Clinical and biomarker results from phase I/II study of PI3K inhibitor BYL 719 (alpelisib) plus nab-paclitaxel in HER2-negative metastatic breast cancer.

Sharma, Priyanka; Abramson, Vandana G.; O’Dea, Anne; Pathak, Harsh B.; Pessetto, Ziyan Y.; Wang, Yen Y.; Finke, Karissa; Hoffmann, Marc; Elia, Manana; Lewis, Sharon L.; Scott, Jecinta; Jong, J. de; Urban, Julia; Heldstab, Jaimie; LaFaver, Stephanie; Williamson, Stephen K.; Reed, Greg; Kimler, Bruce F.; Khan, Qamar J.; Godwin, Andrew K.

doi:10.1200/jco.2018.36.15_suppl.1018

Cited by 23 publications

(18 citation statements)

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“…Finally, the proportion of PIK3CA mutations differed by BC subtype with HR+/HER2− disease having the highest proportion, followed by HER2+ disease and TNBC. Although less frequent in the HER2+ and TNBC, the proportion is not negligible and several studies, including pivotal or registrational clinical trials, are focusing on these two populations [5][6][7]. To our knowledge, this is the first report to perform a comprehensive analysis of PIK3CA mutations in BC and to relate these findings with the type of mutations captured by the therascreen PIK3CA assay across the three main subtypes of BC.…”

Section: Discussionmentioning

confidence: 93%

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Frequency and spectrum of PIK3CA somatic mutations in breast cancer

Martínez-Sáez¹,

Chic²,

Pascual³

et al. 2020

Breast Cancer Res

249

162

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Purpose: The therascreen PIK3CA mutation assay and the alpha-specific PI3K inhibitor alpelisib are FDA-approved for identifying and treating patients with advanced PIK3CA-mutated (PIK3CAmut) breast cancer (BC). However, it is currently unknown to what extend this assay detects most PIK3CA mutations in BC. This information is critical as patients and clinicians are using this and other genomic assays to indicate alpelisib. Methods: Data from 6338 patients with BC was explored across 10 publicly available studies. The primary objective was to evaluate the proportion and distribution of PIK3CA mutations in BC. Secondary objectives were (1) to evaluate in silico the spectrum of PIK3CA mutations in BC that would be captured by the therascreen panel; (2) to evaluate the proportion and distribution of PIK3CA mutations in hormone receptor-positive/HER2-negative (HR+/ HER2−), HER2+, and triple-negative BC (TNBC); and (3) to explore the identification of PIK3CA mutations in a cohort of 48 HR+/HER2− advanced BC patients by the Guardant B360 circulating tumor DNA (ctDNA) assay. Results: Patients with PIK3CAmut tumors represented 35.7% (2261/6338). Five PIK3CA mutations comprised 73% of all PIK3CA mutations: H1047R (35%), E545K (17%), E542K (11%), N345K (6%), and H1047L (4%). Therascreen gene list would capture 72% of all PIK3CA mutations and 80% of patients with a known PIK3CAmut BC. Among patients with double PIK3CAmut tumors (12% of all PIK3CAmut), the therascreen panel would capture 78% as harboring 1 single PIK3CA mutation, 17% as PIK3CAmut undetected, and 5% as PIK3CA double-mut. PIK3CA mutation rates were lower in TNBC (16%) compared to HR+/HER2 (42%) and HER2+ (31%) BC; however, the distribution of the 4 main PIK3CA mutations across subtypes was similar. Finally, 28% of PIK3CA mutations identified in ctDNA in 48 patients with advanced HR+/HER2− BC were not part of the therascreen panel.

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Section: Discussionmentioning

confidence: 93%

“…In patients with HR+/HER2− BC, mTOR/mTOR pathway has been associated with endocrine therapy resistance [4]. In addition, the role of this pathway is becoming increasingly important in HER2+ and TNBC [5][6][7]. Thus, inhibition of PI3K in PIK3CA-mutated BC has been a major focus in the last decade [3].…”

Section: Introductionmentioning

confidence: 99%

Frequency and spectrum of PIK3CA somatic mutations in breast cancer

Martínez-Sáez¹,

Chic²,

Pascual³

et al. 2020

Breast Cancer Res

249

162

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“…On the other hand, it is known that PTENdeficient tumours are dependent on PI3Kb signalling [37] and this may explain why patients included in the OPPORTUNE trial derived benefit from the pan-PI3Ki pictilisib (which also targets PI3Kb), whether they had PTEN-positive or PTEN-negative tumours [5,6]. Nonetheless, assessment of 'PTEN status' can be challenging, as its 'loss' has been determined by the allelic or complete loss of the PTEN gene [19,21], but also by the ABC, advanced breast cancer; AI, aromatase inhibitor; BC, breast cancer; CBR, clinical benefit rate; CI, confidence interval; CNV, copy number variations; CT, chemotherapy; ctDNA, circulating tumour DNA; ERþ, estrogen receptor positive; ET, endocrine therapy; FISH, fluorescent in situ hybridization; HER2þ, HER2 positive; HER2À, HER2 negative; HR, hazard ratio; IHC, immunohistochemistry; ITT, intention-to-treat population; mPFS, median progression-free survival; mut: mutation; NA, not applicable; NGS, next-generation sequencing; OR, odds ratio; ORR, overall response rate; P, placebo; PCR, polymerase chain reaction; PFS, progression-free survival; PgR, progesterone receptor; PIK3CA-mut, mutation in the PIK3CA gene; Ph, phase of the clinical trial; T, tumour size; WT, wild-type.…”

Section: Pten Expression Lossmentioning

confidence: 99%

“…In most clinical studies evaluating PIK3CA-mut as a predictor of chemotherapy response in BC, inferior response rates were observed in patients with PIK3CA-mut tumours when compared with patients with PIK3CA-wild-type tumours [62,65]. Therefore, the combination of PI3Ki and chemotherapy is being investigated as an attempt to overcome treatment resistance, but no promising results have been observed so far (Table 2) [9,11,21,49,59]. Ongoing trials are evaluating the association of PI3Ki with chemotherapy in HER2-negative BC (Table 3).…”

Section: With Chemotherapymentioning

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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“…Thus, biomarker selection and more selective inhibitors were argued. In a phase I/II trial of patients with HER2-negative BC 66 , the α-selective PI3K inhibitor alpelisib combined with nab-paclitaxel provided the largest benefit in the population harboring PIK3CA mutations (mPFS 13 months). Similar results were obtained in the phase II randomized trial LOTUS, where the AKT inhibitor ipatasertib combined with paclitaxel provided meaningful benefit in patients carrying PIK3CA/AKT1/PTEN alterations 67,68 .…”

Section: Introductionmentioning

confidence: 99%

Practical classification of triple-negative breast cancer: intratumoral heterogeneity, mechanisms of drug resistance, and novel therapies

et al. 2020

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Triple-negative breast cancer (TNBC) is not a unique disease, encompassing multiple entities with marked histopathological, transcriptomic and genomic heterogeneity. Despite several efforts, transcriptomic and genomic classifications have remained merely theoretic and most of the patients are being treated with chemotherapy. Driver alterations in potentially targetable genes, including PIK3CA and AKT, have been identified across TNBC subtypes, prompting the implementation of biomarker-driven therapeutic approaches. However, biomarker-based treatments as well as immune checkpoint inhibitor-based immunotherapy have provided contrasting and limited results so far. Accordingly, a better characterization of the genomic and immune contexture underpinning TNBC, as well as the translation of the lessons learnt in the metastatic disease to the early setting would improve patients’ outcomes. The application of multi-omics technologies, biocomputational algorithms, assays for minimal residual disease monitoring and novel clinical trial designs are strongly warranted to pave the way toward personalized anticancer treatment for patients with TNBC.

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Clinical and biomarker results from phase I/II study of PI3K inhibitor BYL 719 (alpelisib) plus nab-paclitaxel in HER2-negative metastatic breast cancer.

Cited by 23 publications

References 0 publications

Frequency and spectrum of PIK3CA somatic mutations in breast cancer

Frequency and spectrum of PIK3CA somatic mutations in breast cancer

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

Practical classification of triple-negative breast cancer: intratumoral heterogeneity, mechanisms of drug resistance, and novel therapies

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