Characterization of breast cancers with PI3K mutations in an academic practice setting using SNaPshot profiling

Abramson, Vandana G.; Lloyd, Maxwell R.; Ballinger, Tarah J.; Sanders, Melinda E.; Du, Liping; Lai, Darson; Su, Zengliu; Mayer, Ingrid A.; Levy, Mia A.; LaFrance, Delecia R.; Shyr, Yu; Dahlman, Kimberly B.; Pao, William; Arteaga, Carlos L.

doi:10.1007/s10549-014-2945-3

Cited by 20 publications

(18 citation statements)

References 35 publications

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“…DNA was initially subjected to SNaPShot (18) analysis of 18 mutations in PIK3CA , PTEN and AKT1 , including the common hot-spot mutations in exons 9 and 20 of PIK3CA , as previously described(19). SNaPShot is based on multiplex PCR, primer extension with fluorescently-tagged dideoxy-nucleotides and capillary electrophoresis; it is a fast, high-throughput, multiplex profiling method based on the Applied Biosystems SNaPshot platform.…”

Section: Methodsmentioning

confidence: 99%

A Phase Ib Study of Alpelisib (BYL719), a PI3Kα-Specific Inhibitor, with Letrozole in ER+/HER2− Metastatic Breast Cancer

Mayer

Abramson

Formisano

et al. 2017

Clinical Cancer Research

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Purpose Alpelisib, a selective oral inhibitor of the class I PI3K catalytic subunit p110α, has shown synergistic anti-tumor activity with endocrine therapy against ER+/PIK3CA mutated breast cancer cells. This phase Ib study evaluated alpelisib plus letrozole’s safety, tolerability and preliminary activity in patients with metastatic ER+ breast cancer refractory to endocrine therapy. Patients and Methods Twenty-six patients received letrozole and alpelisib daily. Outcomes were assessed by standard solid-tumor phase I methods. Tumor blocks were collected for DNA extraction and Next Generation Sequencing. Results Alpelisib’s maximum-tolerated dose (MTD) in combination with letrozole was 300 mg/d. Common drug-related adverse events included hyperglycemia, nausea, fatigue, diarrhea and rash with dose-limiting toxicity occurring at 350 mg/d of alpelisib. The clinical benefit rate (lack of progression ≥6 months) was 35% (44% in patients with PIK3CA mutated and 20% in PIK3CA wild-type tumors; 95% CI [17%; 56%]), including five objective responses. Of eight patients remaining on treatment ≥12 months, six had tumors with a PIK3CA mutation. Among evaluable tumors, those with FGFR1/2 amplification and KRAS and TP53 mutations did not derive clinical benefit. Overexpression of FGFR1 in ER+/PIK3CA mutant breast cancer cells attenuated the response to alpelisib in vitro. Conclusion The combination of letrozole and alpelisib was safe, with reversible toxicities. Clinical activity was observed independently of PIK3CA mutation status although clinical benefit was seen in a higher proportion of patients with PIK3CA mutated tumors. Phase II and III trials of alpelisib and endocrine therapy in patients with ER+ breast cancer are ongoing.

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Section: Methodsmentioning

confidence: 99%

A Phase Ib Study of Alpelisib (BYL719), a PI3Kα-Specific Inhibitor, with Letrozole in ER+/HER2− Metastatic Breast Cancer

Mayer

Abramson

Formisano

et al. 2017

Clinical Cancer Research

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280

222

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“…In multiple large population-based studies, 9–12 the incidence of PIK3CA mutations in oestrogen receptor-positive, HER2-negative cancers is approximately 40%. However, the role of these mutations in mediation of downstream activation of the PI3K pathway and endocrine therapy resistance is unclear.…”

Section: Introductionmentioning

confidence: 99%

Pictilisib for oestrogen receptor-positive, aromatase inhibitor-resistant, advanced or metastatic breast cancer (FERGI): a randomised, double-blind, placebo-controlled, phase 2 trial

Krop

Mayer

Ganju³

et al. 2016

The Lancet Oncology

251

164

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Summary Background Inhibition of phosphatidylinositol 3-kinase (PI3K) is a promising approach to overcome resistance to endocrine therapy in breast cancer. Pictilisib is an oral inhibitor of multiple PI3K isoforms. The aim of this study is to establish if addition of pictilisib to fulvestrant can improve progression-free survival in oestrogen receptor-positive, endocrine-resistant breast cancer. Methods In this two-part, randomised, double-blind, placebo-controlled, phase 2 study, we recruited postmenopausal women aged 18 years or older with oestrogen receptor-positive, HER2-negative breast cancer resistant to treatment with an aromatase inhibitor in the adjuvant or metastatic setting, from 123 medical centres across 21 countries. Part 1 included patients with or without PIK3CA mutations, whereas part 2 included only patients with PIK3CA mutations. Patients were randomly allocated (1:1 in part 1 and 2:1 in part 2) via a computer-generated hierarchical randomisation algorithm to daily oral pictilisib (340 mg in part 1 and 260 mg in part 2) or placebo starting on day 15 of cycle 1, plus intramuscular fulvestrant 500 mg on day 1 and day 15 of cycle 1 and day 1 of subsequent cycles in both groups. In part 1, we stratified patients by presence or absence of PIK3CA mutation, primary or secondary aromatase inhibitor resistance, and measurable or non-measurable disease. In part 2, we stratified patients by previous aromatase inhibitor treatment for advanced or metastatic disease or relapse during or within 6 months of an aromatase inhibitor treatment in the adjuvant setting and measurable or non-measurable disease. All patients and those administering treatment and assessing outcomes were masked to treatment assignment. The primary endpoint was progression-free survival in the intention-to-treat population for both parts 1 and 2 and also separately in patients with PIK3CA-mutated tumours in part 1. Tumour assessment (physical examination and imaging scans) was investigator-assessed and done at screening and after 8 weeks, 16 weeks, 24 weeks, and 32 weeks of treatment from day 1 of cycle 1 and every 12 weeks thereafter. We assessed safety in as-treated patients who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov, number NCT01437566. Findings In part 1, between Sept 27, 2011, and Jan 11, 2013, we randomly allocated 168 patients to the pictilisib (89 [53%]) or placebo (79 [47%]) group. In part 2, between March 18, 2013, and Jan 2, 2014, we randomly allocated 61 patients to the pictilisib (41 [67%]) or placebo (20 [33%]) group. In part 1, we found no difference in median progression-free survival between the pictilisib (6.6 months [95% CI 3.9–9.8]) and placebo (5.1 months [3.6–7.3]) group (hazard ratio [HR] 0.74 [95% CI 0.52–1.06]; p=0.096). We also found no difference when patients were analysed according to presence (pictilisib 6.5 months [95% CI 3.7–9.8] vs placebo 5.1 months [2.6–10.4]; HR 0.73 [95% CI 0.42–1.28]; p=0.268) or absence (5.8 months [3.6–11.1] vs 3.6 mon...

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“…However, when exon 9 and 20 mutations were analyzed separately, exon 9 mutations were independently associated with early recurrence and death, but exon 20 mutant tumors had better prognosis as compared to those with PIK3CA wild-type tumors [17]. Similarly, another study reported significantly more recurrences among patients with exon 9 mutations as compared to those with exon 20 mutations (recurrence rate for exon 9 vs exon 20, 89 % [39 of 44] vs 63 % [22 of 35], P = 0.007) [32]. Collectively, these data add to the complexity of interpreting studies that did not differentiate between both exon mutations when assessing the prognostic impact of PIK3CAm.…”

Section: Pik3cam and Prognosis Of Breast Cancermentioning

confidence: 91%

“…A recent meta-analysis of 4754 patients from 26 studies reported significant association with ER and PR expression [29]. On the other hand, PIK3CAm have been recently found to have no association with HER2 overexpression [17,30] or rather to be associated with negative HER2 overexpression [31,32]. Later studies reported associations of PIK3CAm with good prognostic features, such as lower histological grade [31], luminal A subtype [33], smaller tumor size [31], lower levels of Ki67 [33], and exon 20 mutations were particularly associated with PR expression [34,35].…”

Section: Pik3cam and Prognosis Of Breast Cancermentioning

confidence: 99%

Defining the Prognostic and Predictive Role of PIK3CA Mutations: Sifting Through the Conflicting Data

Al-Sukhun¹,

Lataifeh

Al-Sukhun³

2016

Curr Breast Cancer Rep

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PIK3CA is one of the most commonly mutated oncogenes in breast cancer, albeit at variable distribution among the different biological subtypes. Overall, it appears that PIK3CA mutations are most likely found in tumors with less aggressive characteristics, especially estrogen receptor (ER)-positive, luminal A tumors. Studies assessing its prognostic or predictive role have reported conflicting data, in part due to different methodologies used for detection and small sample sizes. The majority of reports used retrospective data from clinical trials thus could not exclude the effect of treatment heterogeneity when evaluating prognostic factors, and analysis was not subtype specific. Since breast cancer subtypes differ in terms of biology, treatment, and outcomes, it is critical that the effects of PIK3CA mutations on pathophysiology and therapy responsiveness are analyzed independently in each subtype. This short review discusses these issues and the significance of PIK3CA mutations in relation to the expression of HER2 and hormone receptors.

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Characterization of breast cancers with PI3K mutations in an academic practice setting using SNaPshot profiling

Cited by 20 publications

References 35 publications

A Phase Ib Study of Alpelisib (BYL719), a PI3Kα-Specific Inhibitor, with Letrozole in ER+/HER2− Metastatic Breast Cancer

A Phase Ib Study of Alpelisib (BYL719), a PI3Kα-Specific Inhibitor, with Letrozole in ER+/HER2− Metastatic Breast Cancer

Pictilisib for oestrogen receptor-positive, aromatase inhibitor-resistant, advanced or metastatic breast cancer (FERGI): a randomised, double-blind, placebo-controlled, phase 2 trial

Defining the Prognostic and Predictive Role of PIK3CA Mutations: Sifting Through the Conflicting Data

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