bluuebunny/crossref_metadata_2025_split huggingface dataset:
Utilization of post-lumpectomy radiation therapy in women 70 years of age or older: A report from the National Cancer Data Base.
Authors: Yao Katharine , Czechura Tomasz , Huo Dezheng , Winchester David Porter , Edge Stephen B. , Winchester David J. 
Published: March 2020

1033 Background: The Cancer and Leukemia Group B (CALGB) 9343 trial published in 2004 showed no overall survival benefit from radiation in patients >70 years old with estrogen receptor (ER) positive, pT1 tumors with the use of tamoxifen. We tested the hypothesis that the use of radiotherapy decreased in this group of patients following publication of the trial, utilizing the National Cancer Data Base. Methods: 34,853 breast cancer patients 70 years or older with pT1N0/NX, ER positive tumors who underwent a lumpectomy between 2004 and 2007 were studied. Chi-square tests and logistic regression models were used to determine trends and factors related to the use of radiation. Results: The use of radiation decreased from 70.6% in 2004 to 66.4% in 2005, 66.6% in 2006, and 67.2% in 2007 (p<0.001). The use of standard external beam radiation decreased from 58.8% in 2004 to 45.8% in 2007 while the use of accelerated partial breast radiation using brachytherapy (APBI) increased from 4.5% to 10.0%, IMRT radiation from 3.1% to 5.3%, and 3D conformal radiation from 3.7% to 5.7% (p<0.001). Patients between the ages of 86+ years old were less likely to undergo radiation than patients 70-75 years old (OR=0.12, 95% CI: 0.11-0.13). Asian Pacific Islanders were more likely to undergo radiation than whites (OR=1.39, 95% CI: 1.13-1.70). In community cancer programs, 67% patients received radiation, compared to 69.1% in comprehensive community programs and 65.5% in academic programs (p<0.001). The use of radiation varied by facility location; 73.5% of facilities located in the Midwest radiated these patients as opposed to 62.6% in the South. In patients who had no nodes examined, 37% underwent radiation as opposed to 74% who did have nodes examined (p<0.001). Likewise, 79.4% of patients who received hormone therapy underwent radiation as opposed to 54.6% of patients who did not receive hormonal therapy (p<0.001). Conclusions: The use of radiation therapy decreased only slightly and remained high in women with ER+ stage I breast cancer over the age of 70, despite findings from the CALGB 9343 study. However, there was a large shift in radiation modality over the study period in the older patients.
A phase II study of foretinib in triple-negative, recurrent/metastatic breast cancer: NCIC CTG trial IND.197 (NCT01147484).
Authors: Rayson Daniel , Lupichuk Sasha M. , Chia Stephen K. L. , Potvin Kylea R. , Dent Susan , Tsao Ming Sound , Prady Catherine , Ellard Susan , Salim Muhammad , Allo Ghassan , Ludkovski Olga , Goodwin Rachel Anne , Wainman Nancy , Walsh Wendy , Farmer Pat , Eisenhauer Elizabeth A. 
Published: March 2020

1036 Background: Met, a receptor tyrosine kinase, is preferentially expressed in basal-like compared to luminal breast cancer. In murine models, overexpression of the oncogenic Met receptor transgene induces tumors with human basal gene expression characteristics supporting Met inhibition as a treatment strategy for triple negative (TN) breast cancer. Foretinib is an oral multi-kinase inhibitor of Met, RON, AXL, TIE-2 and VEGF receptors with anti-tumor activity in advanced HCC and papillary renal cell cancer. Methods: Patients (pts) with TN breast cancer and 0-1 prior regimens for metastatic disease received daily foretinib 60 mg po in a 2-stage single arm trial. Primary endpoints were objective response and early progression rates per RECIST 1.1. Tumor samples were centrally reviewed to confirm ER/PR/HER2 status and for correlative studies including Met, PTEN and EGFR expression. Stage 1 accrual required 23 response-evaluable Met unselected patients with accrual continuing if >/= 1 response or < 17 early progressions (PD <= 8 weeks on study) were observed. Results: Accrual is 29 pts to date; 24 are eligible, 22 evaluable for toxicity and 15 for response. Median age is 56 y (43-81), ECOG PS 0-1 in 23/24. Grade 3 laboratory adverse events were: lymphopenia (9%), elevations in ALT (5%), GGT (5%) and INR (5%). Treatment-related non-hematologic toxicities included (all/grade 3-4) fatigue (64%/5%), nausea (55%/5%), diarrhea (41%/5%), hypertension (32%/14%), vomiting (27%/0%), anorexia (23%/5%) and rash (14%/0%). Three SAEs possibly related to foretinib included; asymptomatic pulmonary embolism, reversible CHF and pleural effusion with QTc prolongation. One PR (7%), 8 early PD (53%) and 6 SD (40%) have been observed to date with median SD duration of 5.4 months (range 2.7-5.5). Preliminary correlative results (IHC): 5/8 (62.5%) evaluable Met positive cases had SD and 4/5 (80%) Met negative cases had PD as best response. Met IHC was negative in the pt with PR. Conclusions: Foretinib shows preliminary evidence of activity and tolerability in metastatic, TN breast cancer. Stage 2 of accrual will include 15 pts with pre-treatment biopsies of metastases and circulating tumor cell collection.
Epigenetic aspects of triple-negative in patients with breast cancer.
Authors: Martínez-Galan Joaquina , Rios Sandra , Delgado Juan Ramon , Torres-Torres Blanca , Lopez-Peñalver Jesus , Núñez M. Isabel 
Published: March 2020

1041 Background: Identification of gene expression-based breast cancer subtypes is considered a critical means of prognostication. Genetic mutations along with epigenetic alterations contribute to gene-expression changes occurring in breast cancer. However, the reproducibility of differential DNA methylation discoveries for cancer and the relationship between DNA methylation and aberrant gene expression have not been systematically analysed. The present study was undertaken to dissect the breast cancer methylome and to deliver specific epigenotypes associated with particular breast cancer subtypes. Methods: By using Real Time QMSPCR SYBR green we analyzed DNA methylation in regulatory regions of 107 pts with breast cancer and analyzed association with prognostics factor in triple negative breast cancer and methylation promoter ESR1, APC, E-Cadherin, Rar B and 14-3-3 sigma. Results: We identified novel subtype-specific epigenotypes that clearly demonstrate the differences in the methylation profiles of basal-like and human epidermal growth factor 2 (HER2)-overexpressing tumors. Of the cases, 37pts (40%) were Luminal A (LA), 32pts (33%) Luminal B (LB), 14pts (15%) Triple-negative (TN), and 9pts (10%) HER2+. DNA hypermethylation was highly inversely correlated with the down-regulation of gene expression. Methylation of this panel of promoter was found more frequently in triple negative and HER2 phenotype. ESR1 was preferably associated with TN(80%) and HER2+(60%) subtype. With a median follow up of 6 years, we found worse overall survival (OS) with more frequent ESR1 methylation gene(p>0.05), Luminal A;ESR1 Methylation OS at 5 years 81% vs 93% when was ESR1 Unmethylation. Luminal B;ESR1 Methylation 86% SG at 5 years vs 92% in Unmethylation ESR1. Triple negative;ESR1 Methylation SG at 5 years 75% vs 80% in unmethylation ESR1. HER2;ESR1 Methylation SG at 5 years was 66.7% vs 75% in unmethylation ESR1. Conclusions: Our results provide evidence that well-defined DNA methylation profiles enable breast cancer subtype prediction and support the utilization of this biomarker for prognostication and therapeutic stratification of patients with breast cancer.
Preclinical evaluation of PARP inhibition in breast cancer: Comparative effectiveness of olaparib and iniparib.
Authors: Cotter Maura B. , Pierce Aisling , McGowan Patricia M. , Flanagan Louise , Quinn Cecily , Evoy Denis , Crown John , McDermott Enda , Duffy Michael J. 
Published: March 2020

1042 Background: The main function of PARP1 is repair of single-strand DNA. Phase I/II clinical trials have shown that the PARP inhibitor, olaparib has efficacy in BRCA1/2-related breast cancer. Due to the similarities between BRCA1/2-associated and triple negative breast cancer (TNBC), we hypothesise that TNBC may also be sensitive to PARP inhibition. In order to assess this we addressed the effects of 2 PARP/PARP-like inhibitors, on a panel of breast cancer cell lines. Methods: PARP1 was measured by immunohistochemistry in 101 TNBC and 116 non-TN cancers. Comparative growth inhibitory capacity of olaparib and iniparib was evaluated using cell viability (MTT) and colony formation assays in 12 breast cancer cell lines (TN=7, non-TN=5). Results: Using immunohistochemistry, PARP1 staining was predominantly nuclear with some cytoplasmic staining. High staining intensity for PARP1 was found more frequently in ER-negative (p = 0.001), in high grade (p = 0.013) and in Ki67-positive ( p = 0.003) samples. Potentially important was the finding that high PARP1 staining intensity was detected more frequently in TN than non-TN samples (p = 0.0001). IC50 concentrations across 12 cell lines ranged from 3.7-31 µM for olaparib and 13-70 µM for iniparib. No difference in sensitivity was observed between the TN and non-TN cell lines (by MTT). Olaparib also reduced the ability of cells to form colonies with IC50 values ranging from <0.01-2.5 µM. Addition of the CDKI inhibitor CDK1i (Calbiochem) to olaparib resulted in formation of significantly fewer colonies compared with either inhibitor alone, in a cell line dependent manner. Conclusions: Our results suggest that although PARP1 is expressed in the majority of breast cancer, significantly higher staining intensity was found in TN than non-TN samples. Furthermore, our work suggests that olaparib is a more potent inhibitor of the in vitro growth of breast cancer cells than iniparib. Combined inhibition of PARP1 with olaparib and CDK1 with CDK1i may be a way forward for the treatment of TNBC. Acknowledgement: The authors thank SFI (SRC award, 08/SRC/B1410 MTCI) for funding this work.
Neoadjuvant weekly nab-paclitaxel (wA), carboplatin (Cb) plus bevacizumab (B) with or without dose-dense doxorubicin-cyclophosphamide (ddAC) plus B in ER+/HER2-negative (HR+) and triple-negative (TN) breast cancer (BrCa): A BrUOG study.
Authors: Sinclair Natalie Faye , Abu-Khalaf Maysa M. , Rizack Tina , Rosati Kayla , Chung Gina , Legare Robert Duffy , DiGiovanna Michael , Fenton Mary Anne , Bossuyt Veerle , Strenger Rochelle , Sakr Bachir Joseph , Lannin Donald R. , Gass Jennifer S. , Harris Lyndsay , Sikov William M. ,   Brown University Oncology Group (BrUOG)
Published: March 2020

1045 Background: High risk BrCa patients (pts) often receive weekly paclitaxel (wP) as well as ddAC. Switching to wA(Abraxane) or adding B or Cb may enhance its efficacy, especially in TN pts. Methods: Pts with clinical stage IIA-IIIC BrCa received wA 100 mg/m2, Cb AUC 6 + B 15 mg/kg q3wks x 12 wks only (cohort 1/Yale) or followed by ddAC + B x 4 (cohort 2/Brown). Endpoints: pathologic complete response (pCR) - absence of invasive BrCa in breast + axillary nodes, residual cancer burden (RCB), clinical CR/partial response (cCR/cPR), and toxicity. Correlative studies are being performed on biopsies obtained at baseline and after run-in doses of wA or B only. Post-op pts resume B for 34 wks; other systemic therapy, including ddAC in cohort 1, is at MD discretion. Results: 55 of 60 pts (median age 47, range 25-68; 31 HR+/29 TN) are evaluable for response (see table below). Median # doses wA 11,Cb 4, ddAC 4. Dose reductions: wA 25% for neutropenia (ANC), Cb 15% for thrombocytopenia (tcp). B 7% held for hypertension. Grade 3-4 toxicities (>5%): ANC 85%, tcp 35%, anemia 25%. Serious adverse events during wA: 3 nausea/dehydration (N/D), 3 infection w/o neutropenic fever (FN), 2 GI bleed; during ddAC: 6 (21%) FN despite G-CSF, 3 N/D. Conclusions: The combination of wA, q3wk Cb + B was well tolerated, with cCR+cPR 84%. However, overall pCR was only 11% (27% in TN) after 12 wks of this regimen (cohort 1). Subsequent preop ddAC raised overall pCR to 54%, and 81% in TN, demonstrating that longer treatment duration or inclusion of anthracycline-based therapy improves responses. Results for cohort 2 compare favorably with those from I-SPY, GeparQuinto and NSABP B-40; the addition of Cb and/or B in TN is being evaluated in CALGB 40603. [Table: see text]
Patterns in circulating microRNA in black (B) versus white (W) patients with triple-negative (TN) breast cancer (BC).
Authors: Shapira Iuliana , Lee Annette , Oswald Michaela , Weiselberg Lora Rose , Ballard David , Taioli Emanuela , Cheng Kit , Mekan Sabeen Fatima , Barginear Myra F. , Keogh Mary , Mason Cathleen , Budman Daniel R. 
Published: March 2020

1046 Background: Breast cancer is by far more common in W than in B women. Black women have more aggressive disease that occurs almost a decade earlier, it is usually triple negative and has a lower survival. Objectives to determine 1) if plasma miRNA expression differs between B and W women, and 2) if variation in miRs may explain the observed survival difference in TNBC in W compared to B women. Methods: We determined miRNA profiles in plasma collected before removal of breast tumors in three groups of W and B women: 1) normal controls (N), 2) TN and 2) ER/PR positive BC. Expression miRNA profiling of 754 miRNAs on the ABI Open Array detected 101miRNAs in plasma. We compared miRNA expression in cancer patients and race-matched controls. A moderated t-statistic through the R/Bioconductor 'limma' was used to compare the mean response between subject factors of interest. Results with a p<0.05 were considered statistically significant. Characteristics: 32 patients were included in this analysis (mean age 50 years; range 31-68), 10 had stage III TNBC (5 B & 5 W); 10 had stage III ER/PR+BC (5 B, 5 W); and 12 were controls (6 B, 6 W) Results: W TNBC patients overexpressed (15 fold higher than normal) 20 miRs in plasma (let-7d, let7g, miR-103, -10a, 15a, -9, -99b, -181a, -18a, -502, -187, -365 and others), these miRs were not found in any of the B patients. Six microRNAs (such as miR-34a, -127 and others) were 15 fold higher than normal controls in B cancer patients, these miRs were not detected in W patients with TNBC. Four miRs in B and 8 miRs in W were not previously reported in association with breast cancer suggesting that they may be connected to the host response. Conclusions: The striking difference in the patterns of plasma miRNA expression between B and W patients may provide the key to the large difference in outcome between these groups when receiving similar treatments, the worse prognosis group may carry the miRs that promote metastasis. The seed-soil hypothesis may explain the better prognosis in W patients. W women may carry those miRNAs that support an “exaggerated” response to systemic treatment, while the B may have the miRs that favour metastasis.
Gene expression-based predictors of chemotherapy response in basal-like breast cancer.
Authors: Prat Aleix , Lluch Ana , Albanell Joan , Fang Cheng , Chacon Lopez-Muniz Jose Ignacio , Parker Joel S , Calvo Lourdes , Plazaola Arrate , Arcusa Lanza Angels , Seguí-Palmer Miguel Angel , Burgues Octavio , Vicioso Luis , Sanchez-Simon Raquel , Bermejo Begoña , Ribelles Nuria , Melendez Asensio Barbara , Caballero Rosalia , Carrasco Eva Maria , Perou Charles M. , Alba E. ,   Spanish Breast Cancer Research Group GEICAM
Published: March 2020

10500 Background: The Basal-like subtype is generally associated with high chemo-sensitivity, but not all tumors respond and/or benefit to the same extend. In this study, we sought to identify gene expression predictors of neoadjuvant chemotherapy sensitivity in Basal-like breast cancer. Methods: Expression of 542 genes was measured using the Nanostring nCounter platform from 69 FFPE pre-treated samples of the GEICAM/2006-03 phase II trial, which were treated with epirrubicin/cyclophosphamide followed by docetaxel+/-carboplatin. Research-based PAM50 and Claudin-low predictors were also evaluated. The association between response (Miller-Payne criteria) and gene/signature expression was assessed by multivariable ordinal logistic regression. Significant findings were evaluated in 109 independent triple-negative and Basal-like tumors treated with anthracycline/taxane-based chemotherapy (Hatzis et al.). Finally, interaction tests were performed to identify genes/signatures associated with carboplatin response. Results: In GEICAM/2006-03, 61/69 (88%) tumors were identified as Basal-like by PAM50. High correlation to the Basal-like centroid, or high expression of proliferation-related genes (i.e. FANCA), were found to be significantly associated with high chemo-sensitivity, whereas high expression of genes associated with mesenchymal/stem cell biological processes (i.e. SNAI1 and IL6) and/or luminal differentiation (i.e. MUC1 and FOXA1) were significantly associated with chemo-resistance; similar findings were observed in Hatzis et al. Finally, high expression of genes associated with proliferation/DNA-repair (i.e. ATR) and tight junctions (i.e. CLDN3/4/7) were found associated with carboplatin response, whereas expression of the Claudin-low signature was found associated with carboplatin resistance. Conclusions: High expression of Basal-like and/or proliferation-related genes and low expression of luminal/mesenchymal/stem cell-like biological processes were consistently identified as predictive of chemotherapy response. Our data suggests that gene expression profiling might help shed light into the biological and clinical heterogeneity of Basal-like breast cancer.
Circulating tumor cell counts (CTC) as prognostic of overall survival (OS) in SWOG S0421-docetaxel with or without atrasentan for metastatic castration resistant prostate cancer (mCRPC).
Authors: Vogelzang Nicholas J. , Ely Benjamin , Fink Louis M. , Goldkorn Amir , Tangen Catherine M. , Twardowski Przemyslaw , Van Veldhuizen Peter J. , Agarwal Neeraj , Carducci Michael Anthony , Monk J. P. , Datar Ram H , Garzotto Mark , Mack Philip C. , Lara Primo , Higano Celestia S. , Hussain Maha , Quinn David I. , Cote Richard J , Thompson Ian Murchie 
Published: March 2020

10503 Background: CTC are promising biomarkers in mCRPC but have not been prospectively validated for docetaxel treatment (Rx). Using CellSearch technology (J&J), we enumerated CTC in this Phase 3 trial & assessed prognostic value for OS. The aim of this correlative study nested within 0421 was to compare CTC via CellSearch technology to newer microfilter technologies (Cote & Goldkorn PIs RO1 CA141077). Comparative data analysis is ongoing. Methods: CTC were drawn at baseline (d1) & pre-cycle 2 (d21) of Rx & shipped overnight to a central site for enumeration (CTC/7.5 ml). Cox regression evaluated the association between OS and (i) baseline CTC counts & (ii) CTC dynamics (d1 to d21) in pts with good (<5) vs. poor (>=5) baseline CTC counts. Receiver operator characteristic (ROC) analysis and Characteristics & Regression Trees (CART) were used to explore further prognostic CTC cutpoints for 2-yr survival. Results: Of 263 patients (pts) consented, 238 were evaluable at d1 & 232 at d21. At d1 median CTC was 5 (range 0-5916) & d1 CTC < vs. >= 5 was associated with baseline PSA (mean 99 vs. 320 ng/ml, p=0.004) and worse bone pain (36% vs. 51%, p=0.03). There was a significant difference in OS for d1 CTC < vs. >=5, with a hazard ratio (HR) of 2.92 (95% CI 1.92-4.43, p<0.001) after adjustment for PSA & other factors. In pts with low d1 CTC (< 5), an increase in CTC was associated with shorter OS, HR 4.04 (95%CI 1.56-10.44, p=0.004); in pts with high d1 CTC (>=5), a >=2-fold decrease in CTC was associated with longer OS, HR 0.45 (95%CI 0.24-0.84, p=0.012); adjusting for risk factors. D1 CTC and 2-year survival had ROC AUC of 0.781. CART analysis identified prognostic subgroups based on CTC of 0, 1-5, 6-53, and >53: (HR 0.36, 0.77,1.3 and 2.8). Conclusions: In this phase 3 trial, d1 CTC was prognostic of OS after risk factor adjustment. CTC dynamics from d1 to d21 were also prognostic of OS. These data are an exploratory subset analysis of the overall study. Yet, they comprise the largest docetaxel-based prospective cohort to date, which validates a 5 CTC prognostic threshold for OS & identifies new potential prognostic subgroups that may extend the clinical utility of CTC enumeration in mCRPC.
PTEN assessment and PI3K/mTOR inhibitors: Importance of simultaneous assessment of MAPK pathway aberrations.
Authors: Janku Filip , Broaddus Russell , Bakkar Rania , Hong David S. , Stepanek Vanda M.T. , Naing Aung , Falchook Gerald Steven , Fu Siqing , Wheler Jennifer J. , Piha-Paul Sarina Anne , Moulder Stacy L. , Luthra Rajyalakshmi , Tsimberidou Apostolia Maria , Kurzrock Razelle 
Published: March 2020

10510 Background: Loss of PTEN function increases PI3K/mTOR signaling. Preclinical data suggest that PTEN aberrations can predict sensitivity to drugs targeting the PI3K/mTOR pathway. Methods: Tumors from 461 patients with diverse cancers referred to the Clinical Center for Targeted Therapy were tested for cytoplasmic immunohistochemical expression of PTEN using the following scoring system: negative (no staining); positive (intact staining); reduced staining, with stroma serving as an internal positive control. Whenever possible, tumors were also tested for mutations in the MAPK pathway (KRAS, NRAS, and BRAF). We analyzed outcomes of patients treated with PI3K /mTOR with respect to their PTEN status. Results: Of 461 patients, 47 (10%) had negative PTEN expression, 168 (36.5%) had positive PTEN expression, and 246 (53.5%) had reduced PTEN. In tumor types with >10 patients tested, negative PTEN was most frequent in uterine (10/33, 33%), renal (3/11, 27%), salivary gland (2/10, 20%), colorectal (15/82, 18%), breast (2/15, 13%), pancreatobiliary (3/24, 13%), and prostate cancers (2/19, 11%). Of 206 patients tested for MAPK (KRAS, NRAS, and BRAF) pathway mutations, patients with either negative or reduced PTEN had more MAPK mutations than patients with positive PTEN expression (72/144, 50% vs. 20/62, 32%, p=0.02). A total of 153 (33%) patients received therapies with PI3K /mTOR inhibitors and 17 (11%, 95% CI 0.07-0.17) achieved a partial response (PR). Proportions of PRs were 2/13 (15%) for PTEN negative, 3/50 (6%) for PTEN positive, and 12/90 (13%) for reduced PTEN. There was no significant difference in PR rate amongst patients with positive PTEN expression compared to patients with negative or reduced PTEN (3/50, 6% vs. 14/103, 14%; p=0.27). Conclusions: Complete loss of PTEN expression was found in 10% of patients. Positive PTEN expression was found in 36.5% of patients. PTEN status did not predict response to PI3K/mTOR inhibitors, perhaps because patients with negative and reduced PTEN expression had a higher incidence of simultaneous MAPK (KRAS, NRAS, BRAF) mutations.