Author
Saeed Sadeghi
Bio: Saeed Sadeghi is an academic researcher from University of California, Los Angeles. The author has contributed to research in topics: Breast cancer & Circulating tumor cell. The author has an hindex of 16, co-authored 31 publications receiving 2510 citations.
Topics: Breast cancer, Circulating tumor cell, Gemcitabine, Medicine, Lapatinib
Papers
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TL;DR: In this paper, the authors evaluated the effect of adding lapatinib, a dual tyrosine kinase inhibitor blocking epidermal growth factor receptor and HER2, to the aromatase inhibitor letrozole as first-line treatment of hormone receptor-positive metastatic breast cancer.
Abstract: Purpose Cross-talk between human epidermal growth factor receptors and hormone receptor pathways may cause endocrine resistance in breast cancer. This trial evaluated the effect of adding lapatinib, a dual tyrosine kinase inhibitor blocking epidermal growth factor receptor and human epidermal growth factor receptor 2 (HER2), to the aromatase inhibitor letrozole as first-line treatment of hormone receptor (HR) –positive metastatic breast cancer (MBC). Patients and Methods Postmenopausal women with HR-positive MBC were randomly assigned to daily letrozole (2.5 mg orally) plus lapatinib (1,500 mg orally) or letrozole and placebo. The primary end point was progression-free survival (PFS) in the HER2-positive population. Results In HR-positive, HER2-positive patients (n 219), addition of lapatinib to letrozole significantly reduced the risk of disease progression versus letrozole-placebo (hazard ratio [HR] 0.71; 95% CI, 0.53 to 0.96; P .019); median PFS was 8.2 v 3.0 months, respectively. Clinical benefit (responsive or stable disease 6 months) was significantly greater for lapatinib-letrozole versus letrozole-placebo (48% v 29%, respectively; odds ratio [OR] 0.4; 95% CI, 0.2 to 0.8; P .003). Patients with centrally confirmed HR-positive, HER2-negative tumors (n 952) had no improvement in PFS. A preplanned Cox regression analysis identified prior antiestrogen therapy as a significant factor in the HER2-negative population; a nonsignificant trend toward prolonged PFS for lapatinib-letrozole was seen in patients who experienced relapse less than 6 months since prior tamoxifen discontinuation (HR 0.78; 95% CI, 0.57 to 1.07; P .117). Grade 3 or 4 adverse events were more common in the lapatinib-letrozole arm versus letrozole-placebo arm (diarrhea, 10% v 1%; rash, 1% v 0%, respectively), but they were manageable.
903 citations
01 Nov 2009
TL;DR: It is demonstrated that a combined targeted strategy with letrozole and lapatinib significantly enhances PFS and clinical benefit rates in patients with MBC that coexpresses HR and HER2.
869 citations
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University of Texas Health Science Center at Houston1, Memorial Sloan Kettering Cancer Center2, Heidelberg University3, Mayo Clinic4, Harvard University5, University of California, Los Angeles6, Autonomous University of Barcelona7, University of Southern California8, University of California, San Francisco9, Université catholique de Louvain10, Seoul National University11, Wayne State University12, National Cheng Kung University13, Mahidol University14, Katholieke Universiteit Leuven15, National Taiwan University16, Ohio State University17, Novartis18
TL;DR: BGJ398 is a first-in-class FGFR kinase inhibitor with manageable toxicities that shows meaningful clinical activity against chemotherapy-refractory cholangiocarcinoma containing FGFR2 fusions.
Abstract: PurposeNo standard treatment exists for patients with cholangiocarcinoma for whom first-line gemcitabine-based therapy fails. Fibroblast growth factor receptor 2 (FGFR2) fusions/translocations are present in 13% to 17% of intrahepatic cholangiocarcinomas. BGJ398, an orally bioavailable, selective pan-FGFR kinase inhibitor, has shown preliminary clinical activity against tumors with FGFR alterations.MethodsA multicenter, open-label, phase II study (ClinicalTrials.gov identifier: NCT02150967) evaluated BGJ398 antitumor activity in patients age ≥ 18 years with advanced or metastatic cholangiocarcinoma containing FGFR2 fusions or other FGFR alterations whose disease had progressed while receiving prior therapy. Patients received BGJ398 125 mg once daily for 21 days, then 7 days off (28-day cycles). The primary end point was investigator-assessed overall response rate.ResultsSixty-one patients (35 women; median age, 57 years) with FGFR2 fusion (n = 48), mutation (n = 8), or amplification (n = 3) participated. ...
473 citations
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TL;DR: The sequential and combination regimens incorporating three drugs were equally effective but differed in toxicity profile.
Abstract: Purpose Anthracyclines, taxanes, and alkylating agents are among the most active agents in treatment of adjuvant breast cancer (BC), but the optimal schedule for their administration is unknown. We performed an adjuvant trial to compare the sequential regimen of doxorubicin with cyclophosphamide (AC) followed by docetaxel (ie, AC>T) with the combination regimen of TAC. Patients and Methods Women with node-positive, human epidermal growth factor receptor 2–nonamplified, operable BC were stratified by number of axillary nodes and hormone receptor status and were randomly assigned to adjuvant chemotherapy with six cycles of TAC (75/50/500 mg/m2 every 3 weeks) or four cycles of AC (60/600 mg/m2 every 3 weeks) followed by four doses of docetaxel at 100 mg/m2 every 3 weeks (AC>T). After completion of chemotherapy, radiation therapy was given as indicated, and patients with hormone receptor (HR) –positive disease received adjuvant hormonal therapy with tamoxifen and/or aromatase inhibitors. Results In 30 months,...
133 citations
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University of Texas MD Anderson Cancer Center1, Ohio State University2, University of California, San Francisco3, University of California, Los Angeles4, University Hospital Heidelberg5, University of Cologne6, Harvard University7, University of Southern California8, Mayo Clinic9, National University of Singapore10, University of Tübingen11, Chulalongkorn University12, Memorial Sloan Kettering Cancer Center13
TL;DR: In this article, Infigratinib is a selective, ATP-competitive inhibitor of fibroblast growth factor receptors (FGFR2) in patients with locally advanced or metastatic cholangiocarcinoma.
130 citations
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2,314 citations
01 Jan 2014
TL;DR: Lymphedema is a common complication after treatment for breast cancer and factors associated with increased risk of lymphedEMA include extent of axillary surgery, axillary radiation, infection, and patient obesity.
1,988 citations
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TL;DR: It is reported that PTEN activation contributes to trastuzumab's antitumor activity and PTEN deficiency is a powerful predictor for trastzumab resistance, suggesting that PI3K-targeting therapies could overcome this resistance.
Abstract: 2458 Despite dramatic improvements in treatment over the past 40 years, acute lymphoblastic leukemia (ALL) remains one of the most common causes of death from disease in childhood. Glucocorticoids are among the most effective agents used in the treatment of lymphoid malignancies, and patient response to treatment is an important determinant of long-term outcome in childhood ALL. In spite of its clinical significance, the molecular basis of glucocorticoid resistance is still poorly understood. The aim of this study was to develop an experimental model system to define clinically relevant mechanisms of glucocorticoid resistance in childhood ALL. An in vivo model of childhood ALL has been developed in our laboratory, using patient biopsies established as xenografts in immune-deficient nonobese diabetic severe-combined immunodeficient (NOD/SCID) mice. This model is highly representative of the human disease (Lock et al., Blood, 99: 4100-4108, 2002). The in vivo responses of these xenografts to the glucocorticoid dexamethasone (DEX) correlated significantly with patient outcome (p 1 μM) in xenografts from six patients, five of whom died of their disease. In contrast, four DEX-sensitive xenografts (IC50 values 2-fold in sensitive xenografts within 8 hours of treatment. In contrast, Bim induction was dramatically attenuated in DEX-resistant xenografts. These results have identified a clinically significant and novel mechanism of glucocorticoid resistance in childhood ALL, which occurs downstream of receptor-ligand interactions, but upstream of the signalling pathway resulting in Bim induction and apoptosis.
1,574 citations
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TL;DR: Palbociclib (PD-0332991) is an oral, small-molecule inhibitor of cyclin-dependent kinases (CDKs) 4 and 6 with preclinical evidence of growth-inhibitory activity in oestrogen receptor-positive breast cancer cells and synergy with anti-oestrogens as mentioned in this paper.
Abstract: Summary Background Palbociclib (PD-0332991) is an oral, small-molecule inhibitor of cyclin-dependent kinases (CDKs) 4 and 6 with preclinical evidence of growth-inhibitory activity in oestrogen receptor-positive breast cancer cells and synergy with anti-oestrogens. We aimed to assess the safety and efficacy of palbociclib in combination with letrozole as first-line treatment of patients with advanced, oestrogen receptor-positive, HER2-negative breast cancer. Methods In this open-label, randomised phase 2 study, postmenopausal women with advanced oestrogen receptor-positive and HER2-negative breast cancer who had not received any systemic treatment for their advanced disease were eligible to participate. Patients were enrolled in two separate cohorts that accrued sequentially: in cohort 1, patients were enrolled on the basis of their oestrogen receptor-positive and HER2-negative biomarker status alone, whereas in cohort 2 they were also required to have cancers with amplification of cyclin D1 ( CCND1 ), loss of p16 (INK4A or CDKN2A), or both. In both cohorts, patients were randomly assigned 1:1 via an interactive web-based randomisation system, stratified by disease site and disease-free interval, to receive continuous oral letrozole 2·5 mg daily or continuous oral letrozole 2·5 mg daily plus oral palbociclib 125 mg, given once daily for 3 weeks followed by 1 week off over 28-day cycles. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population. Accrual to cohort 2 was stopped after an unplanned interim analysis of cohort 1 and the statistical analysis plan for the primary endpoint was amended to a combined analysis of cohorts 1 and 2 (instead of cohort 2 alone). The study is ongoing but closed to accrual; these are the results of the final analysis of progression-free survival. The study is registered with the ClinicalTrials.gov, number NCT00721409. Findings Between Dec 22, 2009, and May 12, 2012, we randomly assigned 165 patients, 84 to palbociclib plus letrozole and 81 to letrozole alone. At the time of the final analysis for progression-free survival (median follow-up 29·6 months [95% CI 27·9–36·0] for the palbociclib plus letrozole group and 27·9 months [25·5–31·1] for the letrozole group), 41 progression-free survival events had occurred in the palbociclib plus letrozole group and 59 in the letrozole group. Median progression-free survival was 10·2 months (95% CI 5·7–12·6) for the letrozole group and 20·2 months (13·8–27·5) for the palbociclib plus letrozole group (HR 0·488, 95% CI 0·319–0·748; one-sided p=0·0004). In cohort 1 (n=66), median progression-free survival was 5·7 months (2·6–10·5) for the letrozole group and 26·1 months (11·2–not estimable) for the palbociclib plus letrozole group (HR 0·299, 0·156–0·572; one-sided p Interpretation The addition of palbociclib to letrozole in this phase 2 study significantly improved progression-free survival in women with advanced oestrogen receptor-positive and HER2-negative breast cancer. A phase 3 trial is currently underway. Funding Pfizer.
1,466 citations
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TL;DR: How the combination of standard clinical‐pathological markers with the information provided by these genomic entities might help further understand the biological complexity of this disease, increase the efficacy of current and novel therapies, and ultimately improve outcomes for breast cancer patients is discussed.
1,236 citations