PIKHER2: A phase IB study evaluating buparlisib in combination with lapatinib in trastuzumab-resistant HER2-positive advanced breast cancer

Guérin, Mathilde; Rezai, Keyvan; Isambert, Nicolás; Campone, Mario; Autret, A.; Pakradouni, Jihane; Provansal, Magali; Camerlo, Jacques; Sabatier, Renaud; Bertucci, François; Charafe‐Jauffret, Emmanuelle; Hervieu, Alice; Extra, Jean-Marc; Viens, Patrice; Lokiec, François; Boher, Jean-Marie; Gonçalvès, Anthony

doi:10.1016/j.ejca.2017.08.025

Cited by 50 publications

(36 citation statements)

References 28 publications

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“…Twenty-six samples had been collected from patients treated at Institut Paoli-Calmettes at various stages of the disease: four from HER2-positive advanced breast cancer patients enrolled in the PIKHER2 study (NCT01589861) [ 39 ], six from HER2-positive IBC patients enrolled in the BEVERLY-2 trial -(NCT00717405) [ 40 ], sixteen from HER2-positive and negative early breast cancer patients enrolled in the prospective institutional BC-BIO cohort (NCT01521676). All patients given informed consent.…”

Section: Methodsmentioning

confidence: 99%

Development of parallel reaction monitoring (PRM)-based quantitative proteomics applied to HER2-Positive breast cancer

et al. 2018

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Introductiontreatments targeting the Human Epidermal Growth Factor Receptor 2 (HER2/ERBB2) have improved the natural history of HER2-positive breast cancer. However, except HER2 protein expression and gene amplification, there is no predictive biomarker to guide the HER2-targeted therapies. We developed Parallel reaction monitoring (PRM) a powerful approach, to quantify and evaluate key proteins involved in the HER2 pathway and/or anti-HER2 treatment sensitivity.Resultsin BCLs, PRM measurements correlated with western blot immunocytochemistry and transcriptomic data. At baseline, higher expression of HER2, EGFR, PTEN and HER3 but lower expression of phospho-HER2 correlated with trastuzumab sensitivity. Under trastuzumab, PRM demonstrated a decrease in HER2 and an increase in phospho-HER2, which correlated with drug sensitivity. The opposite was observed under lapatinib. HER2 quantification was also correlated with immunohistochemistry in PDXs and clinical breast cancer samples.Discussionin conclusion, PRM-based assay, developed to quantify proteins of the HER2 pathway in breast cancer samples revealed a large magnitude of expression, which may have relevance in terms of treatment sensitivity.Materials and Methodswe first evaluated PRM in term of sensitivity, linearity and reproducibility. PRM was then applied to breast cancer cell lines (BCLs) including BCLs exposed to anti-HER2 agents, patient-derived xenografts (PDXs) and frozen breast cancer samples.

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Section: Methodsmentioning

confidence: 99%

Development of parallel reaction monitoring (PRM)-based quantitative proteomics applied to HER2-Positive breast cancer

et al. 2018

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“…Likewise, in HER2-positive BC patients, presence of a PIK3CA-mut is associated with worse response rates to neoadjuvant treatment [62]. Phase I/II studies demonstrated the overall feasibility of combining anti-HER2 treatments with PI3Ki (Table 2) [46,[50][51][52][53][54][55][56][57][58][59]63]. A phase II study including HER2-positive, trastuzumab-resistant metastatic BC patients treated with buparlisib and trastuzumab showed an overall response rate of 10%, but grade !…”

Section: With Anti-her2 Agentsmentioning

confidence: 99%

Biomarkers of response and resistance to PI3K inhibitors in estrogen receptor-positive breast cancer patients and combination therapies involving PI3K inhibitors

et al. 2019

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In this review, we discuss biomarkers of response and resistance to PI3K inhibitors (PI3Ki) in estrogen receptor-positive breast cancer, both in the early and advanced settings. We analyse data regarding PIK3CA mutations, PI3K pathway activation, PTEN expression loss, Akt signalling, insulin levels, 18F FDG-PET/CT imaging, FGFR1/2 amplification, KRAS and TP53 mutations. Most of the discussed data comprise retrospective and exploratory studies, hence many results are not conclusive. Therefore, among all of these biomarkers, only PIK3CA mutations have proved to have a predictive value for treatment with the a-selective PI3Ki alpelisib (SOLAR-1 trial) and the b-sparing PI3Ki taselisib (SANDPIPER trial) in the advanced setting. Since the accuracy of current individual biomarkers is not optimal, a composite biomarker, including DNA, RNA and protein expression data, to more precisely assess the PI3K/AKT/mTOR pathway activation status, may arise as a promising approach. Finally, we describe the rational for new combination therapies involving PI3Ki and anti-HER2 agents, chemotherapy, CDK4/6 inhibitors, mTOR inhibitors or new endocrine treatments and discuss the ongoing trials in this field.

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“…Disease control rate was 79% (one patient with complete response and six patients with stable disease for ≥24 weeks). 47 Finally, this trial showed preliminary evidence of antitumor activity in this heavily pretreated population with manageable safety profile.…”

Section: Methodsmentioning

confidence: 81%

“…Buparlisib has also been studied in combination with lapatinib in a Phase IB/II trial including patients with HER2+, trastuzumab-resistant, metastatic BC. 47 In the Phase IB part, the PI3K pathway activation status was assessed in a retrospective exploratory analysis, and evidence of PI3K pathway activation was an inclusion criterion for Phase II. Twenty-four patients were treated at five dose levels.…”

Section: Methodsmentioning

confidence: 99%

Profile of buparlisib and its potential in the treatment of breast cancer: evidence to date

Viale¹,

Curigliano²,

Goldhirsch³

2018

BCTT

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Alteration of the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin signaling pathway is key for the growth and survival of several cancers, including breast cancer. In addition, dysregulation of PI3K signaling may contribute to resistance to several anticancer agents. PI3K inhibitors may, therefore, be effective as antineoplastic therapy. Buparlisib is a potent and highly specific oral inhibitor of the pan-class I PI3K family. Buparlisib specifically inhibits class I PIK3 in the PI3K/AKT kinase signaling pathway in an ATP-competitive manner, thus inhibiting the production of the secondary messenger phosphatidylinositol (3,4,5)-trisphosphate and activation of the PI3K signaling pathway. This may induce inhibition of tumor cell growth and survival in susceptible tumor cell populations. Buparlisib is currently under investigation in patients with a variety of solid tumors, including breast cancer. Buparlisib has been validated as a promising anticancer agent, and tremendous efforts have been taken to develop it. However, buparlisib monotherapy has resulted in humble benefit so far. Results from studies combining buparlisib with different anticancer agents – namely, endocrine therapy, anti-HER2 therapy, and chemotherapy – have showed variable efficacy with consistent substantial toxicity.

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PIKHER2: A phase IB study evaluating buparlisib in combination with lapatinib in trastuzumab-resistant HER2-positive advanced breast cancer

Cited by 50 publications

References 28 publications

Development of parallel reaction monitoring (PRM)-based quantitative proteomics applied to HER2-Positive breast cancer

Development of parallel reaction monitoring (PRM)-based quantitative proteomics applied to HER2-Positive breast cancer

Biomarkers of response and resistance to PI3K inhibitors in estrogen receptor-positive breast cancer patients and combination therapies involving PI3K inhibitors

Profile of buparlisib and its potential in the treatment of breast cancer: evidence to date

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