bluuebunny/crossref_metadata_2025_split huggingface dataset:
Kinome reprogramming response to MEK inhibition: A window-of-opportunity trial in triple-negative breast cancer (TNBC).
Authors: Johnson Gary L. , Amos Keith D. , Duncan James S , Whittle Marty , Zawistowki Jon , Goulet Dan , He Xiaping , Noe Jeanne , Perou Charles M. , Earp Shelton , Carey Lisa A. 
Published: March 2020

512 Background: Targeted therapy (Rx) in TNBC is challenging due to heterogeneity and cancer cell kinome “reprogramming” in response to targeted kinase inhibitors (Cell 149:307, 2012). In preclinical TNBC models specific kinases (e.g., DDR1/2, PDGFRbeta, VEGFR2, AXL) are activated in response to MEK inhibition. Our studies define unique kinome reprogramming in basal-like (BBC) versus claudin-low (CL). This study compared kinome profiles of TNBC pre- and post- MEK1/2 inhibition with GSK1120212 (trametinib, T) using multiplexed inhibitor beads coupled with mass spectrometry (MIB/MS). Methods: Eligible patients (pts) with untreated TNBC received T (initial dose 1.5mg/d raised after interim analysis of kinome effects to 2mg/d) for 7 days preceding breast surgery. Fresh tumor tissue was obtained before and after T. Kinase activation state was analyzed as post:pre(-)treatment ratio; molecular subtype was by gene expression analysis. Results: Kinome response profiling was completed in 7 of 9 pts by abstract submission. Toxicities included grade 2 (2pts) or grade 1 (1pt) rash, grade 1 diarrhea (1pt), and grade 1 nausea (1pt). Two of the 9 pts profiled did not have sufficient pre-treatment tumor for kinome analysis. Molecular subtypes included 6 BBC patients (one of which was CL after T), 2 CL patients (one of which was BBC after T), and 1 normal-like patient (which was BBC after T). MEK1/2 inhibition and kinase reprogramming was seen in 6 of the 7 tumors where both pre- and post T samples could be analyzed. The results show kinome reprogramming in response to MEK1/2 inhibition occurs in human tumors similar to preclinical modeling in TNBC cell lines and credentialed engineered mouse models; the kinase reprogramming pattern differed between BBC and CL. Conclusions: MEK1/2 inhibition upregulates and activates specific receptor tyrosine kinases in BBC that are different from CL.A subset of BBC and CL may have plasticity, changing their molecular subtype and kinome profile, and responding heterogeneously to MEK1/2 inhibition. Analysis of kinome reprogramming identifies upregulation of druggable targets for individual patients that suggest rational combinations with MEK inhibition in TNBC. Clinical trial information: NCT01467310.
Clinical evidence for drug penetration of capecitabine and lapatinib uptake in resected brain metastases from women with metastatic breast cancer.
Authors: Morikawa Aki , Peereboom David M. , Smith Quentin R , Thorsheim Helen , Lockman Paul R , Simmons Ahkeem James , Weil Robert J. , Tabar Viviane , Steeg Patricia Schriver , Seidman Andrew David 
Published: March 2020

514 Background: Brain metastasis (BM) is a challenging complication of metastatic breast cancer (MBC). Although systemic therapy is not commonly considered as a primary therapeutic approach, its potential in BM management has recently become apparent (Bachelot T et al Lancet Oncol 2013). Capecitabine and lapatinib in particular have been evaluated in HER2+ breast cancer BM (BCBM), but evidence for drug/metabolite CNS penetration is solely derived from preclinical animal models. In this study, we examined capecitabine, its metabolites, and lapatinib uptake in BCBMs resected due to medically indicated craniotomy. Methods: Study patients had BCBM requiring surgical resection. Patients with HER2-negative MBC received a single preoperative oral dose of capecitabine (1250mg/m2) 2-3 hrs before surgery. Those with HER2+ MBC received 2-3 oral doses of lapatinib (1250mg) daily, the last dose 2-3 hrs before surgery. On the day of surgery, serum was collected serially starting just before drug administration, intraoperatively, and through one hour after the conclusion of surgery. The concentration of capecitabine, its metabolites, and lapatinib from serum and BM were measured using liquid chromatography with tandem mass spectroscopy (LC-MS/MS). Results: 10 patients enrolled; PK data is available for 9: 6 for capecitabine and 3 for lapatinib. Capecitabine, its intermediate metabolites, 5FU, and lapatinib were detected in all BMs. Tumor capecitabine and 5-FU concentrations ranged from 3% to 129% and from 168% to 1422%, respectively, of serum concentrations. For lapatinib, the range was 21% to 700%. In a number of the BMs, drug concentrations were in the therapeutic range, whereas in others the concentrations were up to 10 fold lower. Conclusions: This is the first study to show capecitabine and lapatinib were detected in clinically relevant concentrations in a number of non-irradiated human BCBMs. This provides evidence for their ability to cross the blood-brain barrier, is consistent with prior published clinical activity, and supports further evaluation in a clinical setting prior to whole brain radiotherapy. Clinical trial information: NCT00795678.
Phase III trial of non-pegylated liposomal doxorubicin (M) in combination with trastuzumab (T) and paclitaxel (P) in HER2+ metastatic breast cancer (MBC).
Authors: De La Pena Lorena , Cortes Javier , Manikhas Alexey , Roman Laslo , Semiglazov Vladimir , Biakhov Mikhail Yu , Dasappa Lokanatha , Llombart Antonio , Rozencweig Marcel , Forenza Salvatore , Goldfarb Ronald H. , Matera Jeri , Azarnia Nozar , Hudis Clifford , Baselga Jose 
Published: March 2020

517 Background: M in combination with T has shown promising activity and cardiac safety in MBC patients (pts). We conducted a randomized Phase III trial of first-line M plus T and P (MTP) versus T plus P (TP) in HER2+ MBC pts. Methods: Pts with HER2+ (by FISH) MBC ≥ 18 years and ECOG 0-1, who had received no prior chemotherapy for metastatic disease, were eligible. Left ventricular ejection fraction should be within normal institutional limits. Prior (neo-) adjuvant anthracyclines, T or P were permitted, if completed >1 year before the start of the study. Pts received M 50 mg/m2 q3w for 6 cycles, T 4 mg/kg loading dose followed by 2 mg/kg qw, and P 80 mg/m2qw, or T+P at the same doses until progression or toxicity. Primary outcome was progression-free survival (PFS). Enrollment of 332 pts would provide 80% power with a 5% significance to detect an improvement in PFS with MTP, assuming a median PFS of 8 months in TP and a hazard ratio (HR) of 0.70. Results: 363 pts enrolled (MTP 181, TP 183), 360 received treatment. The two groups were well balanced for demographics, pretreatment characteristics and extent of disease. One third of the pts had prior exposure to anthracyclines, but almost none to trastuzumab (1% and 2% in MTP and TP arms, respectively). Six cycles of M could be given to 72% of the pts. With a median follow-up of 31 months, median PFS was 16.1 and 14.5 months with MTP and TP, respectively (HR 0.84, P=0.174). In pts with ER and PR-negative tumors, PFS was 20.7 and 14.0 months, respectively (HR, 0.68; 95% CI 0.47–0.99). Median overall survival (OS) was 33.6 and 28.9 months, respectively (HR, 0.79, P=0.083). In ER and PR-negative tumors, OS was 38.2 and 27.9 months, respectively (HR, 0.63; 95% CI 0.42–0.93). The incidence of NYHA Class III/IV congestive heart failure was 3% with MTP and there were 2 cardiac deaths with TP. The frequency of adverse events was higher with MTP, especially myelosuppression, stomatitis and gastrointestinal intolerance. Conclusions: The trial failed to demonstrate a significant clinical improvement with the addition of M to TP. The clinical benefit observed in an exploratory analysis in the ER and PR-negative population deserves consideration for further clinical trials. Clinical trial information: NCT00294996.
TBCRC 002: A phase II, randomized, open label trial of preoperative letrozole versus letrozole (LET) in combination with bevacizumab (BEV) in post-menopausal women with newly diagnosed stage II/III breast cancer.
Authors: Forero-Torres Andres , Rugo Hope S. , Vaklavas Christos , Lin Nancy U. , Carey Lisa A. , Liu Minetta C. , Nanda Rita , Puhalla Shannon , Storniolo Anna Maria , Krontiras Helen , Saleh Mansoor N. , Li Yufeng , LoBuglio Albert F. , De Los Santos Jennifer F. ,   on behalf of the Translational Breast Cancer Research Consortium (TBCRC)
Published: March 2020

527 Background: A study from UAB Breast SPORE showed that expression of vascular endothelial growth factor (VEGF) in MCF7 breast tumor xenografts imparts tamoxifen resistance, increases tumor growth and metastatic potential. We postulated that anti-VEGF therapy would enhance anti-estrogen therapy. Methods: Randomized 2:1 phase II selection trial of LET (2.5 mg/day) with/without BEV (anti-VEGF monoclonal antibody; 15 mg/kg q3 weeks) for 24 weeks prior to surgery in post-menopausal patients with stage II/III, ER+/HER2- breast cancer. Primary objective was pathologic complete remission (pCR). Secondary objectives included response rates, down-staging, and toxicity. The trial was not powered to compare arms, but sized to estimate pCR rates to a certain precision (SE<5% for combination, SE<2% for single agent). Biopsies of the tumor and circulating tumor cells were collected. Results: 75 patients were randomized; 50 in the combination and 25 in the LET alone arm; 45 and 24 patients underwent surgery, respectively. Median age was 61 and 65 years, respectively. 5 patients in the combination arm had a pCR (11%; CI 1.9-20.1%) (no evidence of invasive cancer) , and 3 a near pCR (7%; 0%-14.5%) (microscopic disease only); thus pCR/near pCR rate 18% (6.8-29.2%). No patient treated with LET alone achieved a pCR/near pCR. The objective response rate was 64.5% in the combination arm and 37.5% in the single agent arm. 45% of the patients in the combination arm attained stage 0/I; 25% in the letrozole alone arm attained stage I, none attained stage 0. Therapy was well tolerated in both arms with no grade 4/5 toxicity. The most common AEs in the letrozole arm were hot flashes, fatigue, arthralgias/stiffness, myalgias, nausea/vomiting, and night sweats; in the combination arm they were hypertension, arthralgias/stiffness, hot flashes, headache, fatigue, proteinuria, dyspnea, rash, and myalgias. Conclusions: Neoadjuvant therapy with LET and BEV was well-tolerated and resulted in increased objective responses and down-staging. “Next-Gen” genomic analysis of the biopsies will allow for a trial with a targeted patient enrolment. Clinical trial information: F061229006.
Extended adjuvant tamoxifen for early breast cancer: A meta-analysis.
Authors: Amir Eitan , Al-Mubarak Mustafa , Tibau Ariadna , Templeton Arnoud J. , Ocana Alberto , Seruga Bostjan 
Published: March 2020

539 Background: Hormone receptor positive breast cancer is characterized by the potential for disease recurrence many years after initial diagnosis. Endocrine therapy has been shown to reduce the risk of such recurrence, but the optimal duration of endocrine therapy remains unclear. Methods: We conducted a systematic review and meta-analysis to quantify the relative and absolute benefits and harms of extended adjuvant tamoxifen (>5 years of therapy) compared with adjuvant tamoxifen (≤5 years of therapy). Odds ratios (ORs), 95% confidence intervals (CIs), absolute risks, and the number needed to treat (NNT) were computed for pre-specified events including disease recurrence, distant recurrence, all-cause death, endometrial carcinoma, cardiovascular death and treatment discontinuation. Subgroup analyses by timing of recurrence and baseline lymph node and menopause status were carried out. Results: Six trials comprising 25,326 patients were included. Extended adjuvant tamoxifen was associated with a non-significant reduction in the risk of recurrence (OR 0.89, 95% CI 0.77-1.04, p=0.14, NNT 74). Similar results were seen for distant recurrence (OR 0.88, 95% CI 0.75-1.04, p=0.14, NNT 70). There was no association between extended adjuvant tamoxifen and all-cause death (OR 1.06, 95% CI 0.86-1.31, p=0.58). There was no reduction in risk during extended adjuvant therapy (i.e. between years 5 and 9), but a potential reduction in the risk of recurrence after completion of extended adjuvant tamoxifen (i.e. beyond 10 years after diagnosis). Subgroup analysis suggested benefit in lymph node positive patients. Endometrial carcinoma was substantially more frequent with extended adjuvant tamoxifen (OR 1.81, 95% CI 1.45-2.25, p<0.001, NNT 102), but among those with endometrial carcinoma, the odds of death were lower among the extended tamoxifen group (OR 0.50, 95% CI 0.28-0.90, p=0.02). Conclusions: Extended adjuvant tamoxifen is not associated with a significant reduction in recurrence or death in unselected patients. Patients with lymph node positive breast cancer may derive more benefit. Reduction in the risk of recurrence only appears after completion of extended adjuvant therapy.
Predictors of patient-reported toxicities from endocrine therapy: Importance of illness perceptions, treatment beliefs, and fear of recurrence.
Authors: Song Xinni , Dent Susan Faye , Verma Shailendra , Clemons Mark J. , Graham Nadine A. , Bedard Marc , Paquet Lise 
Published: March 2020

542 Background: Numerous studies have documented the toxicities of endocrine therapy (ET) for early breast cancer (EBC) and their deleterious impact on quality of life and adherence. However, little is known about the factors that underlie patient's susceptibility to report toxicities. The identification of risk factors for toxicities from ET is important as it would allow early targeting of symptom management interventions for women more vulnerable to adverse effects of ET. This prospective study aims to examine the impact of pre-treatment perceptions of EBC, ET beliefs and fear of breast cancer (BC) recurrence (FBCR) on toxicities reported after 6 months of ET. Methods: Women diagnosed with EBC completed a survey prior to initiating endocrine therapy, then at 3, 6 and 12 months. Standardized self-report instruments were used to assess EBC perceptions, ET beliefs, FBCR and toxicities. Clinical and treatment variables were also evaluated. Univariate analyses and mulitivariate regression were conducted to identify factors associated (p<0.1) with side effects at 6 months. Results: Since 9/2010, 173 patients have consented and 84 (mean age = 60 y) have completed the questionnaires at baseline and after 6 months of ET. Controlling for age, none of the clinical or treatment variables (stage of disease, type of surgery, receipt of chemotherapy and radiation therapy) were significant univariate predictors of toxicities. In multiple regression, stronger perceptions that BC has serious consequences on their lives (β=0.218, p<0.05), greater concerns about the adverse effects of ET (β=0.215, p<0.05) and higher levels of FBCR (β=0.316, p<0.01) at baseline were associated with higher levels of reported toxicities. Conclusions: Baseline psychological factors predicted level of patient-reported toxicities to a larger extent than clinical/treatment factors. How patients perceived their illness, their beliefs about ET side effects and their fear of cancer recurrence are strongly associated with side effects experienced after 6 months of ET. These results could facilitate the identification of a subgroup of patients for early interventions to improve symptom management.
Luminal A and Luminal B subtypes in patients with breast cancer 65 years of age and older.
Authors: Konigsberg Robert , Pfeiler Georg , Hammerschmid Nicole , Klement Tatjana , Dittrich Christian 
Published: March 2020

549 Background: In 2011, the St. Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer (bc) suggested the distinction between Luminal A and Luminal B subtypes. In Luminal A patients (pts) endocrine therapy seems to be sufficiently effective, whereas in Luminal B pts the additional application of chemotherapy should be considered. It is currently unknown, whether the risk stratification into Luminal A and B is comparably or more discriminatory than the established pathologic tumor size (pT) and lymph node (pN) status in pts ≥ 65 years. This analysis evaluates the discriminatory capacity of the new distinction between Luminal A and B and the established prognostic factors in bc pts ≥ 65 years treated with endocrine therapy only. Methods: Clinico-pathological data of 190 bc pts ≥ 65 years diagnosed between 1998 and 2004 were retrospectively analyzed. Pts were classified as Luminal A [ER (+) and/ or PR (+) and Her/2neu (-) and Ki-67 < 14%] or Luminal B [ER (+) and/ or PR (+) and Her2 (-) and Ki-67 ≥ 14%]. The Kaplan-Meier method was used to assess the progression-free survival (PFS) and overall survival (OS) estimates. Differences in survival between groups were tested for significance by the log-rank test. Results: Median age was 74 years (65–92 years) and median time of follow-up was 69 months (0–134 months). 68.9% and 31.1% pts had Luminal A and B subtypes, respectively. 73.3% and 26.7% of pts had pT1 and pT2 tumors, respectively. 79.7% and 20.3% of pts had pN0 and pN1 status, respectively. Overall, median PFS was 33 months. No significant difference regarding PFS could be detected between Luminal A and B pts, between pT1 and pT2 tumors and between pN0 and pN1 status (p=0.458; 0.172; 0.156), respectively. Overall, median OS was not reached. No significant difference regarding OS could be detected between Luminal A and B pts, between pT1 and pT2 tumors and between pN0 and pN1 status (p=0.328; 0.951; 0.976), respectively. Conclusions: In bc pts ≥ 65 years treated with endocrine therapy only, neither the recently consented dichotomization into Luminal A and B subtypes nor pathologic tumor size and lymph node status could be confirmed to be discriminative as propagated in the 2011 St. Gallen Consensus for the overall bc population.
Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer (SOC) and a BRCA mutation (BRCAm).
Authors: Ledermann Jonathan A. , Harter Philipp , Gourley Charlie , Friedlander Michael , Vergote Ignace , Rustin Gordon J. S. , Scott Clare L. , Meier Werner , Shapira-Frommer Ronnie , Safra Tamar , Matei Daniela , Fielding Anitra , Macpherson Euan , Dougherty Brian , Jürgensmeier Juliane M. , Orr Maria , Matulonis Ursula 
Published: March 2020

5505 Background: Previously, we reported that maintenance treatment with the oral PARP inhibitor olaparib (400 mg bid) led to a significant PFS improvement vs placebo in patients (pts) with platinum-sensitive relapsed SOC (Ledermann et al NEJM2012). A preplanned subgroup analysis from this randomized, double-blind Phase II trial (NCT00753545) suggested that olaparib may lead to a greater PFS, and an OS, benefit in pts with a known germline BRCAm (gBRCAm). Since gBRCA wild-type (gBRCAwt) pts may develop somatic tumor (t)BRCAm, efficacy analyses were performed for all pts with BRCAm. Methods: gBRCAm status was determined retrospectively for all consenting pts (n = 166) using blood samples taken before randomization. tBRCAm status was determined from archival tumor samples of 196 pts. We analyzed PFS/OS by gBRCAm and total BRCAm status. Preliminary data are reported. Results: gBRCA status was known for 218/265 pts (gBRCAm, 96; gBRCAwt, 122). Including tBRCAm, 136 pts had a BRCAm (BRCAwt, 116). gBRCAm pts had the greatest PFS benefit with olaparib maintenance vs placebo (median: 11.2 vs 4.1 months [m]; HR, 0.17; 95% CI 0.09-0.32; P<0.001) and a significant QoL improvement, as measured with Trial Outcome Index (OR, 4.08; 95% CI 1.11-19.85; p = 0.03). The PFS benefit was consistent when tBRCAm pts were included (median: 11.2 vs 4.3 m; HR, 0.19; 95% CI 0.11-0.32; p <0.0001). In an interim analysis of OS (58% maturity), a comparison of olaparib vs placebo in the overall population led to a HR of 0.88 (95% CI 0.64-1.21) with medians of 29.8 vs 27.8 m, respectively. Although HRs from the gBRCAm and gBRCAwt subgroups were similar (0.85 and 0.84, respectively), 13/37 gBRCAm placebo pts received a subsequent PARP inhibitor, confounding the OS data in this subgroup. The analysis of all BRCAm pts was less confounded and resulted in an OS HR of 0.74 (95% CI 0.46-1.19; median: 34.9 vs 31.9 m). 19 pts have received olaparib for >3 years. Olaparib tolerability was similar in BRCAm pts and the overall population. Conclusions: Olaparib maintenance treatment led to the greatest clinical benefit in pts with a BRCAm. These compelling data warrant confirmation in phase III trials. Clinical trial information: NCT00753545.
A multicenter open-label phase II study of the efficacy and safety of ganitumab (AMG 479), a fully human monoclonal antibody against insulin-like growth factor type 1 receptor (IGF-1R) as second-line therapy in patients with recurrent platinum-sensitive ovarian cancer.
Authors: Ray-Coquard Isabelle , Haluska Paul , O'Reilly Seamus , Cottu Paul H. , Elit Lorraine , Provencher Diane M. , Beckmann Matthias W. , Bosserman Linda D. , Jacod Sylvie , Houe Vincent , Loberg Robert D. , Glaspy John A. , Karlan Beth , Slamon Dennis J. , Konecny Gottfried E. 
Published: March 2020

5515 Background: IGF signaling has been implicated in the pathogenesis and progression of ovarian cancer (OC). Single agent activity and safety of ganitumab (AMG 479), a fully human monoclonal antibody against IGF-1R that blocks binding of IGF1 and IGF2, were evaluated in asymptomatic patients with platinum-sensitive recurrent OC. Differential expression of IGF-1R pathway genes in OC underscores the potential of developing predictive biomarkers for patient selection. Methods: Pts with CA125 progression (GCIG criteria) and/or measurable disease per RECIST failing primary platinum-based therapy received 18 mg/kg of ganitumab q3w. Objective response rate per RECIST or CA125 criteria was the primary end point (complete response, CR; partial response, PR). Secondary end points included, progression-free survival (PFS) and safety. Tumor tissue was collected for gene expression profiling (Nanostring) and sequencing. Results: From 02/2009 to 05/2010, 61 pts were accrued from 20 centers. Pt characteristics were: Serous (77%), median platinum-free interval (11 months), measurable disease (74%), and ECOG performance status 0 (67%). According to CA125 criteria median PFS was 6.8 months (95%CI, 2.8-10.8); 2 CR (3.4%) 2 PR (3.4%), and 38 stable disease (SD, 64%) were observed. When using RECIST criteria, median PFS was 2.1 months (95%CI, 2.0-2.8), 2 PR (3.4%) and 22 SD (38%) were observed. Toxicity has been mild; grade 2 hyperglycemia was seen in 5 pts (8.2%). Grade 3 related events included hearing loss (1), nausea (1), asthenia (2), fatigue (1), and hypersensitivity (5). There were no grade 4 or 5 treatment-related events. Efficacy is being correlated with gene expression profiles and mutational data. Conclusions: IGF-1R inhibition with ganitumab was well tolerated and demonstrated modest single-agent activity in unselected patients with platinum-sensitive recurrent OC. However, encouraging activity was seen in a subset of patients. Ongoing predictive biomarker analyses may facilitate patient selection. Clinical trial information: NCT00719212.