bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical significance of circulating tumor cells (CTCs) in hormone receptor-positive (HR+) metastatic breast cancer (MBC) patients (pts) receiving letrozole (Let) or Let plus bevacizumab (Bev): CALGB 40503 (Alliance).
Authors: Magbanua Mark Jesus Mendoza , Oleksandr Savenkov Oleksandr , Asmus Erik , Ballman Karla V. , Scott Janet H , Park John , Dickler Maura N. , Partridge Ann H. , Carey Lisa A. , Winer Eric P. , Rugo Hope S. 
Published: May 2019

1049 Background: CALGB 40503 randomized HR+ MBC postmenopausal pts to Let alone or Let+Bev as first-line therapy. Adding Bev to Let prolonged progression-free survival (PFS) but not overall survival (OS) (Dickler JCO 2016). We performed a correlative study to assess prognostic and predictive value of CTCs in this population. Methods: Blood was collected prior to initiation of treatment. CTCs were enumerated using US FDA-cleared CellSearch assay; samples with ≥5 CTCs per 7.5 mLs of blood were considered CTC-positive (CTC+). Correlation of CTCs with PFS and OS was assessed using Cox regression analysis. Median follow-up was 39 months (mo). Results: Of 343 pts treated, 294 had CTC data and were included in this analysis. Original study results that showed improved PFS (HR = 0.75; 95% CI: 0.59-0.96) but not OS (HR = 0.87; 95% CI: 0.65-1.18) in pts receiving Let+Bev compared to Let were recapitulated in this subset. In multivariable analysis, CTC+ pts (31%) had significantly reduced PFS (HR = 1.49; 95% CI: 1.12-1.97) and OS (HR = 2.08; 95% CI: 1.49-2.93) compared to CTC- pts. Moreover, CTC+ pts who did not receive Bev had worse PFS (HR = 2.31; 95% CI: 1.54-3.47) and OS (HR = 2.64; 95% CI: 1.59-4.40) (Table). CTC+ pts who received Bev had numerically longer median PFS (18.0 vs. 7.0 mo) and OS (33.6 vs. 27.1 mo) compared to CTC+ pts with no Bev; however, tests for interaction between CTC status and Bev (yes vs. no) were not statistically significant for PFS (p=0.70) or OS (p=0.84). Conclusions: CTCs were highly prognostic in this study involving addition of Bev to first-line Let in postmenopausal HR+ MBC. Further research to determine the potential predictive value of CTCs in the setting of both metastatic disease and early breast cancer is warranted. Support: U10CA180821, U10CA180882; Genentech; https://acknowledgments.alliancefound.org ; NCT00601900. Survival in HR+ MBC pts receiving Let or Let+Bev stratified by CTC status. Clinical trial information: NCT00601900. [Table: see text]
Molecular characterization and monitoring of patient ctDNA in phase I study of H3B-6545 in ER+ MBC.
Authors: Rimkunas Vicki , Zhang Zhaojie , Hamilton Erika Paige , Juric Dejan , Wang Judy Sing-Zan , Dees Elizabeth Claire , Yu Lihua , Zhu Ping , Yao Huilan , Ankstitus Laura , Das Subhasree , Korpal Manav , Smith Peter , Schindler Joanne , Kumar Pavan 
Published: May 2019

1052 Background: Because of lack of effective treatment in endocrine resistant metastatic breast cancer (MBC), we developed H3B-6545, a novel selective ERa covalent antagonist, capable of irreversibly inactivating both wild-type and mutant ERa. The aims of this study are to 1) characterize hotspot mutation profiles in heavily pretreated MBC and correlate ESR1, PIK3CA and AKT1 mutations in plasma vs tumor tissue 2) determine if mutations in ESR1 or PIK3CA predict response to H3B-6545 and 3) evaluate if longitudinal tracking of ctDNA correlates with response to H3B-6545. Methods: Fresh plasma samples were collected at baseline (predose), cycle 1 day 15 (C1D15), C2D1, C3D1 and every 8 weeks thereafter with a final sample collection at disease progression. At baseline, BEAMing digital PCR was used to evaluate hotspot mutations in ESR1, PIK3CA and AKT1. Patient specific ctDNA mutations were subsequently monitored by ddPCR. Baseline tumor biopsies were subjected to a targeted Next Generation Sequencing (NGS) panel to identify hotspot mutations. Results: In 77% of patients (30/39), mutations were detected at baseline by the BEAMing assay and of those, 21/39, 16/39 and 3/39 had mutations in ESR1, PIK3CA and AKT1, respectively. 20% (9/39) of patients exhibited co-mutations in ESR1 and PIK3CA. In 60% (9/15) of patients, DNA mutations identified by the plasma BEAMing assay were also detected in the tumor biopsy whereas; DNA mutations found in tissue were also detected in plasma in 86% (12/14) of cases. Serial ctDNA monitoring revealed that in patients with confirmed partial responses (3/3), ctDNA levels were undetectable by C2D1. In contrast, ctDNA levels increased from baseline in 3/4 patients with progressive disease. Exploration of ctDNA ratios (day 15/baseline and day 30/baseline) and correlations of PIK3CA and ESR1 mutations with response to H3B-6545 will be presented. Conclusions: ctDNA is a reliable sample type for assessing ESR1, PIK3CA, and AKT1 mutations in MBC, overcoming the challenges of obtaining biopsies in the metastatic setting. In addition, ctDNA dynamics may be a useful tool to monitor the efficacy of H3B-6545. Clinical trial information: NCT03250676.
A large retrospective analysis of CDK 4/6 inhibitor retreatment in ER+ metastatic breast cancer (MBC).
Authors: dos Anjos Carlos Henrique , Razavi Pedram , Herbert Joshua , Colon Jodecy , Gill Kaitlyn , Modi Shanu , Bromberg Jacqueline , Dang Chau T. , Liu Dazhi , Norton Larry , Chandarlapaty Sarat , Robson Mark E. , Jhaveri Komal L. 
Published: May 2019

1053 Background: Sequential retreatment with endocrine therapy (ET) has been the clinical paradigm for ER+ MBC due to persistent dependence on hormone signaling. Recently CDK4/6i + ET have improved PFS and are routinely utilized in the first/second- line setting. Whether this paradigm of sequential retreatment holds for CDK 4/6i is unknown. To evaluate the potential benefit of CDK4/6i re-treatment we conducted this retrospective analysis. Methods: We identified ER+/HER2- MBC pts treated with ≥ 2 lines of CDK4/6i at our institution between 2015-2018. We categorized pts based on reason for discontinuation of their first CDK4/6i: cohort 1 – switch to alternate CDK4/6i due to toxicity; cohort 2 – retreatment with same CDK4/6i beyond progression with change of ET and cohort 3- switch to alternate CDK4/6i as monotherapy or with same or another ET. We analyzed pt demographics, imaging reports and time to subsequent therapy (TTST) for every CDK4/6i line for each cohort. If a pt received > 2 lines of CDK4/6i, then that pt was evaluated for every CDK4/6i exposure. Results: 135 pts received ≥ 2 lines of CDK4/6i treatment (Tx). Cohorts 1, 2 and 3 had 23, 43 pts and 84 pts respectively. In Cohort 2, 95% of pts received 2 subsequent CDK 4/6i + ET Tx; 56% had the second CDK4/6i in second-line met setting. TTST1 (1st CDK4/6i Tx) was 9.6m (95% CI 4.9 - 11 m), TTST2 (second CDK4/6i Tx) was 4.5m (95% CI 3.3 – 7.6 m) and 35% had TTST2 ≥ 24 weeks. For Cohort 3, 48% were retreated with a different CDK 4/6i in ≥ fifth-line. 51% received 2 subsequent CDK 4/6i Tx with 18% in second-line met setting. TTST1 was 9.6 m (95% CI 5.9 – 12 m), TTST2 was 4.4 m (95% CI 3.8 – 5.9 m) and 29% had TTST2 ≥ 24 weeks. In cohort 3, 29% (n=24) pts had PD as best response at the time of first CDK4/6i exposure but 29% (7/24) achieved a radiologic response to their second CDK4/6i Tx. Pts had tumor sequencing using MSK-IMPACT which will be correlated with TTST. Conclusions: This large single institution retrospective analysis suggests that retreatment with a CDK4/6i regimen should be evaluated in prospective trials. Additionally, despite PD as best response with the first CDK4/6i (palbociclib/ribociclib) regimen, a subset of pts had radiologic response to a subsequent abemaciclib-containing regimen, which is an hypothesis generating observation.
Phase I dose escalation of H3B-6545, a first-in-class highly Selective ERα Covalent Antagonist (SERCA), in women with ER-positive, HER2-negative breast cancer (HR+ BC).
Authors: Hamilton Erika Paige , Dees Elizabeth Claire , Wang Judy Sing-Zan , Kim Amy , Korpal Manav , Rimkunas Vicki , Rioux Nathalie , Schindler Joanne , Juric Dejan 
Published: May 2019

1059 Background: H3B-6545 inactivates both wild-type and mutant ERα by targeting cysteine 530 and enforcing a unique antagonist conformation. Methods: Women with locally advanced or metastatic HR+ BC are treated (tx) with H3B-6545 administered once daily orally over a 28 day cycle after progression on at least one hormonal therapy and at least one additional therapy/regimen. Dose escalation uses a 3+3 design with the option to backfill previously cleared doses and allows for intrapatient dose escalation. This phase 1 explores the safety, pharmacokinetics and pharmacodynamics of H3B-6545 in women with HR+ BC to identify the recommended Phase 2 dose. Results: As of 10-Dec-2018, 32 pts have been tx with H3B-6545 at doses of 100 to 450 mg/day; 97% had prior tx with a CDK4/6 inhibitor and 56% had received ≥3 lines of prior anti-cancer therapy. No dose-limiting toxicities and only one Grade 3 treatment related adverse event (TRAE) have been observed (lymphocyte count decrease). The most common (≥10%) TRAEs include asymptomatic sinus bradycardia, diarrhea, nausea, fatigue, anemia, decreased appetite, and hot flush. H3B-6545 was rapidly absorbed with a tmax of 2-4 h. Plasma concentration increased with dose from 100 to 450 mg, and was similar on C1D1 and C1D15. Consistent with the H3B-6545 mechanism of action and preclinical data, H3B-6545 inhibits ER target gene expression and shows a 50% decrease in Ki67 levels across all dose levels post-tx. ESR1 (60%) and PIK3CA (34%) mutations were detected in plasma at baseline and changes in mutant allele frequencies show correlation in response to tx. Stable disease was observed in 15 pts (47%) and 34% of pts completed at least 6 months of tx. Partial responses (PRs) were observed in 3 pts: 1 pt (mutant) received 2 prior lines of therapy and 2 pts (1 mutant and 1 wild-type) received >5 prior lines of therapy including fulvestrant and capecitabine; all 3 pts received a prior CDK4/6 inhibitor. Conclusions: H3B-6545 has been well-tolerated up to the 450 mg dose level with early signs of single-agent anti-tumor activity in a post CDK4/6 setting. Dose escalation continues in pts with advanced HR+ BC. Clinical trial information: NCT03250676.
The Affordable Care Act and cost-related medication non-compliance in cancer survivors.
Authors: Barnes Justin , Johnson Kimberly J. , Boakye Eric Adjei , Varvares Mark Alex , Osazuwa-Peters Nosayaba 
Published: May 2019

106 Background: Cost-related medication non-compliance (CRN), which is associated with access-to-care barriers and poorer health outcomes, is more prevalent among cancer survivors than other adults. While CRN in survivors has been decreasing recently, evidence for a change driven by the Affordable Care Act (ACA) is limited. We aimed to quantify the impact of the ACA on CRN in non-elderly cancer survivors using population-based data and a quasi-experimental design. Methods: We utilized 2011-2017 National Health Interview Survey data. CRN was defined as not being able to afford medication or taking less than prescribed, skipping doses, or delaying prescription filling due to cost. Linear probability models applied to difference-in-difference analyses were used to compare CRN changes after the ACA in non-elderly ( < 65 years) cancer survivors relative to control groups expected to be impacted less by ACA provisions--non-elderly adults without a cancer history, elderly survivors, and non-elderly survivors with high income. Results: We identified 6,176 non-elderly and 8,508 elderly cancer survivors and 142,732 other non-elderly adults. Non-elderly cancer survivors had a 6.31 (95% CI = 3.47, 9.15; p < .001) percentage point (PP) decrease in CRN relative to non-elderly adults without a cancer history, particularly for those earning 125-249% of the federal poverty limit (FPL) (8.46 PP; 95% CI = 0.45, 16.46; p = .038) and < 125% FPL (11.8 PP; 95% CI = 4.51 to 19.1; p = .002). Relative to elderly survivors, CRN decreased 6.01 PP (95% CI = 3.12, 8.90; p < .001) in non-elderly survivors after the ACA, especially for individuals earning < 125% FPL (15.7 PP; 95% CI = 7.7, 23.7; p < .001). Relative to non-elderly survivors earning > 400% FPL, those earning < 125% FPL had an 8.36 PP (95% CI = 1.44, 15.3; p = .018) reduction in CRN. Conclusions: CRN decreased in non-elderly cancer survivors after the ACA relative to both elderly survivors and adults without a history of cancer. Furthermore, reductions in CRN were observed in low relative to high income survivors. Thus, the ACA is associated with decreasing CRN in cancer survivors, especially those with low income, and hence may improve health care access and affordability for this vulnerable population.
Association of drug-related polymorphisms with palbociclib-related neutropenia: Pharmacogenetic analysis of PALOMA-2/-3 (P2/3).
Authors: Iwata Hiroji , Fletcher Olivia , Liu Yuan , Umeyama Yoshiko , Zhang Zhe , Schnell Patrick , Marshall Jean-Claude , Johnson Jillian G. , Wood Linda S. , Toi Masakazu , Finn Richard S. , Cristofanilli Massimo , Turner Nicholas C. , Bartlett Cynthia Huang 
Published: May 2019

1060 Background: The most common PAL treatment related adverse event is neutropenia. ABCB1 and ERCC1 variants are associated with increased chemotherapy drug exposure and CYP3A7*1C may be associated with reduced exposure. Pharmacogenetic analyses of these variants in patients (pts) from P2/3 may reveal associations between single nucleotide polymorphisms (SNPs) and early occurrence of grade 3/4 (G3/4) neutropenia. Methods: ABCB1 (rs1045642, rs1128503), ERCC1 (rs3212986, rs11615), and CYP3A7*1C (rs45446698) variants were analyzed in germline DNA from pts with HR+/HER2– advanced breast cancer from P2 (n=584) and P3 (n=442) by TaqMan assay. Association between variants and incidence of G3/4 low absolute neutrophil count (ANC) at Cycle 1 Day 15 (C1D15) was assessed with the exact Cochran-Armitage trend test. Odds ratios (OR) and 95% confidence intervals (CI) were estimated by logistic regression. Results: In total, 652 PAL-treated pts had SNP, race, and C1D15 ANC data. Minor allele frequencies (MAF), incidence rates, and relative risk of G3/4 C1D15 ANC for ABCB1 and ERCC1 variants are given in the Table. CYP3A7*1C was only found in non-Asians (MAF 6%). Conclusions: This is the first comprehensive assessment of pharmacogenetic data from P2/3. ABCB1 and ERCC1 SNP allele frequencies differ between Asians and non-Asians. Despite combining P2/3 data, we lacked power to detect moderate associations; further investigation of these SNPs with G3/4 C1D15 ANC is warranted. Pfizer Clinical trial information: NCT01740427, NCT01942135. [Table: see text]
Association of SOX9 expression with sensitivity to CDK7 inhibition and overall survival in triple-negative breast cancer.
Authors: Guan Xiaoxiang , Jin Juan , Tang Lin , Wang Xin , Wang Yucai , Shu Yongqian 
Published: May 2019

1065 Background: Triple-negative breast cancer (TNBC) has been shown to display cyclin-dependent kinase 7 (CDK7)-dependent transcriptional addition and is sensitive to a CDK7 inhibitor THZ1. As tumor heterogeneity is well known, we sought to identify predictive markers of sensitivity to CDK7 inhibition in TNBC. Methods: Published mRNA microarray data was analyzed to identify genes associated with sensitivity of TNBC cells to the CDK7 inhibitor THZ1. Cell survival assay after THZ1 treatment was performed using Cell Counting Kit-8. Expression of SOX9 was examined by Western blot in cell lines and IHC in breast cancer tissue microarray. Patient survival analysis was done using the Kaplan-Meier method. Results: Analysis of published mRNA microarray data showed that SOX9 was overexpressed in the MDA-468 and BT-549 TNBC cell lines, which were sensitive to the CDK7 inhibitor THZ1 and showed decreased SOX9 expression with THZ1 treatment. We treated 10 TNBC cell lines with various concentrations of THZ1 and found that these cell lines displayed a wide spectrum of sensitivity to THZ1, with an IC50 ranging from 20-30 nM in sensitive lines (MDA-468 and MDA-231) to ~300 nM in insensitive lines (BT-20 and MDA-157). There was a strong correlation of SOX9 expression by Western blot and sensitivity to THZ1 in these cell lines (Pearson correlation, r = 0.82, P= 0.01). IHC of two tissue microarrays containing 278 breast cancer samples showed that SOX9 expression was significantly higher in TNBC (n = 59) compared to hormone positive breast cancer (n = 173; P< 0.01). Among the 59 TNBC cases, 43 had high SOX9 expression and 16 had low SOX9 expression. Patients with high or low SOX expression had similar grade, T stage and nodal involvement (All P> 0.20). Finally, with standard of care treatment, TNBC patients with high SOX9 expression had a significantly worse overall survival (OS) compared to patients with low SOX9 expression (2 year OS rate 100% vs 92.9%, 5 year OS rate 93.8% vs 83.3%, log rank P= 0.03). Conclusions: SOX9 expression level in TNBC cell lines was associated with sensitivity to the CDK7 inhibitor THZ1. TNBC patients with high expression of SOX9 had worse OS, and may benefit from CDK7 inhibition as a novel therapy.
Outcomes of talazoparib (TALA) versus physician's choice of chemotherapy (PCT) in patients (pts) with advanced breast cancer (ABC) and a germline BRCA (gBRCA) mutation by line of chemotherapy (CT) in the EMBRACA trial.
Authors: Ettl Johannes , Hurvitz Sara A. , Rugo Hope S. , Lee Kyung-Hun , Mina Lida A. , Woodward Natasha E. , Yerushalmi Rinat , Diab Sami , Martin Miguel , Tudor Iulia Cristina , Czibere Akos Gabor , Gauthier Eric Roland , Litton Jennifer Keating , Goncalves Anthony 
Published: May 2019

1071 Background: The PARP inhibitor TALA was approved in the US for treatment of g BRCA-mutated ABC based in part on the EMBRACA study. Understanding the outcomes of EMBRACA pts relative to prior CT is a current unmet need. Methods: EMBRACA was a randomized Phase 3 trial comparing TALA 1 mg daily vs PCT (capecitabine, eribulin, gemcitabine, vinorelbine) in g BRCA-mutated ABC. Clinical outcomes were assessed by line of prior CT for ABC in intent-to-treat (ITT), triple-negative breast cancer (TNBC), and hormone receptor-positive (HR+) breast cancer cohorts. Results: 431 pts were randomized (ITT; TALA 287; PCT: 144). TALA was generally more effective than PCT across efficacy endpoints regardless of line of CT (Table). For the ITT population, TALA improved progression-free survival (PFS) and objective response rate (ORR) vs PCT for each line of CT assessed. Other prespecified subgroups (TNBC and HR+) will be presented. Conclusions: In pts with g BRCA-mutated ABC, TALA demonstrated improvements in clinical outcomes compared with PCT regardless of prior lines of CT. Clinical trial information: NCT01945775. [Table: see text]
Brain metastasis in patients with hereditary BRCA-mutated invasive breast cancer.
Authors: Garber Haven , Raghavendra Akshara Singareeka , Hess Kenneth R. , Arun Banu , Ibrahim Nuhad K. 
Published: May 2019

1074 Background: In the past six months, two poly(ADP-ribose) polymerase (PARP) inhibitors have been approved for the treatment of patients with metastatic breast cancer and germline pathogenic variants in BRCA1 or BRCA2 ( gBRCA). In addition, recent data from the IMpassion 130 trial lends support for the role of immunotherapy in a subset of patients with triple negative breast cancer (TNBC). Approximately 60% of patients with gBRCA1 have TNBC. There is evidence that both PARP inhibitors and checkpoint inhibitors cross the blood-brain barrier and both classes of agents have entered clinical trials for patients with brain metastases in other tumor types. We studied the clinical course of breast cancer patients with gBRCA and brain metastasis at our institution to inform clinical trial design for this group of patients with poor outcomes. Methods: Patients with stage I to III invasive breast cancer, gBRCA, and eventual development of brain metastasis were identified from clinical databases. Data analyzed included breast cancer subtype and stage at diagnosis, treatment, time to distant recurrence and to discovery of brain metastasis, and overall survival from time of development of brain metastasis. Results: Patients in our cohort (n = 24, to date) were diagnosed at a young age (median age 39) and primarily had TNBC (21/24, 87.5%) with infiltrating ductal carcinoma histology. Nineteen patients had gBRCA1 and 4 patients had gBRCA2. All but 1 patient received anthracycline-based chemotherapy in the neoadjuvant/adjuvant setting. Median time to distant metastasis was 2 years (range: 0.8 – 15) and the brain was the first site of recurrence in 5 of 24 (21%) patients. Median time from diagnosis to development of brain metastasis was 2.6 years (range: 1.2 – 19) and most patients (18/25, 72%) had multiple brain metastases discovered on the initial brain MRI. Median overall survival (OS) was 3.7 years (range: 1.8 – 24) and median OS from the time of brain metastasis was 7 months (range: 1 month – 13 years). Conclusions: Breast cancer patients with germline pathogenic variants in BRCA1/2 who develop brain metastasis have a dismal prognosis. These patients may benefit from an agent with intracranial activity at the time of first distant recurrence.
A phase II, single-arm study of apatinib and oral etoposide in pretreated metastatic HER2-negative breast cancer.
Authors: Hu Nanlin , Yuan Peng 
Published: May 2019

1076 Background: There is no standard treatment strategy for patients with locally advanced or metastatic breast cancer suffering progression after one prior chemotherapy with metastasis setting. Apatinib is a tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor 2(VEGFR-2). Etoposide is a highly active chemo-drug in the treatment of advanced breast cancer, both as a single agent or in combination regimens, and is well tolerated, with a low incidence of severe toxicity. This study is performed to assessed the efficacy and safety of apatinib and oral etoposide in patients with HER2 negative locally advanced or metastatic breast cancer for whom at least one lines of prior chemotherapy had failed. Methods: This open-label, single arm study enrolled patients with HER2-negative breast cancer, pretreated with anthracycline, taxanes, and who failed in the metastatic setting at least one prior chemotherapy regimens and at least one endocrine drug for hormone receptor-positive patients. Apatinib was administered 425/500mg daily according to patients ECOG(Eastern Cooperative Oncology Group) status, oral etoposide was administered 50mg/m2 for first 10 days in a 21-days cycle. The primary end point of this study was progression free survival (PFS). Secondary end points included objective response rate (ORR), disease control rate (DCR), overall survival (OS), and toxicity. The treatment duration is until disease progression or intolerability of apatinib or oral etoposide. Results: 20 eligible patients were enrolled in this, open-label, single arm study and received apatinib and oral etoposide with a median age of 54 years old(range 36 to 66 years). Median follow-up time was 11months. 20 patients were eligible for efficacy analysis. Median PFS was 5.6 months (95% confidence interval (CI), 4.01 m – 8.42 m). ORR was 20% (4/20). DCR was 70% (14/20). Median OS was 11.2 months (95% CI, 9.6 m – 14.95 m). The most common grade 3/4 treatment-related AEs were hypertension (30%), and proteinuria (5%), nausea (5%). 35%(7/20) patients had dose reduction because of adverse events, after that all adverse events can return to less than 2 grade. Conclusions: Apatinib with oral etoposide exhibited objective efficacy in pretreated, metastatic HER2-negative breast cancer with manageable toxicity. Prospective studies enrolling more patients are needed. Clinical trial information: NCT03535961.