bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase II clinical trial using anti-CD3 x anti-HER2 bispecific antibody armed activated T cells (HER2 BATs) for HER2-negative (0-2+) metastatic breast cancer.
Authors: Lum Lawrence G. , Thakur Archana , Al-Kadhimi Zaid S. , Deol Abhinav , Simon Michael S. , Schalk Dana , Liu Qin , Flaherty Lawrence E. 
Published: May 2019

1080 Background: This study presents a phase II cell therapy trial in 32 women with metastatic or locally advanced HER2- breast cancer (BrCa) who received infusions of anti-CD3 x anti-HER2 bispecific antibody armed activated T cells (BATs). This phase II study (NCT 01022138) was conducted to determine if BATs infusions could improve time to progression (TTP) and overall survival (OS), as well as to confirm the toxicity profile of BATs. Methods: The phase II included 32 patients with a median of 4 lines of therapy (7 TNBC and 25 HR/PR+ HER2- patients) with an average age of 52.5 years (range 28-75 years). Twenty-one patients had ≥3 lines of prior therapy and 11 patients had 1-2 lines. Peripheral blood mononuclear cells (PBMC) were stimulated with anti-CD3 antibody and expanded in IL-2, armed with HER2Bi, and aliquoted for the clinical trial. Patients received oncologist’s choice of chemotherapy (4 cycles/4 months) followed by 3 infusions of BATs given once per week for 3 weeks and a boost given 12 weeks after the 3rd infusion. Results: Fifteen of 32 (ORR of 46.8%) who had received any cells had stable disease (SD) at 1 month after the last infusion, and 8 of 15 (25%) had SD > 4 months. For patients who completed 3 or 4 infusions (17-83 x 109 BATs), 8 of 31 patients had TTP > 4 months. One patient completed 2 infusions (17 x 109 BATs). There were no dose limiting toxicities (DLTs). Tumor markers decreased in 13 of 23 (56.5%) patients with evaluable markers. The median OS was 13.8, 16.5, and 12.4 months for all, ER/PR+, and TNBC, respectively. OS for all patients with chemosensitive (chemoS) and chemoresistant (chemoR) disease was 14.6 and 8.6 months (NS), respectively. OS for chemoS and chemoR disease in HER2- ER/PR+ patients was 16.5 and 8.6 months (NS), respectively. OS for chemoS and chemoR disease in TNBC patients was 12.4 and 22.6 months, respectively (NS). The median TTP for all, HER2- ER/PR+, and TNBC patients was 2.7, 2.9, and 1.4 months, respectively. Increases in serum IL-2 and IL-12 were associated with BATs infusions. Conclusions: Targeting HER2- tumors was safe. There were trends toward improved survival in patients who were HER2-/ER/PR+ TNBC, patients who were chemoS, was associated with increased TTP and OS in all groups, and was associated with decreased tumor markers in those who received 4 infusions. Immune studies showed evidence for induction of adaptive immunity directed at breast cancer antigens. Targeting metastatic HER2- BrCa with BATs shows promise. Clinical trial information: NCT 01022138.
ARID1a as a marker of prognosis and increased sensitivity to CDK4/6, mTOR 1/2 and Src homology region 2 phosphatase (SHP 1/2) inhibitors in breast cancer (BC).
Authors: Mariotti Veronica , McLeod Howard L. , Soliman Hatem Hussein 
Published: May 2019

1082 Background: ARID1a (AT Rich Interactive Domain 1A) is part of the SWI/SNF complex, which regulates gene transcription, and is believed to be a tumor suppressor gene. Low ARID1a expression has been associated with poor prognosis in BC. The aim of this study was to explore the clinical significance of ARID1a mutation and expression loss, and its potential as a therapeutic target in BC. Methods: We analyzed publicly available genomic databases to study the clinical implication of ARID1a mutations and gene expression in BC. Results: ARID1a was mutated in ~5-7 % of BCs within TCGA/METABRIC/MSK (5511 samples), but did not show differences in frequency between histology, grade, or estrogen receptor (ER)/HER2 receptor status. MSK metastatic tissue samples had higher incidence of ARID1a mutation compared to primary tumor samples (7.6% vs 4.4%, χ2 P = 0.0073). Analysis of ARID1a in KMPLOT showed that lower gene expression was associated with worse relapse-free survival and overall survival across all BCs, but the difference was primarily in molecularly classified luminal A tumors. Mutations in ARID1a did not show an association with outcomes in TCGA/METABRIC/MSK datasets. Pathway analysis of ARID1a showed it is involved in regulating ER ligand driven signaling and interacts with targets regulated by CDK4 and mTOR activity. CancerRxgene drug sensitivity analyses on BC cell lines revealed that ARID1a mutated BC cell lines were significantly more sensitive to palbociclib, SHP1/2, and mTOR1/2 inhibitors compared to ARID1a wildtype cell lines. Conclusions: Reduced activity of ARID1a in luminal BC cells may negatively affect prognosis by altering ER signaling leading to activation of druggable resistance mechanisms, particularly in metastatic tissue. Loss of function ARID1a mutations may sensitize cancer cells to CDK4/6, mTOR1/2, and SHP1/2 inhibitors in vitro. Further research in ARID1a mutated ER+ BCs using combinations of these inhibitors is warranted.
Evaluation of oral S-1 as a first-line chemotherapy for metastatic HER2-negative breast cancer: An analysis of two randomized phase III studies (SELECT BC-CONFIRM and SELECT BC).
Authors: Nishimura Reiki , Mukai Hirofumi , Uemura Yukari , Akabane Hiromitsu , Park Youngjin , Takahashi Masato , Sagara Yoshiaki , Takashima Tsutomu , Fujisawa Tomomi , Hozumi Yasuo , Kawahara Takuya , Watanabe Takanori 
Published: May 2019

1083 Background: Anthracycline regimens and taxane have been first line chemotherapeutic options for HER2 negative metastatic breast cancer. In a previous phase III trial (SELECT BC), non-inferiority of S-1 was demonstrated in terms of overall survival (OS). The SELECT BC-CONFIRM study was designed to confirm the results of the SELECT BC study and to combine the two randomized studies. Methods: Patients (n = 618) in the first trial were randomly assigned (1:1) to the S-1 group or the taxane group. Patients (n = 230) in the second trial (SELECT BC-CONFIRM) were randomly assigned to the anthracycline group or the S-1 group. Treatment continued until tumor progression, unacceptable toxic effects, or completion of six courses in the standard regimen group and four courses in the S-1 group. The primary endpoint was OS and secondary endpoints were progression-free survival (PFS), time to treatment failure, adverse events, HRQOL and cost-effectiveness. A pooled analysis of the two studies was predefined to confirm the results of the SELECT BC study. Results: 1. The HR for the anthracycline group was 1.09 [95%CI 0.80-1.48] in SELECT BC-CONFIRM, and the estimated predictive posterior probability that the HR does not exceed the threshold 1.333 was 90.27%. 2. Median OS was 32.7 months (S-1 group) and 36.3 months (standard treatment group). S-1 was not inferior to standard treatment in terms of OS (p non-inferiority = 0.0062). Median PFS was 11.2 months (S-1 group) and 11.2 months (standard treatment group). 3. Treatment was discontinued due to adverse events (i.e., neutropenia, febrile neutropenia, fatigue and edema) in 5.7% in the S-1 group and 6.6% in the standard treatment group 4. The EORTC QLQ-C30 questionnaire (global health status) revealed that there was no difference between the S-1 and anthracycline groups (p = 0.257), but there was a significant difference between the S-1 and taxane groups (p = 0.0039). Conclusions: S-1 is not inferior to taxane or anthracycline with respect to OS as a first-line treatment for MBC. S-1 should be considered a new option as a first-line chemotherapy for HER2-negative metastatic breast cancer patients. Clinical trial information: UMIN000005449.
Oral paclitaxel in the treatment of metastatic breast cancer (MBC) patients.
Authors: Dai Ming-Shen , Chao Ta-Chong , Chiu Chang-Fan , Lu Yen-Shen , Shiah Her-Shyongi , Wu Yi-Yin , Cheng Wei-Hong , Chan Wing Kai , Hung Tak , Hung Noelyn , Cutler David , Kwan Rudolf , Kramer Douglas , Chao Tsu-Yi 
Published: May 2019

1084 Background: Intravenous (IV) paclitaxel is an effective treatment for breast cancer. Oral administration paclitaxel is preferable to IV regarding minimizing IV injections, anaphylactic reactions to cremaphor, steroid pre-medications, hospital visits, and relevant costs. However, paclitaxel has poor oral absorption due to active excretion by P-glycoprotein (P-gp) in the intestinal cells. Oraxol (Athenex, USA) is an oral paclitaxel and HM30181, a novel oral inhibitor of intestinal P-gp which enables the oral administration of paclitaxel. We report the final results of a pharmacokinetics (PK) study, including clinical response and tolerability of Oraxol in treatment of metastatic breast cancer patients. Methods: Multicenter, single-arm, open-label, PK study of Oraxol (HM30181A at 15mg, plus oral paclitaxel 205mg/m2) administered orally for 3 consecutive days weekly for up to 16 weeks. Paclitaxel PK was assessed at week-1 and week-4. Tumor Response was measured at weeks 8 and 16 using RECIST criteria 1.1. Toxicity was assessed using CTCAE v4.03. Results: Twenty-eight MBC patient were studied with a mean age of 56.6 years (range: 38 - 79 yrs). 26 patients had failed mutiple previous chemotherapies. There were 11 (42.3%) partial response, 12 (46.2%) stable disease and 3 (11.5%) progressive disease in 26 evaluable patients. Three patients had treatment-related SAEs (grade ≥3 neutropenia) and all patients recovered completely. PK results showed that the AUC of oral paclitaxel at week-1 was reproducible at week-4 (3050 to 3594 ng-hr/mL). Conclusions: Oral paclitaxel showed very encouraging anti-cancer activity in MBC patients who failed previous chemotherapies with acceptable toxicity. Weekly oral paclitaxel can achieve paclitaxel exposure similar to that of weekly IV paclitaxel (80mg/m2) reported previously. PK of oral paclitaxel is reproducible. Clinical trial information: NCT03165955.
Differences in breast cancer outcomes amongst Black United States-born and Caribbean-born immigrants.
Authors: Barreto Coelho Priscila , Cerbon Danielle , Schlumbrecht Matthew , Parra Carlos , Hurley Judith , George Sophia 
Published: May 2019

1088 Background: The Black population in the US constitutes of 4 million immigrants, with 50% from the Caribbean. It has been shown that breast cancer is responsible for 14%-30% of cancer deaths in the Caribbean; this is up to two times higher than the USA. Methods: Retrospective cohort of 1369 self-identified Black women with breast cancer. Data was obtained from Jackson Memorial Health Systems and University of Miami Health System Tumor Registry. Individual-level data from 1132 cases was used to estimate hazard rations (HRs) of women born in the Caribbean (CB) or in the USA (USB) using Cox proportional hazards regression analysis for overall survival. Median follow-up was 115 months (interquartile range, 91.9-138.1 months) per participant. Results: Data from 622 (54.9%) USB women and 507 (45%) CB women diagnosed with breast cancer between 2006-2017. 90% (n = 1232) of the cohort is of non-Hispanic ethnicity. Caribbean immigrants from Haiti (18.3%), Jamaica (6.5%), Bahamas (3.1%), Cuba and Dominica Republic (2.8% each), Trinidad and Tobago (1%) and other nationalities from the Organization of Eastern Caribbean States were included, mean age 55.7 [95% CI, 54.7-56.8]; USB mean age 57.6 [95% CI, 56.4-58.7] (P = 0.02). Compared to USB, CB had lower BMI at diagnosis 29.6 [95% CI, 28.9-30.3] versus 30.9 [95% CI, 30.1-31.7, P = 0.015]. Compared to CB patients, USB patients had more ER- [31.4% vs 39.1 %, P = 0.018] and triple negative breast cancers [19.6% vs 27.9%, P = 0.003]. Compared to USB patients, CB presented at more advanced stage, III and IV [44.2% vs 35.2%], p = 0.016. In spite of higher advanced stage at diagnoses, CB patients had a better breast cancer overall survival [HR = 0.75; 95%CI, 0.59-0.96; P = 0.024]. Black Hispanic patients had a better overall survival [HR = 0.51; 95%CI, 0.28-0.93; p = 0.028] compared to non-Hispanic Blacks. Compared to Hispanic Caribbean, non-Hispanic Caribbean had a worse overall survival [HR = 1.98; 95%CI, 1.00-3.94; P = 0.048]. The distribution of patients treated at the private cancer center and the safety net hospital were the same, differences in outcomes observed are due to intrinsic differences. Conclusions: This is the largest analysis to date of self-identified Black breast cancer patients in the context of nativity, race, ethnic identity and overall survival with clinico-pathologic characteristics. CB immigrants diagnosed with breast cancer have a better overall survival than US born Black patients. This finding suggests that within the African diaspora in the USA, additional factors beyond race contribute to the outcomes.
RUBY: A phase II study testing rucaparib in germline (g) BRCA wild-type patients presenting metastatic breast cancer (mBC) with homologous recombination deficiency (HRD).
Authors: Patsouris Anne , Tredan Olivier , Nenciu Daniel , Tran-Dien Alicia , Campion Loic , Goncalves Anthony , Arnedos Monica , Sablin Marie-Paule , Gouraud Wilfried , Jimenez Marta , Droin Nathalie , Bieche Ivan , Callens Celine , Loehr Andrea , Vicier Cecile , Andre Fabrice 
Published: May 2019

1092 Background: PARP-inhibitors improve PFS in mBC patients (pts) harboring a gBRCA mutation (mut). However, unlike ovarian cancer, there is no evidence until now that this class of agents has efficacy in gBRCA wild-type (WT) pts. In RUBY, we evaluated rucaparib in gBRCA WT mBC pts, and whose tumor present with HRD as assessed by genome-wide Loss of Heterozygosity (LOH) score. Methods: 713 gBRCA WT women with HER2- mBC, initiating a first metastatic chemo, were screened for high (≥18%) genomic tumor LOH generated from a SNP array on metastatic sample. Eligible pts with a high LOH score or somatic (s) BRCA mut and ≥1 prior chemo regimen were proposed to enter RUBY and receive oral rucaparib 600 mg BID continuously in 28-day cycles until disease progression. The primary endpoint was clinical benefit rate (CBR), defined by complete (CR) and partial response (PR) or stable disease (SD) ≥16 weeks. We used a Simon’s two-stage design (p0=20%; p1=40%), responses in ≥4/17 pts were expected to move to second step, and ≥11/37 pts to be considered of clinical interest (α=10% and power of 90%). Whole genome sequencing (WGS) was performed retrospectively to further assess potential biomarkers of PARP inhibitor response. Results: Tumors from 221 (31%) pts were LOH high. 41 pts were enrolled, including 4 pts with sBRCA mut. Median prior metastatic chemo lines was 2 (1-5), 17 pts had TNBC at diagnosis. As of 14 Jan 2019, 16 pts were alive, 5 are still on treatment. The median number of cycles was 2 (1 -20), and 37/40 patients were evaluable for CBR. 5 pts (13.5%) demonstrated clinical benefit (1 CR [LOH high], 3 PR [2 LOH high, 1 sBRCA2] and 1 SD>31 weeks [sBRCA1]). 19 pts had grade 3-4 toxicities. 3 pts discontinued due to toxicity. 4/5 responders pts had their tumor profiled by WGS: preliminary analyses showed that 4 pts presented high large scale state transitions, and 3 presented a somatic biallelic loss of function in HR-related genes. The fifth responder harbored a mut on gPALB2 and sBRCA2 at inclusion. Conclusions: In this study, rucaparib demonstrates antitumor activity in a subset of gBRCA WT mBC pts whose tumor has high LOH. Final analyses of WGS will provide insights about HRD signatures and drivers alterations associated with response. Clinical trial information: NCT02505048.
Survival outcomes of premenopausal patients diagnosed with invasive lobular carcinoma.
Authors: Kim Hee Jeong , Kim Seon-Ok , Freedman Rachel A. , Partridge Ann H. , Metzger-Filho Otto 
Published: May 2019

1093 Background: The survival outcomes of postmenopausal women with invasive lobular carcinoma (ILC) are similar to invasive ductal carcinoma (IDC) when treated with aromatase inhibitor, but inferior when treated with tamoxifen. We sought to investigate the survival outcomes of premenopausal ILC when compared to IDC using a population-based analysis. Methods: We used Surveillance, Epidemiology, and End Results data (SEER) between 1990 to 2015 to identify premenopausal patients (defined as < 50 years old), diagnosed with stage I to III IDC or ILC. Breast Cancer Specific Survival (BCSS) was assessed using log-rank test and piecewisecox models. Annual hazard of BCCS for hormone receptor positive (ER+) ILC and ER+ IDC were calculated from year 0 to 20 and defined as the proportion of patients with a BCSS event during a 1-year interval. Results: The study includes a total of 170,352 pts diagnosed with either IDC (n = 158,733) and ILC (n = 11,619). 71% of IDC and 95% of ILC pts were ER+. Median age was 44 years old and median follow up was 90 months(IQR 40-151 months). Survival analysis revealed a significant time-dependent effect of histology for BCSS (p < .0001). When compared to IDC, ILC pts had better BCSS in the first 10 years after diagnosis (HR 0.73, 95% CI 0.68-0.78), but worse BCSS outcome after year 10 (HR 1.80, 95% CI 1.59- 2.03). Similar results were observed when adjusting for ER status, histologic grade and stage on multivariate analysis. Among pts ≤ 35 years old(n = 371 ILC; 18086 IDC) survival analysis revealed a non-significant trend towards inferior outcome for ILC compared to IDC throughout the whole follow-up period (HR = 1.2 95% CI 0.96-1.52). Annual hazard of BCCS events showed a peak at year 5 for both IDC and ILC. In the subset of IDC, we noticed a decreasing hazard of BCSS from years 6 through 20. By contrast, in the subset of ILC, we observed higher frequencies of BCSS from years 6-20 when compared to IDC (p < 0.0001). Conclusions: In this population-based analysis, premenopausal ILC had worse BCSS estimates when compared to premenopausal IDC. This is explained by a higher incidence of late events in the subset of ILC when compared to IDC.
Patients with metastatic breast cancer enrolled in phase I clinical trials: Clinical outcomes and cohort trends.
Authors: Weiss Jennifer , Gao Dexiang , Elias Anthony D. , Borges Virginia F. , Kabos Peter , Davis S. Lindsey , Leong Stephen , Diamond Jennifer Robinson 
Published: May 2019

1099 Background: Phase I clinical trials have traditionally enrolled patients with advanced solid tumors and many providers perceive the likelihood of clinical benefit as low. The purpose of this study was to evaluate clinical outcomes for patients with metastatic breast cancer enrolled on Phase I clinical trials and explore differences in outcomes for patients enrolled in all-comer versus breast cancer-specific cohorts. Methods: We performed a retrospective chart review of patients with metastatic breast cancer enrolled in Phase I clinical trials at the University of Colorado Cancer Center from 2012-2018. We included trials with Phase I and/or Phase Ib in the title. Studies or cohorts enrolling patients with ≥ 3 tumor types were considered all-comer and those with enrollment restricted to breast cancer or a breast cancer subtype were considered breast cancer-specific. Results: A total of 208 patients were enrolled in Phase I clinical trials, 168 in breast cancer-specific cohorts and 40 in all-comer trials. Patients on average were 56.9 years old (range 31-79), 98.6% (205/208) female, 1.4% (3/208) male, 57.2% ER+/Her2-, 30.1% ER-/Her2- and 11.1% Her2+. Patients received on average 2.1(range 0-10) prior lines of chemotherapy in the metastatic setting. Patients enrolled on Phase I clinical trials remained on study without progression on average for 138 days (CI 95%, 112.64 to 163.91). Patients enrolled on breast cancer-specific studies remained on study for 152 days (CI 95%, 120.66 to 182.56) compared to 82 days (CI 95%, 59.43 to 105.13) for those enrolled on all-comer trials, p< 0.05. Patients went off study for disease progression (83.17%), adverse events (7.69%), and other (9.14%), including withdrawal of consent. Conclusions: Patients with metastatic breast cancer previously treated with multiple lines of chemotherapy in the metastatic setting enrolled in Phase I clinical trials received clinical benefit from treatment that is favorable compared to historical controls of late-line chemotherapy. The majority of patients were treated on breast cancer-specific cohorts consistent with trends in Phase I trial design including more tumor specific cohorts.
Real-world outcomes of patients with advanced non-small cell lung cancer (aNSCLC) and autoimmune disease (AD) receiving immune checkpoint inhibitors (ICIs).
Authors: Khozin Sean , Walker Mark S. , Jun Monika , Chen Li , Stepanski Edward , Rubinstein Wendy S. , Komatsoulis George Anthony , Roberts Jeremy , Zhi Jizu , Miller Robert S. , Fukushima Ryan , Lau Denise , Hyde Brigham 
Published: May 2019

110 Background: Anecdotal and early evidence suggest ICIs are being used in patients with advanced malignancies and history of AD, despite such patients being typically excluded from traditional clinical trials. We compared the outcomes of patients with or without AD, all of whom had ICI treatment for aNSCLC. Methods: We conducted a retrospective, observational cohort study using de-identified, curated data in ASCO’s CancerLinQ. Patients with Stage III or IV NSCLC who received ≥1 dose of an ICI and had ≥2 visits from Jan 2011 to Nov 2018 were included. AD status prior to ICI treatment was identified using ICD-9/ICD-10 codes or AD medications (including steroids). Symphony claims data were linked via tokenization to build cohorts. Time to treatment discontinuation (TTD), time to next treatment (TTNT), real-world progression-free survival (rwPFS) and overall survival (OS) were compared across the two cohorts using the log-rank test. Cox Proportional Hazards Model was used to adjust for covariates. Adverse events (AEs) were compared using Chi-Square and Fisher’s Exact Test. Active AD was defined as evidence of autoimmune disease in the year prior to starting ICIs. Results: Among 2425 patients with aNSCLC treated with ICIs, AD was present in 22% (N=538). Median OS in all patients was 12.4 months (95% CI 11.3-13.5). TTD, TTNT, rwPFS and OS did not differ between the two cohorts (Table). There was no association between AD status and outcomes. There was no increased incidence of AEs in the AD group; however a sub-analysis among patients with active AD showed higher rates of select AEs including endocrine, GI and blood disorders. Conclusions: This analysis demonstrates that patients with evidence of AD prior to receiving ICI have similar outcomes compared to patients with no evidence of AD. Further research is needed to better understand the impact of active AD on the risk of AEs and patient outcomes. [Table: see text]