100O Results of A Randomized Phase 2 Study of Pd 0332991, A Cyclin-Dependent Kinase (Cdk) 4/6 Inhibitor, In Combination with Letrozole vs Letrozole Alone For First-Line Treatment of ER + /Her2- Advanced Breast Cancer (Bc)

Finn, Richard S.; Crown, John; Boer, Kimberly R.; Làng, István; Parikh, Rupesh J.; Breazna, Aurora; Ho, Steffan N.; Kim, S.T.; Randolph, Sophia; Slamon, DJ; Awada, Ahmad; Chan, Stephen L.; Jérusalem, Guy; Coleman, Robert E.; Huizing, Manon; Mehdi, Aminder; O’Reilly, Susan; Hamm, John; García, Antonio Salmerón; Perez, Edith A.; Cortés, Jorge E.; Rejeeth, Chandrababu; Kannan, Sivakumar; Dowsett, Mitch; Koehler, Maria; Millham, Robert; Borzillo, Gary; A’Hern, Roger; Pierce, Kristen J.; Barton, Jeremy; Giorgetti, C.; Zhukova, O.S.; Shcherbakov, A. M.; Фетисова, Л. В.; Киселевский, М. В.; Nifantiev, Nikolay E.; Payandeh, Mehrdad; Aeinfar, Mehrnoush; Zare, Maryam; Hilderson, I.; Geurs, F.; Criel, M.; Debrucker, P.; Bensalem, A.; Merrouche, M.; Ammari, A.; Benmerzouk, A.; Bouzid, K.

doi:10.1093/annonc/mds045

Cited by 58 publications

(46 citation statements)

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“…46 It can dramatically improve progressionfree survival of women with metastatic estrogen receptor-positive breast cancer by combinational therapy with oral nonsteroidal aromatase inhibitor letrozole in phase 2 trial, suggesting the important role of CDK4 in tumorigenesis. 47 However, there is no other compound that has been shown to be specific for CDK4 without activity on other CDKs. Therefore, it is not the optimal choice to select a CDK4 inhibitor for synthetic lethality-based therapy because "offtarget" side effects in wild-type KRAS cells cannot be avoided.…”

Section: Discussionmentioning

confidence: 99%

Synthetic Lethal Therapy for KRAS Mutant Non-small-cell Lung Carcinoma with Nanoparticle-mediated CDK4 siRNA Delivery

et al. 2014

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The KRAS mutation is present in ~20% of lung cancers and has not yet been effectively targeted for therapy. This mutation is associated with a poor prognosis in non-small-cell lung carcinomas (NSCLCs) and confers resistance to standard anticancer treatment drugs, including epidermal growth factor receptor tyrosine kinase inhibitors. In this study, we exploited a new therapeutic strategy based on the synthetic lethal interaction between cyclin-dependent kinase 4 (CDK4) downregulation and the KRAS mutation to deliver micellar nanoparticles (MNPs) containing small interfering RNA targeting CDK4 (MNPsiCDK4) for treatment in NSCLCs harboring the oncogenic KRAS mutation. Following MNPsiCDK4 administration, CDK4 expression was decreased, accompanied by inhibited cell proliferation, specifically in KRAS mutant NSCLCs. However, this intervention was harmless to normal KRAS wild-type cells, confirming the proposed mechanism of synthetic lethality. Moreover, systemic delivery of MNPsiCDK4 significantly inhibited tumor growth in an A549 NSCLC xenograft murine model, with depressed expression of CDK4 and mutational KRAS status, suggesting the therapeutic promise of MNPsiCDK4 delivery in KRAS mutant NSCLCs via a synthetic lethal interaction between KRAS and CDK4.

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Section: Discussionmentioning

confidence: 99%

Synthetic Lethal Therapy for KRAS Mutant Non-small-cell Lung Carcinoma with Nanoparticle-mediated CDK4 siRNA Delivery

et al. 2014

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“…Palbociclib in combination with letrozole versus letrozole alone (PALOMA-1), a randomized phase II study of the AI letrozole with or without palbociclib as first-line therapy for ER þ , HER2 À MBC (n ¼ 165), reported a striking improvement in PFS from 7.5 to 26.2 months (hazard ratio [HR], 0.32; 95% confidence interval [CI], 0.19-0.56; P < .001) without additional safety concerns. 108 In the final results analysis, the median PFS was 20.2 months with letrozole plus palbociclib compared with 10.2 months for letrozole alone (HR, 0.488; 95% CI, 0.319-0.748; 1-sided P ¼ .0004), and the combination demonstrated significant clinical benefit as first-line treatment in this patient population. 109 Several phase I, II, and III studies of palbociclib in combination with fulvestrant and AIs (eg, PALOMA-2 and PALOMA-3) in HR þ MBC are currently underway or have recently concluded.…”

Section: Cell Cycle Control and Proliferationmentioning

confidence: 85%

“…108 In the final results analysis, the median PFS was 20.2 months with letrozole plus palbociclib compared with 10.2 months for letrozole alone (HR, 0.488; 95% CI, 0.319-0.748; 1-sided P ¼ .0004), and the combination demonstrated significant clinical benefit as first-line treatment in this patient population. 109 Several phase I, II, and III studies of palbociclib in combination with fulvestrant and AIs (eg, PALOMA-2 and PALOMA-3) in HR þ MBC are currently underway or have recently concluded. 110,111 Most recently, treatment with the combination of palbociclib and fulvestrant in patients with advanced HR þ HER2 À breast cancer who had relapsed or progressed during prior endocrine therapy, received FDA approval based on the findings of the phase III study, PALOMA-3.…”

Section: Cell Cycle Control and Proliferationmentioning

confidence: 85%

Consequences of the Convergence of Multiple Alternate Pathways on the Estrogen Receptor in the Treatment of Metastatic Breast Cancer

Glück

2017

Clinical Breast Cancer

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Endocrine therapy is the usual first-line therapy for patients with hormone receptor-positive metastatic breast cancer. However, resistance to hormone therapies frequently occurs during the course of treatment. Growing understanding of the signal cascade of estrogen receptors and the signaling pathways that interact with estrogen receptors has revealed the complex role of these receptors in cell growth and proliferation, and on the mechanism in development of resistance. These insights have led to the development of targeted therapies that may prove to be effective options for the treatment of breast cancer and may overcome hormone therapy resistance. This article reviews current understanding of the cellular receptor signaling pathways that interact with estrogen receptors. It also reviews data from recent ongoing clinical trials that examine the effects of targeted therapies, which might interfere with estrogen receptor pathways and might reduce or reverse resistance to traditional, sequential, single-agent endocrine therapy.

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“…Pre‐clinical evidence has suggested that inhibition of CDK4/6 using the small molecule PD‐0332991 provides synergistic inhibition with tamoxifen, suggesting that cell‐cycle inhibition in conjunction with endocrine therapy might be an effective strategy . As such, a phase II randomized, multicenter trial was conducted with PD‐0332991 plus letrozole as first‐line therapy in advanced BC . The combination was well tolerated and resulted in a statistically significant, substantial increase in PFS over that of letrozole alone.…”

Section: Overcoming Endocrine Resistancementioning

confidence: 99%

Managing Postmenopausal Women with Hormone Receptor-Positive Advanced Breast Cancer Who Progress on Endocrine Therapies with Inhibitors of the PI3K Pathway

Brufsky

2014

Breast J

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Although endocrine therapies that interfere with estrogen receptor (ER)-mediated signaling have revolutionized the management of postmenopausal women with hormone receptor-positive (HR+) breast cancer (BC), long-term management of these patients is suboptimal because of the eventual emergence of endocrine resistance. Intense research has elucidated a number of targets that act downstream or upstream of the ER, as well as those that crosstalk with the ER; however, clinical validation of inhibiting specific targets to overcome endocrine resistance has been lacking. The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway has been implicated to mediate endocrine resistance, and a number of novel agents that target this pathway are in early- and late-stage clinical trials. Recently, everolimus, an inhibitor of mTOR, a critical component of the PI3K/AKT/mTOR pathway, in combination with endocrine therapy, was shown to prolong progression-free survival with a manageable adverse-event profile in postmenopausal patients with HR+ BC. Bolstered by the safety and efficacy observed with concomitant inhibition of the ER and the PI3K/mTOR pathway and the validation of dual inhibition approach in managing postmenopausal patients with HR+ BC, a number of novel agents that inhibit PI3K (pan-PI3K inhibitors) or PI3K and mTOR (dual PI3K/mTOR) are being evaluated in clinical trials. Thus, mTOR inhibitors have provided the much-needed ammunition to oncologists who manage postmenopausal women with BC and have paved the way for the development of novel therapies that target the PI3K/mTOR pathway. Use of these novel therapies in managing postmenopausal women with BC, in combination with endocrine therapies, is expected to improve overall outcomes by overcoming endocrine resistance.

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100O Results of A Randomized Phase 2 Study of Pd 0332991, A Cyclin-Dependent Kinase (Cdk) 4/6 Inhibitor, In Combination with Letrozole vs Letrozole Alone For First-Line Treatment of ER + /Her2- Advanced Breast Cancer (Bc)

Cited by 58 publications

References 0 publications

Synthetic Lethal Therapy for KRAS Mutant Non-small-cell Lung Carcinoma with Nanoparticle-mediated CDK4 siRNA Delivery

Synthetic Lethal Therapy for KRAS Mutant Non-small-cell Lung Carcinoma with Nanoparticle-mediated CDK4 siRNA Delivery

Consequences of the Convergence of Multiple Alternate Pathways on the Estrogen Receptor in the Treatment of Metastatic Breast Cancer

Managing Postmenopausal Women with Hormone Receptor-Positive Advanced Breast Cancer Who Progress on Endocrine Therapies with Inhibitors of the PI3K Pathway

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