A phase II study of anastrazole and fulvestrant in combination with gefitinib in patients with newly diagnosed ER-positive breast cancer

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 1050-1050
Author(s):  
S. A. Massarweh ◽  
Y. L. Tham ◽  
H. Weiss ◽  
S. Fuqua ◽  
J. Huang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Adverse Events ◽  
Endocrine Therapy ◽  
Phase Ii ◽  
Kinase Inhibitor ◽  
De Novo ◽  
Endocrine Resistance ◽  
Neoadjuvant Endocrine Therapy ◽  
Egfr Inhibition ◽  
Biomarker Analysis

1050 Background: Endocrine therapy for ER+ breast cancer is effective and relatively nontoxic, but is limited by de novo and acquired resistance. Preclinical studies suggest that complete ER blockade along with inhibition of co-expressed growth factor receptors enhances endocrine response and overcomes resistance. Methods: We conducted a phase II trial of combined anastrazole and fulvestrant with gefitinib, an EGFR tyrosine kinase inhibitor, as intial therapy in postmenopausal women with locoregional or metastatic ER+ breast cancer. A tumor core biopsy was done at baseline and after 3 weeks. Patients received treatment for 4 months. Surgery was then offered if the tumor was operable. Primary endpoint was clinical response as defined by RECIST criteria and secondary endpoints were safety/tolerability, complete pathologic response rate (pCR), and biomarker analysis. Planned sample size was 60 patients, but the study closed after 15 patients were enrolled because of poor accrual. Results: Median age at diagnosis was 67 years. Median clinical tumor size was 7 cm and 4 patients had metastases. 11 patients (73%) had ER+/PgR+ tumors and 4 (27%) had ER+/PgR- disease. 3 patients withdraw from the study before response was assessed. Of the12 remaining patients there were 2 complete responses (17%), 5 partial responses (42%), 5 with stable disease (42%), and 2 (17%) with progressive disease. Of the 7 patients who had surgery at 4 months, none had pCR. Most common adverse events were rash in 4 patients, Diarrhea in 4, joint symptoms in 3, and abnormal LFT’s in 3. All adverse events were reversible. Biomarkers, including arrays and Ki67, are pending and will be presented at the meeting. Conclusions: Complete ER blockade using anastrazole and fulvestrant with EGFR inhibition is well-tolerated and has activity in this cohort of patients with relatively advanced ER+ breast cancer. Despite its documented benefit and low toxicity, accrual to neoadjuvant endocrine therapy studies remains poor in the US, largely because of physician hesitance to refer patients for non-chemotherapy studies. More effort is needed to increase physician awareness about the value of endocrine therapy, and to increase accrual to trials that address the question of endocrine resistance. [Table: see text]

Treatment Algorithms for Hormone Receptor–Positive Advanced Breast Cancer: Going Forward in Endocrine Therapy—Overcoming Resistance and Introducing New Agents

2013 ◽  
pp. e28-e36 ◽  
Author(s):  
Stephen R. D. Johnston ◽  
Gaia Schiavon
Keyword(s):  
Breast Cancer ◽  
Growth Factor ◽  
Endocrine Therapy ◽  
De Novo ◽  
Endocrine Resistance ◽  
Growth Factor Receptor ◽  
New Agents ◽  
Treatment Algorithms ◽  
Hormone Receptor Positive ◽  
Survival Pathways

Overcoming de novo or acquired endocrine resistance remains critical to further enhancing the benefit of existing endocrine therapies. Recent progress has been made in understanding the molecular biology associated with acquired endocrine resistance, including adaptive “cross-talk” between ER and various growth factor receptor and cell-signaling pathways. Strategies that combine endocrine therapy with targeted inhibitors of growth factor receptors or cell-survival pathways to further enhance first-line response have largely been disappointing, suggesting that any attempts to prevent endocrine resistance by blocking specific pathways from the outset will be futile. In contrast, success has been seen by selecting patients with acquired endocrine resistance and enhancing response to further endocrine therapy by the addition of mTOR antagonists. Numerous other therapeutics are being evaluated in combination with endocrine therapies based on varying levels of preclinical science to support their use, including inhibitors of PI3K, HDAC, Src, IGFR-1, and CDK4/6. Enriching trial recruitment by molecular profiling of different ER+ subtypes will become increasingly important to maximize any additional benefit that these new agents may bring to current endocrine therapies for breast cancer.

Phase II randomized study of the EGFR, HER2, HER3 signaling inhibitor AZD8931 in combination with anastrozole (A) in women with endocrine therapy (ET) naive advanced breast cancer (MINT).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 531-531 ◽  
Author(s):  
Stephen R. D. Johnston ◽  
Mark Basik ◽  
Roberto Hegg ◽  
Wirote Lausoontornsiri ◽  
Lukasz Grzeda ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Phase Ii ◽  
Interim Analysis ◽  
Randomized Study ◽  
Acquired Resistance ◽  
Endocrine Resistance ◽  
Population Data ◽  
Double Blind ◽  
Egfr Inhibition ◽  
Phase Ii Studies

531 Background: Preclinical data suggest a key role for EGFR inhibition in delaying acquired resistance to ET in ER+ breast cancer (BC). Retrospective analyses of 2 Phase II studies suggested adding gefitinib to ET delayed PFS in ET naive (ETN) BC. This randomized, double-blind, placebo-controlled multi-center study (NCT01151215) was conducted to prospectively test the hypothesis that adding AZD8931, an inhibitor of EGFR, HER2 and HER3 signaling, to A would be beneficial in delaying endocrine resistance in an advanced ETN BC population. Methods: Post-menopausal women with ER+ and/or PR+, ETN, HER2-negative, advanced BC were randomized (1:1:1) to receive A (1 mg od) plus AZD8931 20 or 40 mg bd or placebo (P). The primary endpoint was PFS (ITT population). Data presented are from an interim analysis (data cutoff 31 Aug 2012; 39% pts had a progression event). Results: Between Jun 2010 and Jun 2012, 359 pts (median age 61 years) were randomized to A combined with AZD8931 20 mg (n=118), 40 mg (n=120) or P (n=121). At the interim analysis, median PFS in the AZD8931 20 mg, 40 mg and P arms was 10.9, 13.8 and 14.0 months, respectively; PFS HR (95% CI) for AZD8931 20 mg:P was 1.37 (0.91–2.06, P=0.135) and for AZD8931 40 mg:P was 1.16 (0.77–1.75, P=0.485). Deaths were reported for 20 (17%), 16 (13%) and 12 pts (10%) in the AZD8931 20 mg, 40 mg and P arms, respectively. Grade ≥3 AEs were reported for 22 (19%), 44 (37%) and 18 (15%) pts in the AZD8931 20 mg, 40 mg, and P arms, respectively, the most frequent being rash (0% vs 8% vs 2%), acneiform dermatitis (0% vs 7% vs 0%) and hypertension (3% vs 3% vs 2%). Serious AEs were reported for 12%, 14% and 9% pts in the AZD8931 20 mg, 40 mg and P arms, respectively, and discontinuation (of AZD8931 or P) due to an AE in 5%, 8% and 2% pts, respectively. Conclusions: Co-blockade of EGFR, HER2, HER3 in combination with aromatase inhibition does not appear to delay endocrine resistance to ETN BC. Based on the low probability of demonstrating superior efficacy with addition of AZD8931 to A and the overall risk/benefit, the study was closed at the recommendation of the IDMC and pts discontinued AZD8931. Clinical trial information: NCT01151215.

Efficacy of six month neoadjuvant endocrine therapy in postmenopausal, hormone receptor-positive breast cancer patients – A phase II trial

2014 ◽  
Vol 50 (13) ◽  
pp. 2190-2200 ◽  
Author(s):  
Duveken B.Y. Fontein ◽  
Ayoub Charehbili ◽  
Johan W.R. Nortier ◽  
Elma Meershoek-Klein Kranenbarg ◽  
Judith R. Kroep ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Endocrine Therapy ◽  
Phase Ii ◽  
Hormone Receptor ◽  
Phase Ii Trial ◽  
Breast Cancer Patients ◽  
Neoadjuvant Endocrine Therapy ◽  
Hormone Receptor Positive ◽  
Positive Breast Cancer

Phase II study of the multikinase inhibitor dovitinib (TKI258) or placebo in combination with fulvestrant in postmenopausal, endocrine resistant HER2-/HR+ breast cancer.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. TPS1148-TPS1148
Author(s):  
Fabrice Andre ◽  
Richard Greil ◽  
Neelima Denduluri ◽  
Alejandro Javier Yovine ◽  
Cathy Reddick ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Endocrine Therapy ◽  
Phase Ii ◽  
Molecular Mechanisms ◽  
Locally Advanced ◽  
Endocrine Resistance ◽  
Metastatic Breast ◽  
Predictive Biomarkers ◽  
Her2 Breast Cancer ◽  
Patient Reported

TPS1148 Background: Overcoming endocrine resistance is a critical goal in the treatment of hormone receptor−positive (HR+) breast cancer. Molecular mechanisms associated with endocrine resistance include adaptive “cross-talk” between the estrogen receptor and the fibroblast growth factor receptor (FGFR). Up to 8% of HR+/HER2- breast cancer patients (pts) have amplification of the FGFR1 gene, which is associated with resistance to endocrine therapy but can be overcome via FGFR1 inhibition in preclinical models. Dovitinib is a potent FGF, VEGF, and PDGF receptor tyrosine kinase inhibitor that demonstrated antitumor activity in heavily pretreated breast cancer pts with FGF pathway amplification (FGFR1, FGFR2, or ligand FGF3; Andre et al, ASCO 2011). Dovitinib may reverse resistance to endocrine therapy related to FGF-pathway amplification and is studied here to determine if it can improve outcomes when combined with fulvestrant. Methods: Postmenopausal HER2-/HR+ locally advanced or metastatic breast cancer pts (N»150) progressing within 12 months of completion of adjuvant endocrine therapy or after ≤ 1 prior endocrine therapy in the advanced setting will be enrolled in this multicenter, randomized, double blind, placebo controlled, phase II trial. Pts will prospectively undergo molecular screening to enrich for FGF-amplification (FGFR1, FGFR2, or FGF3 amplification by qPCR; 45 amplified and 30 non-amplified pts per arm). Pts will be randomized 1:1 to receive fulvestrant (500 mg q4w [with an additional dose 2 wks after the initial dose]) in combination with oral dovitinib (500 mg, 5 days on/2 days off) or placebo until disease progression, unacceptable toxicity, or death. The primary endpoint is progression-free survival, with tumor assessments performed q8w. Secondary endpoints include overall response rate per RECIST v1.1, duration of response, overall survival, ECOG performance status and patient reported outcome scores over time, and safety. The pharmacodynamic effect of dovitinib on FGFR-associated angiogenic pathways in tumor specimens and potential predictive biomarkers of response to dovitinib will be explored.

scholarly journals Molecular Mechanisms of Endocrine Resistance in Estrogen-Positive Breast Cancer

2021 ◽  
Vol 12 ◽  
Author(s):  
Esmael Besufikad Belachew ◽  
Dareskedar Tsehay Sewasew
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Endocrine Therapy ◽  
Molecular Mechanisms ◽  
De Novo ◽  
Endocrine Resistance ◽  
Therapeutic Modality ◽  
Breast Cancers ◽  
Estrogen Receptor Positive ◽  
Positive Breast Cancer

The estrogen receptor is a vital receptor for therapeutic targets in estrogen receptor-positive breast cancer. The main strategy for the treatment of estrogen receptor-positive breast cancers is blocking the estrogen action on estrogen receptors by endocrine therapy but this can be restricted via endocrine resistance. Endocrine resistance occurs due to both de novo and acquired resistance. This review focuses on the mechanisms of the ligand-dependent and ligand-independent pathways and other coregulators, which are responsible for endocrine resistance. It concludes that combinatorial drugs that target different signaling pathways and coregulatory proteins together with endocrine therapy could be a novel therapeutic modality to stop endocrine resistance.

scholarly journals Endocrine resistance in hormone-responsive breast cancer: mechanisms and therapeutic strategies

2016 ◽  
Vol 23 (8) ◽  
pp. R337-R352 ◽  
Author(s):  
Conleth G Murphy ◽  
Maura N Dickler
Keyword(s):  
Breast Cancer ◽  
Endocrine Therapy ◽  
Hormone Receptors ◽  
De Novo ◽  
Feedback Inhibition ◽  
Acquired Resistance ◽  
Endocrine Resistance ◽  
Breast Cancers ◽  
Potential Relief ◽  
Rational Therapy

The majority of breast cancers may be considered hormone responsive due to expression of hormone receptors (HR+). Although endocrine therapy is always considered for advanced HR+ breast cancer, the emergence of resistance is inevitable over time and is present from the start in a proportion of patients. In this review, we explore the mechanisms underlyingde novoand acquired resistance to endocrine therapy. We comprehensively review newly approved and emerging therapies that have been developed to counteract specific mechanisms of resistance. We discuss the challenges pertinent to this therapeutic arena including the potential relief of negative regulatory feedback inhibition with compensatory pathway activation and the evolution of molecular changes in HR+ breast cancers during treatment. We discuss strategies to address these challenges in order to develop rational therapy approaches for patients with advanced HR+ breast cancer.

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