bluuebunny/crossref_metadata_2025_split huggingface dataset:
Activity and duration of chemotherapy (CT) in different biologic subtype (BS) in metastatic breast cancer (MBC) patients (P).
Authors: Bighin Claudia , Del Mastro Lucia , Dozin Beatrice , Giraudi Sara , Levaggi Alessia , D'Alonzo Alessia , Lambertini Matteo , Poggio Francesca , Iacono Giuseppina , Miglietta Loredana , Pronzato Paolo 
Published: March 2020

1036 Background: In MBC P the benefit of CT after the 1st line (L) is poorly defined. We evaluated activity of subsequent L of CT in different BS of MBC. Methods: MBC P treated in our center from 2007 to 2012 with ER, PgR and HER2 on primary tumor and at least 1 L of CT for MBC were evaluated. P were classified as Luminal A (ER and/or PgR +, HER2 -, Ki67≤14%), Luminal B (ER and/or PgR +, HER2 -, Ki67>14%), HER2+ (HER2+, any ER/PgR) and Triple-Negative ( ER-, PgR- and HER2-). Time on CT was calculated from the start of the 1st L to the end of the last L. Statistical analyses included Chi-square and Kruskal-Wallis tests, Kaplan-Meier curves and log-rank tests, and multivariate logistic regressions. Results: 207 P were identified, 52 were excluded because HER2 was unknown (19) or they did not receive any CT (33). Median follow-up was 31.4 months (m). The median number (N) of CT L was 2 (range 1-10). N of CT L and clinical benefit (CB) for every BS were reported in table. CB was inferior in TN P as compared with the other ones in 1st and in 2nd L ( p=.068 and p=.084 respectively in 1st and 2nd L). From 3rd L onward all P showed the same CB independently from BS. Time on CT related to median survival (S) for every BS was the same. At multivariate analysis the characteristics independently associated with a greater probability of receiving more than 4 CT L were age < 50 years (p=.021), HER2+ or TN disease (p=.027) and site of metastasis other than lung (p=.047). Conclusions: Our analysis showed that, despite the same time spent on CT, TN P received less benefit from 1st and 2nd L CT than other BS. On the other hand, young HER2+ P were more likely to receive multiple L of CT with a significant impact on median S (p=.044). [Table: see text]
RAD001-carboplatin combination in triple-negative metastatic breast cancer (TNMBC): A phase II trial.
Authors: Singh Jasmeet Chadha , Stein Stacy , Volm Matthew , Smith Julia Anne , Adams Sylvia , Meyers Marlene , Speyer James L. , Novik Yelena , Schneider Robert , Formenti Sylvia , Muggia Franco , Jhaveri Komal L. , Goldberg Judith D. , Heese Scott , Li Xiaochun , Davis Samantha , Tiersten Amy 
Published: March 2020

1042 Background: Triple negative breast cancer cells often show genetic instability and inability to repair DNA damage rendering them sensitive to platinum agents. Rapamycin enhances platinum- induced apoptosis in breast cancer cell lines. We sought to explore the activity/toxicity of the of carboplatin with RAD001 in TNMBC. Methods: The primary objective of this study was to estimate clinical benefit rate/CBR (complete remission (CR) + partial remission (PR) + stable disease (SD) lasting >6 months) and the toxicity of this combination in women with TNMBC who have had 0-3 prior chemoregimens for MBC. 25 subjects were recruited. This design had > 80% power to test the null hypothesis that the CBR is ≤10% vs. alternative hypothesis that CBR is ≥ 30% (≥6 would need to achieve a clinical benefit). Prior Carboplatin was allowed. Women with treated brain metastasis were eligible. Originally, Carboplatin AUC 6 was administered q3 weeks with daily 5mg of RAD001 with a 3 patient run-in, then 10 mg daily. Due to excessive thrombocytopenia, the dose of Carboplatin was first amended to AUC 5 and then to AUC 4 with 5 mg of RAD001 (no escalation to 10 mg). Results: All 25 patients have been recruited. Median age is 58.There have been 1 CR, 6 PR’s, 2 SD's lasting >6 months and 6 PD’s. 3 patients were not evaluable. One SD achieved in a patient progressing on single agent Carboplatin. The estimated CBR is 36% (95% C.I.: 17%-55%). Median PFS is 3.3 months (95% C.I.: 2.4-7.7 months) from start of treatment. 7 patients (28%) had grade 3 or 4 thrombocytopenia and 3 (12%) had grade 3 neutropenia (no bleeding/ febrile neutropenia). Since amendment of Carboplatin to AUC 4 the regimen has been very well tolerated with only 11% grade 3 hemetoxicity. The grade 3 non-heme toxicities included nausea/ vomiting (n=1), mucositis (n=1) and dehydration (n=1). Grade 3 insomnia (n=1) and dyspnea (n=1) were thought to be unrelated to the treatment (no grade 3 fatigue/ interstitial lung disease). Conclusions: The study has achieved the primary end point of demonstrating clinical benefit in TNMBC. Dose limiting thrombocytopenia was an unexpected side effect requiring protocol amendment. Clinical trial information: NCT01127763.
A phase I study of neoadjuvant chemotherapy (NCT) with the gamma secretase (GS) inhibitor RO4929097 in combination with paclitaxel (P) and carboplatin (C) in women with triple-negative breast cancer (TNBC).
Authors: Mrozek Ewa , Wesolowski Robert , Lustberg Maryam B. , Layman Rachel M. , Ling Yonghua , Schaaf Larry J. , Phelps Mitch A. , Ivy S. Percy , Grever Michael R. , Shapiro Charles L. 
Published: March 2020

1043 Background: Notch receptors are overexpressed in TNBC. Notch activation involves the cleavage of Notch ligand/receptor complex by GS. RO4929097 (RO) is an oral inhibitor of GS. We are conducting a phase I NCT trial of intermittent RO in combination with P and C in TNBC to determine the dose limiting toxicity (DLT) and the maximum-tolerated dose (MTD) of RO. Because RO induces CYP3A4/5, plasma P and RO are quantified in real time to ensure P AUC exposure is not decreased. Methods: Women ≥ 18 years with clinical stage II/III TNBC received C AUC=6 on day 1 and weekly P 80 mg/m2 in combination with RO on days 1-3, 8-10 and 15-17 for six 21-day cycles. The starting dose of RO was 10 mg and escalated according to the 3+3 rule. DLT was defined as grade ≥3 (G3) non-hematologic toxicity (n-HT), grade 4 (G4) thrombocytopenia (TCP) or G4 neutropenia (NP) during cycle#1 (c1). Plasma specimens were analyzed for PK by a validated LC-MS/MS assay. Results: 13 pts were enrolled. Two pts enrolled at 10 mg RO with C AUC 6 developed G3,4 TCP during c1. The study was amended; the dose of C was decreased to AUC 5. No DLTs were observed with 10 mg RO and C AUC 5. Only 1 DLT ( G3 HTN) occured with 20 mg RO, but all 4 pts enrolled on this cohort required dose reductions of RO during subsequent cycles. The RO dose was de-escalated to 10 mg, additional 3 pts were treated with 10 mg RO. G≥3 HT included: G4 NP in 2 pts, G4 TCP in 1 pt, G3 NP in 6 pts, G3 anemia in 4 pts and G3 TCP in 5 pts. G≥3 n-HT included: G3 sensory neuropathy in 3 pts. G3 HTN, G3 fatigue and G3 depression occured in 1 pt each. There were no hospitalizations for treatment-related toxicities. PK studies indicate that P AUC ranged from 80% to 134% on week 3 compared to week 1. Ten pts completed 6 cycles of NCT, 3 are still receiving NCT. Five of 10 (50%) pts had complete pathologic response (pCR) in breast and axilla and 3 (30%) pts had minimal residual cancer in breast. Conclusions: The MTD of intermittent RO administered in combination with P and C is 10 mg. This MTD does not result in decreased P exposures. The pCR (50%) and minimal residual disease (30%) suggests this regimen is active in TNBC. Supported by the NCI/NIH Award Number U01CA076576. Clinical trial information: NCT01238133.
Next-generation sequencing (NGS) in patients with advanced metastatic breast cancer: Identification of molecular alterations and analysis of associations with treatment on phase I studies at MD Anderson Cancer Center.
Authors: Wheler Jennifer J. , Yelensky Roman , Moulder Stacy L. , Tsimberidou Apostolia Maria , Falchook Gerald Steven , Janku Filip , Atkins Johnique T. , Zinner Ralph , Karp Daniel D. , Hong David S. , Stephens Phil , Wolff Robert A. , Kurzrock Razelle 
Published: March 2020

1051 Background: Matching molecular alterations in patients with breast cancer to targeted therapy may increase response rates. Methods: We analyzed 22 sequential breast cancer patients with next generation sequencing (NGS) profiling of their tumors profiling (FoundationOne) treated on Phase I trials at the Clinical Center for Targeted Therapy at MD Anderson Cancer Center. Objectives included: (1) characterize molecular alterations including mutations, amplifications and deletions, (2) evaluate associations between molecular alterations and response to therapy. Results: Twenty-two breast cancer patients, all female with median age 56 years were included. Twenty-one of 22 of patients (95%) analyzed demonstrated at least one molecular alteration. Twenty-one of 22 patients were evaluable for response to therapy (1 patient had not yet reached restaging). Sixteen patients were treated on Phase I trials with targeted therapy that was either directly or indirectly associated with a molecular alteration. Seven of these 16 patients (44%) achieved stable disease (SD) ≥6 months/partial response (PR)/complete response (CR) including 3 patients with PR and 1 patient with CR. Examples of molecular alterations include: mutations in PIK3CA (8 patients), PIK3R1 (2 patients), PTEN (1 patient), cMET (1 patient), NF1 (one patient); amplifications in CCND1 (8 patients), FGFR1 (4 patients), MYC (3 patients), MCL1 (3 patients), IRS2 (2 patients) and CCNE1(1 patient). Conclusions: A majority of patients with advanced or metastatic breast cancer whose tumors underwent NGS profiling demonstrated molecular alterations. Of the 9 patients who had either SD≥6 months/PR/CR on Phase I treatment, 7 (78%) had molecular alterations, either directly or indirectly associated with therapy. Further investigation of larger cohorts of patients with NGS is ongoing.
In vitro and in vivo activity of regorafenib (REGO) in drug-resistant gastrointestinal stromal tumors (GIST).
Authors: Serrano-Garcia Cesar , Heinrich Michael C. , Zhu Meijun , Raut Chandrajit P. , Eilers Grant , Ravegnini Gloria , Demetri George D. , Bauer Sebastian , Fletcher Jonathan A. , George Suzanne 
Published: March 2020

10510 Background: KIT and PDGFRA mutations (mut) are the crucial transforming events in most GISTs, and tyrosine kinase inhibitors (TKIs) with activity against KIT and PDGFRA, such as imatinib (IM) (front-line therapy) and sunitinib (SU) (second-line therapy), are effective treatments in GIST patients (pts). Resistance to IM and SU is commonly associated with evolution of secondary kinase mut. REGO is a multi-targeted TKI that inhibits KIT, PDGFR, and other oncologic targets and has recently shown benefit in pts with metastatic GIST after progression on standard treatments. We evaluated the in vitro and in vivo activity of REGO compared with IM, SU, and sorafenib (SOR) (a multi-TKI structurally related to REGO). Methods: REGO, IM, SU, and SOR inhibition of viability and KIT phosphorylation was assessed in human GIST cell lines and in Ba/F3 cells transformed by KIT oncoproteins with IM-resistant ATP binding pocket or activation-loop mut. KIT/PDGFRA genotyping was performed in GISTs responding or progressing on REGO in the academic phase II clinical trial. Results: In GISTs with KIT exon 11 mutant oncoproteins, REGO potently inhibited viability, KIT phosphorylation, and downstream effector phosphorylation (AKT, MAPK, S6). IM-resistant activation loop mut were more potently inhibited by REGO than SU, whereas the gatekeeper IM-resistant mut T670I was inhibited by both REGO and SU, and the common ATP-binding pocket mutant V654A was more potently inhibited by SU than REGO. Two GIST metastases progressing in one pt after initial response to REGO contained KIT V654A mut. SOR and REGO demonstrated comparable in vitro overall activity. Representative GIST cell line viability IC50s are shown in the Table (values in bold indicate expected clinical relevance). Conclusions: In vitro studies confirm REGO is a potent inhibitor of KIT exon 11 mut in GIST and appears to have stronger activity than SU against the most common KIT activation-loop mut observed in GIST. Ongoing clinical correlative analyses from REGO-treated study patients will be presented. [Table: see text]
Can postoperative radiotherapy be omitted in localized standard-risk Ewing sarcoma? An observational study of the Euro-EWING Group.
Authors: Gaspar Nathalie , Brennan Bernadette , Jeys Lee , Dirksen Uta , Foulon Stephanie , Cassoni Anna , Seddon Beatrice M. , Claude Line , Marec-Berard Perrine , Streitbuerger Anne , Whelan Jeremy , Paulussen Michael , Grimer Robert , Le Deley Marie-Cécile , Jurgens Heribert 
Published: March 2020

10518 Background: Uncertainty exists on the most appropriate use of surgery, radiotherapy (RT) or both for treatment of primary Ewing sarcoma (ES). The objective of this study was to assess the impact of postoperative RT on local control in pts with localized ES and good (<10% residual cells) histologic response to chemotherapy (CT). Methods: We analyzed data of all pts included in the EE99-R1 trial (comparing 2 consolidation CT regimens) undergoing surgery after induction CT. Local recurrence (LR) cumulative incidence (CI) was estimated using a competing risk approach. As local therapy was not randomized but tailored to the individual patient and tumor characteristics, impact of RT was assessed in multivariable models, adjusted for possible confounders: country, age, tumor type, site and volume, quality of resection and histologic response. We also evaluated the heterogeneity of RT effect by patient and tumor characteristics (interaction). Results: Among the 599 pts included from 1999 to 2009, 142 (24%) had received postoperative RT. With median follow-up of 6.2 yrs, disease failure was reported in 156 pts, including a LR in 67 (with concomitant metastases in 28), leading to an 8-yr LR-CI = 12% (se 1.4%). Overall survival = 21% (se 5%) 3 yrs after LR (31% in isolated LR). Controlling for possible confounders, the risk of LR was halved in pts treated by surgery + RT (HR=0.43, 95%CI, 0.21-0.88, p=0.02) compared to surgery alone. Postoperative RT had a rather homogeneous positive effect in all studied subgroups. The benefit of RT was very significant in pts with a tumor volume of >200mL at diagnosis and 100% necrosis. Although not significant, we observed a trend for benefit associated with RT in terms of disease-free, event-free and overall survival. Conclusions: LR contributes significantly to disease failures in this standard risk group who experience few systemic failures. Outcome after LR is very poor. Postoperative RT appears to improve local control for all pts. Good histologic response and complete resection of residual mass may not be sufficient criteria to omit RT. Further study of RT in ES is required to assess the balance between benefit and risk (secondary malignancies, functional sequelae). Clinical trial information: NCT00020566.
TBCRC 019: An open label, randomized, phase II trial of nanoparticle albumin-bound paclitaxel (nab-PAC) with or without the anti-death receptor 5 (DR5) monoclonal antibody tigatuzumab (TIG) in patients with metastatic triple negative breast cancer (TNBC).
Authors: Vaklavas Christos , Abramson Vandana Gupta , Lin Nancy U. , Liu Minetta C. , Rugo Hope S. , Nanda Rita , Storniolo Anna Maria , Traina Tiffany A. , Li Yufeng , Patil Sujata , Hayes Daniel F. , Van Poznak Catherine H. , Nangia Julie R. , Irvin William Johnson , Krontiras Helen , De Los Santos Jennifer F. , Haluska Paul , Wolff Antonio C. , Forero-Torres Andres ,   on behalf of the Translational Breast Cancer Research Consortium (TBCRC)
Published: March 2020

1052 Background: TIG, an agonistic anti-DR5 monoclonal antibody, triggers apoptosis in DR5+ human tumor cells without the aid of crosslinking. TIG has shown strong in vitro and in vivo activity against basal-like breast cancer cells that is enhanced by chemotherapy like paclitaxel. Methods: Randomized 2:1 phase II trial of nab-PAC with/without TIG in TNBC patients. Patients stratified by prior exposure to chemotherapy in the metastatic setting. Patients received nab-PAC weekly x 3 and TIG every other week, every 28 days. Primary endpoint was overall response rate (ORR). Secondary objectives were safety, progression free survival (PFS), TIG immunogenicity, and PK. Biopsies and circulating tumor cells were collected. The trial was not powered to compare arms but allowed early stopping for futility and was sized to estimate ORR with 95% CI. Results: 64 patients enrolled, 60 treated; 39 in the combination arm and 21 in the nab-PAC arm. Of the 39 in the combination arm, there were 2 CR, 9 PR (1 near CR, 96% tumor reduction), 11 SD and 17 PD; ORR 28% (95% CI 14%-42%). Of the 21 in the single agent arm, there were no CR, 8 PR, 4 SD and 9 PD; ORR 38% (95% CI 17%-59%). Higher ORRs were seen in the chemotherapy naïve patients (58% vs. 15% combination and 42% vs. 35% single agent). 2 patients with CR, 1 near CR, and 1 PR in the combination arm are still on therapy (602+, 531+, 466+, 460+ days). PFS was similar in both groups (3.6 months); higher in chemotherapy naïve patients. Combination was well tolerated (most toxicities grade 1/2); the most common AEs were fatigue, alopecia, peripheral sensory neuropathy, anemia, neutropenia, nausea, thrombocytopenia, anorexia, diarrhea, and vomiting. No grade 4 or 5 toxicity. No apparent added toxicity with TIG was seen. Conclusions: Combination therapy with nab-PAC + TIG was well tolerated, without apparent improvement in ORR relative to nab-PAC alone; however, 4 subjects treated as first-line had prolonged clinical benefit with the combination, and correlative studies will investigate markers that might predict clinical outcome (Next-Gen genomic analysis). Clinical trial information: F101004001.
Association of perioperative radiation therapy with outcome in 204 patients with primary retroperitoneal sarcoma: A two-institution study.
Authors: Kelly Kaitlyn Jane , Yoon Sam S. , Kuk Deborah , Qin Li-Xuan , Dukleska Katerina , Chang Kevin , DeLaney Thomas F. , Brennan Murray F. , Singer Samuel 
Published: March 2020

10520 Background: Radiation therapy (RT) for retroperitoneal and pelvic sarcomas (RPS) is controversial. We examined the association of perioperative, advanced modality RT on outcomes in primary RPS. Methods: Prospectively maintained databases were reviewed to compare primary RPS patients (pts) treated at two institutions between 2003 and 2011. Clinicopathologic variables were analyzed with endpoints of local recurrence-free survival (LRFS) and disease-specific survival (DSS). Results: At one institution 172 pts were treated with surgery alone while at the other 32 pts were treated with surgery and perioperative proton beam or intensity-modulated RT ± intraoperative RT. The groups were similar in age, gender, tumor grade, tumor size, and margin status (p = NS). The RT group had a lower percentage of retroperitoneal versus pelvic tumors and leiomyo/liposarcoma versus other histologies (p < 0.05). Median follow-up was 38.7 months (36.9 for RT group, 38.8 for surgery alone). Five-year predicted LRFS was 91% (95% CI, 79-100%) in the RT group and 65% (57-74%) in the surgery only group (p = 0.06). RT was marginally significant in univariate analysis of LRFS. Upon adjusting for univariate predictors, RT was significantly associated with better LRFS (p = 0.046; Table). Five-year predicted DSS was 93% (95% CI, 82-100%) in the RT group and 84% (78-91%) in the surgery-only group (p = 0.25). The only independent predictor of DSS was age. Morbidity was higher in the RT group (41% vs 17%; p= 0.004). Conclusions: In this retrospective study, the addition of advanced modality RT to surgery for primary RPS was associated with a reduced risk of local recurrence, although this did not translate into a statistically significant improvement in DSS. This treatment strategy warrants further investigation in a randomized trial. [Table: see text]
Role of glutathione S-transferase and cytochrome P-450 polymorphisms in the clinical outcome of osteosarcoma patients.
Authors: Trujillo-Paolillo Alini , Salinas-Souza Carolina , Dias-Oliveira Indhira , Petrilli Antonio Sergio , Toledo Silvia R. C. 
Published: March 2020

10535 Background: Osteosarcoma (OS) is the most common malignant bone tumor in children and adolescents. Glutathione S-transferase (GST) and Cytochrome P-450 (CYP) family genes are involved in almost all anticancer drugs metabolism. The polymorphisms in these genes are associated with anticancer drugs resistance and toxicity events. This study aims to investigate the genotype frequencies of GSTM1, GSTT1, GSTM3, CYP1A2, CYP2C9 and CYP3A5 genes in OS patients and the influence of these polymorphisms in their clinical outcome. Methods: We investigated the peripheral blood DNA of 70 OS patients (25 metastatic and 45 nonmetastatic at diagnosis), following the GLATO - Latin American Group of Osteosarcoma Treatment - 2006. GSTM1 and GSTT1 deletion polymorphisms were examined through a multiplex-PCR and the GSTM3 polymorphism of three base pair-deletion using PCR-RFLP method. CYP1A2, CYP2C9 and CYP3A5 single nucleotide polymorphisms (SNPs) were investigated through real time PCR using TaqMan probe. Results: We found that GSTM1 null genotype was correlated with relapse occurrence (p=0,031) in patients that received high doses of chemotherapy. The CYP1A2*F allele was associated with lung metastasis (p=0,032), lung relapse (p=0,018) and high grade of ototoxicity (p=0,039). The CYP3A5*3 allele was associated with high grade of hepatotoxicity (p=0,010). The presence of at least one GSTM3*B allele was associated with better overall survival (p=0,045). The presence of CYP3A5*3 homozygous genotype was associated with better overall survival (p=0,043) in metastatic patients at diagnosis. The genotype GSTM3*B/ GSTM1 present, GSTM3*B/ GSTT1 present and GSTM3*B/CYP3A5*3 in metastatic patients at diagnosis were associated with better survival (p=0,048; p=0,004; p=0,012, respectively). Conclusions: The findings of this study suggest that GST and CYP polymorphisms may have a role in treatment response and may be an important marker in the future to personalized therapy in OS. Furthermore, CYP1A2*F allele is correlated with risk of lung metastasis and GSTM3*B homozygous genotype in combination with GSTM1 present, GSTT1 present and CYP3A5*3 were associated with better survival.