Efficacy of palbociclib plus fulvestrant after everolimus in hormone receptor-positive metastatic breast cancer

Rusquec, Pauline du; Palpacuer, Clément; Campion, Loı̈c; Patsouris, Anne; Augereau, Paule; Gourmelon, Carole; Robert, Marie; Dumas, L.E.; Caroline, Folliard; Campone, Mario; Frenel, Jean-Sébastien

doi:10.1007/s10549-017-4623-8

Cited by 29 publications

(39 citation statements)

References 13 publications

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“…These data are consistent with previous reports of in vitro studies that show CDK4/6 inhibitors can reverse acquired resistance to inhibitors of PI3K [36]. Data from two clinical studies with small numbers of patients indicate that palbociclib-based therapies have limited efficacy after progression on the mTORC1 inhibitor everolimus (RAD001) [37,38]. However, the efficacy of CDK4/6 inhibition post-progression on PI3K inhibitor-based therapies is yet to be investigated.…”

Section: Discussionsupporting

confidence: 90%

Targeting activated PI3K/mTOR signaling overcomes acquired resistance to CDK4/6-based therapies in preclinical models of hormone receptor-positive breast cancer

et al. 2020

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Background: Combined targeting of CDK4/6 and ER is now the standard of care for patients with advanced ER+/ HER2− breast cancer. However, acquired resistance to these therapies frequently leads to disease progression. As such, it is critical to identify the mechanisms by which resistance to CDK4/6-based therapies is acquired and also identify therapeutic strategies to overcome resistance. Methods: In this study, we developed and characterized multiple in vitro and in vivo models of acquired resistance to CDK4/6-based therapies. Resistant models were screened by reverse phase protein array (RPPA) for cell signaling changes that are activated in resistance. Results: We show that either a direct loss of Rb or loss of dependence on Rb signaling confers cross-resistance to inhibitors of CDK4/6, while PI3K/mTOR signaling remains activated. Treatment with the p110α-selective PI3K inhibitor, alpelisib (BYL719), completely blocked the progression of acquired CDK4/6 inhibitor-resistant xenografts in the absence of continued CDK4/6 inhibitor treatment in models of both PIK3CA mutant and wild-type ER+/HER2− breast cancer. Triple combination therapy against PI3K:CDK4/6:ER prevented and/or delayed the onset of resistance in treatment-naive ER+/HER2− breast cancer models. Conclusions: These data support the clinical investigation of p110α-selective inhibitors of PI3K, such as alpelisib, in patients with ER+/HER2− breast cancer who have progressed on CDK4/6:ER-based therapies. Our data also support the investigation of PI3K:CDK4/6:ER triple combination therapy to prevent the onset of resistance to the combination of endocrine therapy plus CDK4/6 inhibition.

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Section: Discussionsupporting

confidence: 90%

Targeting activated PI3K/mTOR signaling overcomes acquired resistance to CDK4/6-based therapies in preclinical models of hormone receptor-positive breast cancer

et al. 2020

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“…With a longer follow-up, subsequent large US and international studies have shown similar PFS data and have suggested an OS benefit [13,14]. Other, more limited studies, were in line with those results [26][27][28][29][30][31][32][33].…”

Section: Discussionsupporting

confidence: 58%

Real life efficacy of palbociclib and endocrine therapy in HR positive, HER2 negative advanced breast cancer

et al. 2020

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Background Palbociclib is indicated for the treatment of hormone receptor-positive (HR+), HER2-negative (HER2-) advanced breast cancer (ABC), in combination with endocrine therapy. Emerging real-life data suggest that the efficacy of a palbociclib-based therapy is highly conserved. We report the Institut Curie hospital experience. Patients and methods We retrospectively reviewed all patients with HR + HER2- ABC treated with a palbociclib-based therapy as first or second line for ABC, with an initial prescription from November 2016 to December 2018. Clinical, laboratory and imaging data were retrieved from electronic records. Data lock was December 31st, 2019. Descriptive analyses, univariate and multivariate Cox regression analyses were performed. Results We included 310 consecutive patients. Median age was 61.8 years old. Palbociclib was prescribed in first line in 225 patients (72.6%). Before palbociclib-based therapy initiation, 122 patients (39.3%) were endocrine naive, 96 (31.0%) endocrine sensitive and 92 (29.7%) endocrine resistant. Median follow-up was 20.7 months. Median progression free survival (PFS) was 23.4 months (95%CI: 21.6-NR) in endocrine naive patients, 22.7 months (95%CI: 14.7-NR) in endocrine sensitive, and 13.4 months (95%CI: 10.7–20.8) in endocrine resistant. At 12 months from the initiation of palbociclib, 94.5% of patients were alive. By multivariate analysis, poor prognosis factors for PFS were identified in the endocrine naive/sensitive population: initial ECOG status 2, previous endocrine therapy for ABC, 3 metastatic sites or more. Toxicity profile was similar to previously published data. Conclusion In a non-selected population of patients with HR + HER2- ABC, the efficacy and safety data are strikingly similar to those previously reported.

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“…A prospective nonrandomized single-arm study of the efficacy of palbociclib plus fulvestrant after everolimus in France showed a median PFS after palbociclib combination to be 5.8 months (95% CI, 3.9-7.3). 12 A total of 26.7% had partial response, while 45% had stable disease as best response. No CBR was reported.…”

Section: Discussionmentioning

confidence: 96%

Efficacy of Palbociclib Combinations in Hormone Receptor–Positive Metastatic Breast Cancer Patients After Prior Everolimus Treatment

Dhakal

Matthews

Levine

et al. 2018

Clinical Breast Cancer

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Efficacy of palbociclib plus fulvestrant after everolimus in hormone receptor-positive metastatic breast cancer

Abstract: In this heavily pretreated population including everolimus, fulvestrant plus palbociclib provides an mPFS of 5.8 months with the same magnitude of benefit for fulvestrant-pretreated patients.

Cited by 29 publications

References 13 publications

Targeting activated PI3K/mTOR signaling overcomes acquired resistance to CDK4/6-based therapies in preclinical models of hormone receptor-positive breast cancer

Targeting activated PI3K/mTOR signaling overcomes acquired resistance to CDK4/6-based therapies in preclinical models of hormone receptor-positive breast cancer

Real life efficacy of palbociclib and endocrine therapy in HR positive, HER2 negative advanced breast cancer

Efficacy of Palbociclib Combinations in Hormone Receptor–Positive Metastatic Breast Cancer Patients After Prior Everolimus Treatment

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