. Most AESI (≥86%; either arm) were Gr 1/2. 14% (A+nP) vs 6% (P+nP) received systemic corticosteroids within 30 d of AESI onset. The only any-Gr AESI differing with A+nP vs P+nP were rash (34% vs 26%), hypo- (18% vs 5%) and hyperthyroidism (5% vs 1%) and pneumonitis (4% vs <1%). The leading cause of withdrawal was peripheral neuropathy, with Gr 3 affecting 6% (A+nP) vs 3% (P+nP). AESI median time to onset (TTO) was consistent with A monotherapy trials. Conclusions: A+nP had a tolerable safety profile, with no meaningful changes since the primary data cut. No cumulative toxicities or new or late-onset safety signals were seen with longer FU. Clinical trial information: NCT02425891. [Table: see text]
A phase II clinical trial of pembrolizumab and selective androgen receptor modulator GTx-024 in patients with advanced androgen receptor-positive triple-negative breast cancer.
Authors: Lee-Bitar Jin Sun , Frankel Paul Henry , Yost Susan Elaine , Synold Timothy W. , Martinez Norma , Tang Aileen , Schmolze Dan , Apple Sophia , Hurria Arti , Waisman James Ross , Somlo George , Patel Niki Tank , Sedrak Mina S. , Mortimer Joanne E. , Yuan Yuan 
Published: May 2019

1069 Background: Androgen receptor (AR) targeting therapy has shown single agent activity in triple negative breast cancer (TNBC). GTx-024, a nonsteroidal selective androgen receptor modulator (SARM), demonstrated preclinical and clinical activity in AR+ breast cancer. The current study is designed to test the safety and efficacy of GTx-024 and pembrolizumab in patients with AR+ metastatic TNBC (mTNBC). Methods: This is an open-label phase 2 study for AR+ mTNBC. Eligible participants receive pembrolizumab 200mg IV every 3 weeks in combination with GTx-024 18mg po daily. Key eligibility criteria include patients with AR+ ( > 10%, 1+ by IHC); mTNBC; ECOG 0-1; measurable disease per RECIST 1.1. Patients are excluded if they had prior checkpoint inhibitors or AR targeted agents. The primary objective is to evaluate the tolerability of GTx-024 and pembrolizumab, and determine the response rate. Results: Seventeen patients were enrolled in the study. One patient was ineligible due to previously undiagnosed brain metastases. Ten of 16 patients had visceral metastasis (lung or liver), and 15% of patients had received ≥ 3 previous lines of therapy for mTNBC. Among 16 patients evaluable for response, 2 patients achieved a best response of partial response (PR), 2 patient had stable disease (SD, 18 and 19 weeks ), 11 patients had progressive disease (PD), and 1 patient is too early for restaging imaging. Durable response was found in 1 patient. Grade 3 toxicities include 1 diarrhea and 1 dry skin. Grade 2 adverse events include 3 elevated liver function, 1 adrenal insufficiency, 1 hyperthyroidism, 1 palpitation, 1 diarrhea, 1 hyperhydrosis, 1 hot flashes and 1 headache. Three patients had dose delay and two patients had dose reduction. Conclusions: AR targeted therapy GTx-024 combined with pembrolizumab is well tolerated with clinical activity. Clinical trial information: NCT02971761.
Effector T-cell cytolytic activity modules derived from CD3+ single cells from human primary triple-negative breast cancer (TNBC) in multiple solid tumors to predict response to immune checkpoint blockade therapy (ICB).
Authors: Acharya Chaitanya Ramanuj , Lyerly Herbert K 
Published: May 2019

1073 Background: The prognostic and predictive value of tumor infiltrating lymphocytes for ICB has been recognized in a variety of tumor types, including TNBC. Nonetheless, our understanding of the mechanistic aspects of T cell activation remains incomplete. We hypothesize that a specific effector phenotype of T cell cytolytic activity (ECA) is a consistent feature of epithelial tumors, possibly varying by tumor types with a range of inflammatory features. Methods: We evaluated 6,311 purified CD3+ single cells from human primary TNBC and computed sample set enrichment scores of a set of previously published immune metagenes. Following unsupervised clustering of the enrichment scores of the entire single cell population, two subgroups of cells with highest and lowest average enrichment score of T cell cytolytic activity formed a basis for detecting functional gene expression modules. Spectral decomposition and Jackstraw analysis estimated eight modules with overlapping sets of genes. Each gene expression module was then used to train a Random Forest classifier of ECA phenotype. Results: We discovered that our module-derived classifiers were prognostic not only in TNBC samples obtained from both TCGA (N = 150) and METABRIC (N = 320) datasets but also in 14 other tumor types encompassing 6,000 samples. For example, patient samples from TCGA dataset predicted to be in group ECA ‘High’ have better progression-free survival (p-value: 0.0098l; HR: 0.30) and better overall survival (p-value: 0.0066; HR: 0.17). In both breast datasets, gene within the classifier are relatively under-expressed in ER+ tumors as opposed to HER2+ and TNBC (p-value < 2.2e-16). In a dataset of normal, pure DCIS and mixed DCIS (GSE26304;N = 114), the same genes were relatively under-expressed in DCIS samples relative to invasive tumors (p-value < 2.2e-16). Additionally, in a pre-therapy tumor dataset of fifty-one advanced melanoma patients treated with Nivolumab, who previously either progressed on ipilimumab or were ipilimumab-naïve, our module-derived classifier was able to classify responders and non-responders with 77% accuracy (p-value = 0.02) and was associated with progression-free survival (p-value = 0.03; HR: 0.28). Conclusions: Our study highlights one important application of single-cell genomics in our understanding of immune microenvironment and potentially identify new immunotherapy targets.
First results of a prospective registry in unresectable locally advanced or metastatic breast cancer patients: GEICAM/2014-03 (RegistEM).
Authors: Jara Carlos , Alvarez Isabel , Vila Mireia Margeli , Rodriguez Cesar Augusto , Martinez Purificacion , Batista J. Norberto , Alonso Romero Jose Luis , Antolín Novoa Silvia , Ruíz Sofía , Guerrero Angel , Tusquets Ignasi , Anton Antonio , Chacon Jose Ignacio , Rodríguez-Lescure Álvaro , Tibau Martorell Ariadna , Varela Ferreiro Silvia , Miralles Juan José , Bezares Susana , Rojo Federico , López-Tarruella Sara 
Published: May 2019

1077 Background: In Spain there is limited prospective data for unresectable locally advanced breast cancer (ULABC) or metastatic breast cancer (MBC) patients (pts) treated as per clinical practice. RegistEM study will provide epidemiological, pathological and clinical data, including treatments given for different disease stages. Understanding the real distribution of the different BC subtypes is the primary objective. Methods: This is a non-interventional cohort study enrolling approximately 1,400 pts with advanced disease diagnosed from January 2016 to December 2018, either after recurrence or as first diagnosis, in 38 Spanish sites. Biological samples (primary tumor, metastatic lesions, blood) are currently being collected. In this first analysis, we include 489 pts who met study criteria before October 31, 2017. All data are described in two subgroups: on the most recent tumor lesion or on the primary breast tumor. Results: At first diagnosis, 67.9%, 31.5% and 0.6% of pts had early BC (EBC), MBC and ULABC, respectively. In the total analysis population, median age at diagnosis of advanced disease was 59.6 years, most of pts were white (98.2%), female (99.4%) and postmenopausal (70%). Family history of BC and ovarian cancer was reported in 5.7% pts. In ~390 pts BC clinical subtypes distribution was luminal B(HER2-)-like (~55%), luminal B(HER2+)-like (~16%), luminal A-like or triple negative (TN) (~10% each) and HER2 enriched-like (~8%). Median time to recurrence (years) in EBC pts was: luminal A-like 5.8, luminal B(HER2-)-like 5.1, luminal B(HER2+)-like 3.9, HER2 enriched-like 2.7 and TN 1.7. Bone (59%), visceral (58%) and lymph node (27%) lesions were the most frequent metastatic locations. The two most frequent therapies in first line consisted in: endocrine therapy (ET) (47%) and ET+biological therapy (BT) (29%) for luminal A-like; ET (32%) and ET+BT (32%) for luminal B(HER2-)-like; chemotherapy (CT)+ET+BT (43%) and CT+BT (24%) for luminal B(HER2+)-like; CT+BT (68%) and CT (16%) for HER2 enriched-like; CT (59%) and CT+BT (34%) for TN. Conclusions: These first data confirm that luminal B (HER2-)-like subtype is the most predominant in MBC.
Association of secondary somatic mutations in BRCA1/2 with clinical resistance to PARP inhibitors and chemotherapy.
Authors: Zhu Lingjun , Zhang Yan , Dai Pingping , Zhou Ping , Li Hui , Xu Chunwei , Wang Wen xian , Zhang Chi , Guan Yan-Fang , Xia Xuefeng , Yang Ling , Yi Xin 
Published: May 2019

1087 Background: Somatic reversion mutations in either BRCA1/2 has been reported to lead to the resistance of platinum-based chemotherapy or PARPi. In this study we try to analyze the secondary somatic mutations in BRCA1/2 in patients with germline mutations. Methods: Using gene-panel target-captore next generation sequencing, we analyzed the secondary somatic mutations from 86 patients with BRCA1/2 germline mutations. Results: Eighty-six cases with BRCA1/2 gremline mutations were identified. Secondary somatic mutations restoring BRCA1/2 were identified in 7 patients, including 2 breast cancer, 3 ovarian cancer, 1 prostate cancer and 1cholangiocarcinoma patient. For these seven patients, five had been treated with platinum-based chemotherapy without PARPi and the other two (patient 1 and 2) with PARPi (olaparib). Patient 1 and 2 both received targeting therapy of PARP inhibitor olaparib after the germline BRCA1/2 mutation was detected. About six months later, plasma ctDNA was sequenced. Result showed that the germline mutations remained and additional larger deletions was detected. These secondary somatic mutations are not predicted to significantly affect the BRCA1/2 protein, and are likely to cause resistance to platinum-based chemotherapy or PARPi therapy by restoring BRCA1/2 ORF and DNA repair function. Conclusions: Secondary somatic mutations that restore BRCA1/2 in carcinomas with germline BRCA1/2 mutations predict resistance to platinum-based chemotherapy and PARP inhibitors, some strategies to reverse this type of drug resistance need further investigation. [Table: see text]
Detection of subthreshold microsatellite instability in breast cancer: An ongoing investigation.
Authors: Drago Joshua Z. , Latham Alicia , Modi Shanu , Razavi Pedram , Stadler Zsofia Kinga , Robson Mark E. 
Published: May 2019

1089 Background: Microsatellite instability (MSI) and mismatch repair deficiency (MMRd) can occur sporadically in solid tumors across histologic subtype and predict clinical response to immune checkpoint blockade (ICB). MSIsensor uses next generation sequencing to report the percentage of unstable microsatellites in a given tumor sample as a score. While scores of ≥10 and < 3 have excellent sensitivity/specificity for MSI/MMRd, intermediate scores of 3-10 are of unknown clinical significance, and may include patients with MSI-like genomic signatures who would be overlooked by historical assays. Methods: MSIsensor testing was performed on primary or metastatic tumor specimens from 2,371 patients with breast cancer. Scores of 3-10 were considered MSI-Indeterminate (MSI-I). Concurrent somatic mutations were determined using the MSK-IMPACT assay. Results: Of the 2,371 patients tested, 147 were found to have MSI-I tumors. Ninety-nine (67.3%) were metastatic specimens, and 48 (32.7%) were primary specimens. Of the MSI-I patients, 64 (43.5%) were estrogen receptor positive, 57 (38.8%) were triple negative, and 24 (16.3%) were HER-2 amplified. Somatic TP53 mutations were detected in 109 (74.1%) MSI-I patients, including 54 (94.7%) triple negative patients. Fourteen MSI-I patients were found to have somatic mutations in MMR genes ( MLH1, MSH2, MSH6, PMS2 or EPCAM), but no germline mutations were found. Of the 99 patients with MSI-I metastatic disease, 15 received ICB as part of their clinical care, exhibiting a median progression-free-survival (PFS) of 3 months. Of the 4 patients who demonstrated a PFS of > 6 months on ICB, 2 were found to have somatic mutations in MMR genes. Conclusions: We introduce a subpopulation of breast cancer patients whose tumors exhibit genomic signs of microsatellite instability without meeting the classic criteria for MSI/MMRd as previously defined in colon and endometrial cancers. A subset of these patients may exhibit the properties of MSI/MMRd at the epigenetic and protein-expression levels, and thus potentially benefit from ICB.
Gaps in metastatic breast cancer patient knowledge and understanding in Mexico.
Authors: Villarreal-Garza Cynthia , Fonseca Alan , Pineda Claudia , Platas Ana , Rivera Fernanda , Mesa-Chavez Fernanda , García-García Marisol , Jasqui Ariel , de la Rosa-Pacheco Sylvia , Platas Alejandra 
Published: May 2019

1090 Background: Among patients with metastatic breast cancer (MBC), there is paucity of data regarding knowledge and understanding about disease stage and goals of treatment. The limited evidence shows that up to 40% of MBC patients ignore their stage and reports inadequate educational resources and support. Aim: To assess MBC patients’ knowledge of their disease and satisfaction with the medical information received. Methods: 185 patients diagnosed with MBC who attended follow-up medical appointments at INCan from June to December 2018 were asked to complete a survey to assess their knowledge on MBC curability, subtype, topics reviewed with the oncologist, need of additional information regarding MBC and satisfaction with the quality of the information they received. Clinical data was obtained from the medical records. Descriptive statistics were applied, and the association between qualitative and quantitative variables was assessed with the Chi square test and the Mann Whitney U test, respectively. This study was supported by the SPARC mBC Challenge. Results: Only 52% of patients knew that their disease is not curable, while 31% were not sure and 17% thought it was curable. 82% ignored their MBC subtype and 81% reported to want more information about their cancer. 64% scored their satisfaction with the provided information ≥9 (out of 10), and 74% stated that their most helpful source of information was the medical staff. A statistically significant association was found between the perception of the impossibility of curing MBC and better patient satisfaction (p = 0.038). Likewise, better patients’ satisfaction was associated with older age (p = 0.002), longer time since initial diagnosis (p = 0.018) and since diagnosis of MBC (p = 0.014). Conclusions: Our results dramatically illustrate the lack of understanding patients have regarding their cancer, even when reporting high satisfaction with the received information, and identify a critical need for improvement of healthcare providers’ communication skills. Directed efforts should be implemented to enhance patients’ comprehension to promote their participation in decision-making processes, adherence and, ultimately, outcomes.