bluuebunny/crossref_metadata_2025 huggingface dataset:
Participant hopes and expectations regarding outcomes of genomic sequencing research in pediatric oncology.
Authors: Marron Jonathan M , Quach Emily , Pikman Yana , Janeway Katherine A. , Mack Jennifer W. ,   the GAIN Consortium and LEAP Consortium Investigators
Published: May 2019

10020

Background: Tumor genomic sequencing is rapidly becoming more integrated into pediatric oncology, but for only a minority of individuals does sequencing identify new treatment options or impart an increased chance of cure. Retrospective data show that participants have high hopes for this promising technology, but patient/parent hopes and expectations for the outcomes of genomic sequencing have not previously been evaluated prospectively. Methods: Surveys were administered prospectively to eligible enrollees (young adult patients ≥18y with relapsed/recurrent cancer, rare cancers, and those with poor prognoses, or parents of patients < 18y) prior to return of sequencing results in two clinical sequencing studies through the GAIN (NCT02520713) and LEAP (NCT02670525) Consortia, across 18 pediatric cancer centers. Using previously validated measures, participants were queried about what they most hoped for and thought most likely to happen (most expected) as a result of participating in the sequencing study. Comparisons were made between hopes and expectations using McNemar’s test. Separate multivariate models assessed predictors of most hoping for, and most expecting, increased chance of cure as a result of participating. Models were adjusted for gender, race, disease (leukemia/solid tumor), highest education level achieved, and survey participant (patient/parent). We present interim survey results for 124 participants (67% response rate) who completed surveys between 10/15/17 (GAIN) or 9/1/16 (LEAP) and 1/15/19. Results: 58% (70/121) of respondents selected increased chance of cure as their greatest hope in participating; only 21% (25/119) reported cure as their greatest expectation (p < 0.005). 28% (34/121) most hoped their participation would help cure future patients, and 45% (54/119) most expected this result (p < 0.005). Only 8% (10/121) most hoped to learn more about their/their child’s cancer, but 21% (25/119) most expected this result (p = 0.006). In multivariate analyses, education beyond college level was associated with most hoping for cure as a result of sequencing (OR 2.7 95% CI [1.2, 5.8], p = 0.016). A solid tumor diagnosis was associated with most expecting cure in this setting (OR 2.7 [1.0, 7.2], p = 0.048). Conclusions: Participants derive great hope from participating in pediatric cancer genomic sequencing research, but expectations are more tempered. Some subgroups express heightened expectations of cure, however, potentially identifying target populations for educational intervention.
Subsequent neoplasm risk associated with rare variants in DNA repair and clinical radiation sensitivity syndrome genes: A report from the Childhood Cancer Survivor Study.
Authors: Morton Lindsay M. , Karyadi Danielle M , Hartley Steven , Frone Megan , Sampson Joshua N , Howell Rebecca M. , Neglia Joseph Philip , Arnold Michael A. , Dagnall Casey L , Hicks Belynda , Kristine Jones , Zhu Bin , Leisenring Wendy M. , Yasui Yutaka , Bhatia Smita , Robison Leslie L. , Tucker Margaret A. , Armstrong Gregory T. , Chanock Stephen J.
Published: May 2019

10028

Background: Radiotherapy for childhood cancer is associated with strikingly elevated risk for developing subsequent neoplasms (SNs). Whether mutations in DNA repair and radiation sensitivity genes modulate SN risks is largely unknown. Methods: We conducted whole-exome sequencing in 5105 long-term childhood cancer survivors of European descent (mean follow-up = 32.7 years). SnpEff and ClinVar identified potentially damaging rare variants in 476 DNA repair or radiation sensitivity genes. Conditional logistic regression assessed SN risk associated with these variants aggregated by gene or pathway (N = 155 with ≥5 carriers). Controls were matched on sex, childhood cancer type and diagnosis age, radiation dose to the SN site, and survival. Exact p-values were calculated by permutation. Analyses used all survivors or subsets stratified on radiation dose. Results: A total of 1108 (21.7%) survivors developed at least one SN type known to be related to ionizing radiation exposure (e.g., breast cancer, basal cell carcinoma, meningioma, thyroid cancer, sarcoma). Radiation-related SN risk was associated with homologous recombination (HR) gene variants for SN sites that received > 0- < 10 Gy (20.9% cases, 11.0% controls; odds ratio [OR] = 2.20, 95% confidence interval [CI] 1.52-3.18; P = 1.41x10-4), most notably for FANCM (3.1% cases, 0.5% controls; OR = 9.91, 95%CI 3.73-26.4; P = 2.85x10-4). For radiation-related SNs at sites with higher doses (≥10 Gy), associations were not observed for the HR pathway (14.4% cases, 12.4% controls, P = 0.17) but were observed for two individual genes implicated in double-strand DNA break repair, EXO1 (1.8% cases, 0.4% controls; OR = 6.50, 95%CI 3.49-12.1; P = 7.43x10-4) and NEIL3 (0% cases, 1.0% controls; P = 3.23x10-4). Conclusions: In this discovery study, we identified dose-specific novel associations between SN risk after radiotherapy for childhood cancer and potentially damaging rare variants in genes involved in double-strand DNA break repair, particularly HR. If replicated, these results could impact long-term screening of childhood cancer survivors and risk-benefit assessments of treatment approaches.
Phase II COLET study: Atezolizumab (A) + cobimetinib (C) + paclitaxel (P)/nab-paclitaxel (nP) as first-line (1L) treatment (tx) for patients (pts) with locally advanced or metastatic triple-negative breast cancer (mTNBC).
Authors: Brufsky Adam , Kim Sung-Bae , Zvirbule Zanete , Dirix Luc Yves , Eniu Alexandru E. , Carabantes Francisco , Izarzugaza Yann , Mebis Jeroen , Sohn Joohyuk , Wongchenko Matthew , Chohan Saibah , Amin Reena , McNally V. A. , Miles David , Loi Sherene
Published: May 2019

1013

Background: COLET showed that the addition of C (MEK1/2 inhibitor) to P resulted in an increased ORR (38%; Brufsky, SABCS 2017); IMpassion130 demonstrated clinical benefit with the combination of PD-L1 inhibitor A and nP as 1L tx for pts with mTNBC (Schmid, N Engl J Med, 2018). We investigated the efficacy and safety of A + C + P/nP in pts with mTNBC, as this combination may target multiple cancer immune escape mechanisms simultaneously. Methods: In the multi-stage, multi-cohort Phase II COLET study, pts with histologically confirmed mTNBC were randomized 1:1 to receive 1L tx with A 840 mg IV (d1, d15) + C 60 mg qd (d3-d23) + P 80 mg/m2 IV (d1, d8, d15; cohort 2) or + nP 100 mg/m2 (d1, d8, d15; cohort 3) in 28-day cycles until progression or toxicity. The primary endpoint (EP) was confirmed ORR per investigator-assessed RECIST 1.1. Additional EPs were DOR, PFS, OS, safety and exploratory efficacy by PD-L1 status. Results: As of 10 Aug 2018 (6.5-mo median follow-up), 63 and 62 pts were evaluable for efficacy and safety, respectively. In cohorts 2 and 3, 21 pts (66%) and 20 pts (65%) had received neo/adjuvant taxane tx, 9 pts (28%) and 6 pts (19%) had a disease-free interval of ≤12 mo, respectively. All pts had ≥1 AE; 69% and 70% had Gr 3-5 AEs and 47% and 43% had serious AEs in cohorts 2 and 3, respectively. Efficacy data for all pts and by PD-L1 expression on tumor-infiltrating immune cells (IC ≥1%; PD-L1+) are summarized in the Table. Conclusions: ORRs were similar between the A + C + P arm and A + C + nP arm. Numerically higher ORR and PFS were observed in pts with PD-L1+ disease. The combination’s safety profile was consistent with the known individual safety profiles, and A did not increase toxicity. Clinical trial information: NCT02322814. [Table: see text]
Pembrolizumab (pembro) with paclitaxel (taxol) or capecitabine (cape) as early treatment of metastatic triple-negative breast cancer (mTNBC).
Authors: Page David B. , Chun Brie , Pucilowska Joanna , Kim Isaac , Sanchez Katherine , Redmond William L , Sun Zhaoyu , Wu Yaping , Feryn Alicia , Martel Maritza , Abaya Christina DiLauro , Wadell Dottie , Mellinger Staci L. , Moxon Nicole , Urba Walter John , McAndrew Philomena , El-Masry Maryliza , Basho Reva K. , Conlin Alison Katherine , McArthur Heather L.
Published: May 2019

1015

Background: Atezolizumab (anti-PD-L1) plus nab-paclitaxel was shown to improve outcomes in mTBNC in a phase III clinical trial. Subjects were required to be > 12 months from curative-intent therapy in this trial. It remains unknown whether non-taxane chemo + anti-PD-1/L1 will be beneficial in mTNBC, or whether this approach is effective in rapidly-progressing patients ( < 12 mo from curative-intent therapy). Methods: mTNBC patients were enrolled in a phase Ib study of anti-PD-1 (pembro, 200mg IV q3w) plus physician’s choice chemo (cape: n = 14, 2000mg BID, 7d on/7d off; or taxol: n = 14, 80mg/m2 q1w). Primary/secondary objectives were to evaluate safety/tolerability (primary) and RECIST1.1 response (w12). The exploratory objective was to explore for differences in immunomodulation according to chemo choice. Mixed effects models were employed to compare the longitudinal effects of chemo on peripheral immune cells (flow cytometry) and T-cell diversity (Immunoseq assay). Results: Enrollment of the trial is complete (n = 28), with 100% of evaluable patients tolerating therapy (n = 22) as of 2/1/2019. Cape ORR was 43% (5 PR, 1 CR, 2 SD) with median PFS = 155d. Taxol ORR was 25% (1 CR, 1 PR, 3 SD) with median PFS = 99d. Subjects enrolled < 12 months from curative-intent therapy had numerically lower response (ORR = 27%, 1 CR, 2 PR, 3 SD) than subjects without rapid progression (ORR = 45%, 1 CR, 4 PR, 2 SD). No significant differences in immunomodulation were observed according to chemo type, however both cape & taxol were associated with declines in T-cell quantity (CD4 p < .02, CD8 p < .04) and Immunoseq T-cell fraction over time. Conclusions: Pembro plus cape or taxol is safe with encouraging efficacy, however activity may be lower in the setting of rapid progression following curative-intent chemo. Cape+pembro efficacy is favorable with no measurable differences in immunomodulation, and therefore cape may be preferred as a chemo backbone in selected patients. Both cape and taxol are associated with iatrogenic declines in T-cell quantity, which may explain the observed dropoff in anti-PD-1/L1 activity in later lines. Clinical trial information: NCT02734290.
Characterization of mutational processes in ER+ metastatic breast cancer.
Authors: Buendia-Buendia Jorge , Cohen Ofir , Kim Dewey , Jain Esha , Winer Eric P. , Lin Nancy U. , Wagle Nikhil
Published: May 2019

1019

Background: Diverse mutational processes are active at different stages of cancer development and cause the mutational burden in cancer cells. These processes leave distinctive signatures, characterized by varying frequencies of nucleotide substitutions and their flanking base-pairs. Mutational signatures found in early stage breast cancer have been described, but less is known about the mutational processes in metastatic breast cancer (MBC). Methods: We performed whole exome sequencing (WES) on 209 metastatic tumor biopsies from patients with ER+ MBC. In a subset of patients, we obtained and performed WES on the matched primary biopsy (n = 62). Decomposition of mutational signatures was done by determining the linear combination of 30 previously reported mutational signatures (Alexandrov et al., 2013) that most accurately reconstructs the mutational profile of each tumor sample. For comparison, signature decomposition was also performed on 695 treatment-naïve primary ER+ breast cancers form The Cancer Genome Atlas (TCGA). Results: Cohort-level comparison of signature activity between our cohort of MBC biopsies versus the primary ER+ breast cancers from TCGA demonstrated enrichment of Signature 13 in MBC samples (q = 0.002), attributed to activity of the APOBEC family of cytidine deaminases and implicated in resistance to endocrine therapies. Activity of Signature 22, associated to activity of the nucleotide-excision repair mechanism, was depleted in MBC tumors relative to TCGA ER+ breast tumors (q = 0.02). Decomposition of mutational signatures at the clone level in the subset of patients with both metastatic and matched primary samples allowed us to infer signatures acquired in the metastatic setting. Among mutations in acquired clones, we found enrichment of APOBEC signatures (Sig. 2, q = 0.018; Sig. 13, q = 0.003). Conversely, activity of Signature 1, attributed to the normal aging process, was enriched in mutations shared between primary and MBC samples (q = 0.004). This suggests that mutations developed early in tumor evolution may be driven primarily by natural processes, while later mutations may reflect selective pressures imposed by therapies and cellular defects acquired during disease progression. Conclusions: The profile of somatic mutations in MBC differs from early stage breast cancer. APOBEC-related mutations arising late during tumor evolution are one possible mechanism for this difference. Further studying the associations between clinical features and therapies to mutational processes could inform design of clinical trials and management of MBC.
Effect of HER2/neu 655 polymorphism on trastuzumab-induced cardiotoxicity in HER2-positive breast cancer patients.
Authors: Blancas Isabel , Martín Celia , Legerén Marta , Martos Michel , Sequero Silvia , Mut-Salud Nuria , Gallardo Emma , Garrido Jose Manuel , Rodríguez-Serrano Fernando
Published: May 2019

1025

Background: HER2 overexpression in breast cancer is associated with a poor outcome, high risk of metastasis and a reduced overall survival. The introduction of Trastuzumab in the treatment scheme improved the prognosis of these patients. Nevertheless, around 20% of patients develop cardiotoxicity. The purpose of this study is to analyze the association of the HER2 Ile655Val A > G polymorphism with trastuzumab-induced cardiotoxicity and with survival. Methods: The study included 93 patients recruited from San Cecilio University Hospital in Granada (Spain) who were treated intravenously with Trastuzumab. The cardiotoxicity was diagnosed during the treatment follow-up considering a decrease of the left ventricular ejection fraction (LVEF) from baseline or clinical manifestation of congestive heart failure. HER2 655 A > G was genotyping using TaqMan SNP technology. Results: Genotype frequencies of HER2/neu 655 met Hardy-Weinberg equilibrium ( p= 0.363). We did not find differences in baseline LVEF in patients who developed cardiotoxicity vs those who did not. However, in cardiotoxicity group, the symptomatic patients had a baseline LVEF significantly lower than non-symptomatic patients (57.7 vs 66.1, p < 0.028). Logistic regression analysis adjusted by hormonal status and anthracycline treatment showed significant differences between AG and AA (OR = 3.00, CI95% 1.07-8.41, P= 0.037) or AG and AA+GG (OR = 3.21, CI95% 1.15-8.96, P= 0.026). However, we did not find association between Her2/neu Ile655Val polymorphism and disease-free survival or global survival. Conclusions: HER2 655 A > G polymorphism is significantly associated with higher risk of trastuzumab-induced cardiotoxicity but is not associated to a differential survival rate.
Disparities in treatment patterns and overall survival (OS) in hormone receptor-positive HER2+ metastatic breast cancer (MBC): A National Cancer Database Analysis.
Authors: Statler Abby , Gupta Annie , Blake Cassann N. , Wei Wei (Auston) , Hobbs Brian P , Nahleh Zeina A.
Published: May 2019

1032

Background: Determinants of variation in therapy utilization and OS are unclear for patients diagnosed with hormone receptor+, human epidermal growth factor 2 positive (HER2+) MBC. This study aimed to identify if there are disparities in first-line treatment patterns and outcomes for this subpopulation of MBC patients. Methods: We analyzed MBC patients included in the National Cancer Database diagnosed with estrogen receptor-positive (ER+) and/or progesterone receptor-positive (PR+) and HER2+ disease (i.e. triple positive) treated with endocrine therapy or chemotherapy between 2010 and 2015. Analyses describe the distribution of treatments administered in the first-line setting. Kaplan-Meier method was used to estimate distributions of OS, which were compared among patient cohorts using the log-rank test. Results: Of the 6215 patients diagnosed with triple positive MBC, the majority were 50-70 years old (n=3414 [55%]), female (n= 6122 [98%]), and white (n=4478 [72%]). Four distinct treatment patters were identified; hormonal therapy was the most common (n= 2289 [37%]), followed by hormonal therapy + anit-HER2 (n=1471 [24%]), chemotherapy (1280 [20%]), and chemotherapy + anit-HER2 (n=1175 (19%)). Significant differences in demographic, socioeconomic, and disease characteristics were identified across groups. Disparities in OS were also observed; the unadjusted 5-year OS was substantially lower among older patients, African Americans (AA), those with government insurance, and lower income (Table). Conclusions: This is the first study to report disparities in treatment patterns and OS among real-world triple positive MBC patients. Further investigation is required to determine if there are independent causal associations between poor prognosis and the identified demographic and socioeconomic characteristics. [Table: see text]
Genetic predisposition to breast cancer among African American women.
Authors: Palmer Julie R , Hu Chunling , Hart Steven , Gnanaolivu Rohan David , Gao Chi , Anton-Culver Hoda , Trentham-Dietz Amy , Bernstein Leslie , Weitzel Jeffrey N. , Domchek Susan M. , Goldgar David , Nathanson Katherine , Pal Tuya , John Esther M , Gaudet Mia , Haiman Christopher , Yao Song , Kraft Peter , Polley Eric , Couch Fergus
Published: May 2019

104

Background: The identification of pathogenic mutations in breast cancer susceptibility genes through clinical genetic testing leads to focused screening and prevention strategies for women at increased risk of cancer. However, the frequency of mutations and the risks of cancer associated with breast cancer predisposition genes has not been established for the African American population. Methods: Germline DNA samples from African American women (5,054 breast cancer cases and 4,993 age-matched unaffected controls) from 10 U.S. studies were tested for mutations in 20 established breast cancer predisposition genes using a QIAseq multiplex amplicon panel as part of the “CAnceR RIsk Estimates Related to Susceptibility” (CARRIERS) study. The frequency of mutations in each gene and associations between mutations and breast cancer risk, adjusted for study design, age, and first-degree family history of breast cancer, were evaluated. Results: The mean age at diagnosis of breast cancer cases was 54.4 years and the mean age of controls was 55.2 years. 18.2% of cases and 10.8% of controls reported a first-degree family history of breast cancer. Pathogenic mutations in any of the 20 breast cancer predisposition genes were identified in 7.6% of breast cancer cases and 2.4% of controls. In multivariable analyses, mutations in BRCA1, BRCA2, and PALB2 were associated with high risks of breast cancer (odds ratio (OR) > 5.0). Mutations in CHEK2 were associated with moderate risks of breast cancer (OR > 2.0), whereas mutations in ATM had lower clinical relevance (OR = 1.8). Mutations in BRCA1, BRCA2, PALB2, and RAD51D, but not CHEK2 or ATM, were associated with increased risks of estrogen receptor negative breast cancer. Conclusions: Cancer predisposition genes confer similar risks of breast cancer in the African American population as in non-Hispanic Whites. These studies provide important insights into the risks of breast cancer associated with predisposition gene mutations in the African American population.
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.
Tumor subtype and other prognostic factors in breast cancer patients with brain metastases: The updated graded prognostic assessment (Breast-GPA).
Authors: Sperduto Paul W. , Mesko Shane , Cagney Daniel , Nesbit Eric , Chan Jason , Lee Jessica , Breen Will , Shi Diana , Soliman Hany , Shanley Ryan , Everett Ashlyn S. , Masucci Laura , Remick Jill , Plichta Kristin , Jain Supriya K. , Wu Cheng-Chia , Bryant John , Yu James B. , Nakano Toshimichi , Mehta Minesh P.
Published: May 2019

1079

Background: Brain metastases (BM) are a common and fatal complication of breast cancer but survival varies widely based on various prognostic factors (PF). Hence, patient counseling and therapeutic decisions should be individualized. We previously published a prognostic index (Breast GPA) based on cohort A (1985-2007, n = 642), updated it with tumor subtype in cohort B (1993-2010, n = 400) and are now updating it with a larger contemporary cohort (C). Methods: A multi-institutional (19) multi-national (3) retrospective database of 2473 breast cancer patients with BM diagnosed from 1/1/2006-12/31/2017 was created and compared to our prior cohorts. Demographic, clinical, molecular factors, tumor subtype and treatment were correlated with survival. Kaplan-Meier survival estimates were calculated and compared with log-rank tests. Results: The median survival (MS) for cohorts A, B and C improved over time [12, 14 and 16 mo, respectively ( < 0.01)] despite the subtype distribution becoming less favorable: Luminal B (ER/PR/HER2+) decreased from 26% to 21%; HER2 (HER2+/ER/PR-) decreased from 31% to 17%, Luminal A (ER/PR+/HER2-) increased from 20% to 31%; Basal (ER/PR/HER2-) was unchanged at 24%.MS by subtype improved from 21 to 27 mo in Luminal B, 18 to 25 mo in HER2, 10 to 14 mo in Luminal A and 6 to 9 mo in Basal tumors. The number of BM was 1 in 35%, ≤4 in 67% and > 10 in 18%. PF significant for survival were tumor subtype, age, KPS, number of BM and extracranial metastases (ECM) (all < 0.01). Surprisingly, Hispanic women (7%) showed improved survival (p < 0.01). BRCA1 was mutated in 57/533 (11%) and those patients showed a trend (0.16) toward improved survival. Treatment patterns have changed: the use of whole brain radiation therapy decreased from 71% to 67% to 47% in cohorts A, B and C, respectively. Conclusions: Despite the shift to less favorable tumor subtypes, MS has improvedbut varies widely by diagnosis-specific PF. Compared to prior cohorts, number of BM and ECM were identified as new PF. Ethnic, genetic and treatment differences between the eras are apparent. The updated Breast GPA, based on these data, and the correlation between BRCA1 and tumor subtype will be presented.