Read more about the prevalence and significance of PIK3CA mutations.
Combined endocrine and PI3K-directed treatment may overcome acquired resistance to endocrine therapy in HR+ HER2– advanced breast cancer.
The PI3K pathway is one of the most frequently altered pathways in human cancers and plays a role in disease progression1,2
The PI3K/AKT/mTOR pathway controls multiple cellular processes and is one of the most frequently dysregulated pathways in cancer.1,2
The PI3K pathway, adapted from Porta C, et al. 2014.2
The pathway can be activated by multiple factors, including PIK3CA. PIK3CA encodes the alpha isoform of PI3K.1
PIK3CA is one of the most commonly mutated genes in HR+/HER2− advanced breast cancer.3,4
PIK3CA mutations are non-randomly distributed and occur throughout several domains of the p110 catalytic subunit.4,24–26
PIK3CA mutations can be identified via tumour tissue or plasma samples containing ctDNA.4,24–27
PIK3CA mutations affect a variety of domains24–26,28†
†In SOLAR-1, PIK3CA mutation status was determined with PCR using a tumour-tissue sample, preferably obtained during the most recent progression, and any alteration on exons 7, 9, or 20 qualified patients for enrolment in the PIK3CA mutation cohort.17 For >90% of patients, the tissue tested was archival.29
Class I PI3Ks are heterodimers consisting of a p110 catalytic subunit and a p85 regulatory subunit. PIK3CA is an oncogene that codes specifically for the p110 alpha catalytic subunit of PI3K.24,30
The PI3K isoforms play different roles in cell signalling and cancer31
PIK3CA mutations may lead to hyperactivation of PI3Kα, a key upstream component of the PI3K pathway.17,33,34–36
- PI3Kα hyperactivation affects multiple signalling cascades, including both AKT-dependent and AKT-independent cascades,35 which can result in acquired endocrine resistance in breast cancer cells33
- PIQRAY® is an alpha-specific class I PI3K inhibitor27
- PIQRAY® inhibits the isoform of PI3K 50 times more potently than other PI3K isoforms (β, γ, δ), when studied in vitro17
- Treatment with PIQRAY®, always given in combination with fulvestrant, inhibits phosphorylation of downstream targetsincluding AKT27
- Fulvestrant is a competitive oestrogen receptor antagonist which downregulates oestrogen receptor protein levels37
Combined endocrine and PI3K-directed treatment may overcome acquired resistance to endocrine therapy in HR+/HER2− advanced breast cancer.33,38
Early knowledge of a tumour’s PIK3CA mutation status should inform the patient’s treatment plan.
- PIQRAY® (alpelisib) is indicated in combination with fulvestrant for the treatment of postmenopausal women, and men, with HR+/HER2−, locally advanced or metastatic breast cancer with a PIK3CA mutation after disease progression following endocrine therapy as monotherapy.
PIK3CA testing can be an important component of advanced breast cancer management.
Only patients whose tumour harbours a PIK3CA mutation are eligible for biomarker-driven therapy with PIQRAY® + fulvestrant.27
Patients with HR+/HER2− advanced breast cancer should be selected for treatment with PIQRAY®, in combination with fulvestrant, based on the presence of a PIK3CA mutation in tumour or plasma specimens, using a validated test. If a mutation is not detected in a plasma specimen, tumour tissue should be tested if available.27
*In SOLAR-1, PIK3CA mutation status was determined with PCR, and any alteration on exons 7, 9, or 20 qualified patients for enrolment in the PIK3CA mutation cohort.19 For >90% of patients, the tissue tested was archival.29
AKT, protein kinase B; ctDNA, circulating tumour DNA; HER2−, human epidermal growth factor receptor 2-negative; HR+, hormone receptor-positive; mTOR, mammalian target of rapamycin; PCR, polymerase chain reaction; PI3K, phosphoinositide 3-kinase; PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha.
- Janku, F, et al. Nat Rev Clin Oncol 2018;15(5):273−291.
- Porta C, et al. Front Oncol 2014;4:64.
- The Cancer Genome Atlas Network. Nature 2012;490(7418):61−70.
- Zardavas D, et al. Breast Cancer Res 2014;16(1):201
- Kingston B, et al. GS3-07. Presented at SABCS 2019; 10–14 December 2019; San Antonio, Texas, USA.
- Di Leo A, et al. Lancet Oncol 2018;19(1):87−100.
- Moynahan ME, et al. Br J Cancer 2017;116(6):726−730.
- Neven P, et al. PD2-05. Presented at SABCS 2018; 4–8 December 2018; San Antonio, Texas, USA.
- Bardia A, et al. CT141. Presented at AACR 2019 Annual Meeting; 29 March−3 April 2019; Atlanta, Georgia, USA.
- Hortobagyi GN, et al. Ann Oncol 2018;29:1541−1547.
- Cristofanilli M, et al. Lancet Oncol 2016;17:425−439.
- Tolaney S, et al. 4458 Presented at AACR 2019 Annual Meeting; 29 March−3 April 2019; Atlanta, Georgia, USA.
- Sobhani N, et al. J Cell Biochem 2018;119(6):4287−4292.
- Li SY, et al. Breast Cancer Res Treat 2006;96:91−95.
- Lai YL, et al. Ann Surg Oncol 2008;15:1064−1069.
- Mosele F, et al. Abstract 4895. Presented at AACR 2019 Annual Meeting; 29 March−3 April 2019; Atlanta, Georgia, USA.
- André F, et al. N Engl J Med 2019;380(20):1929−1940.
- Moynahan ME, et al. J Clin Oncol 2016;34(15):519.
- Krop I, et al. Lancet Oncol 2016;17(6):811−821.
- MONALEESA-7 Clinical Study Report. Novartis data on file.
- Signorovitch J, et al. 1069. Presented at ASCO 2020; 29 May 2020; virtual meeting.
- Tolaney S, et al. 766/3. Presented at AACR Virtual Annual Meeting 2020; 22 June; virtual meeting II.
- Cristofanilli M, et al. Eur J Cancer 2018;104:21–31.
- Al-Sukhun S, et al. Curr Breast Cancer Rep 2016;8:73−79.
- Saal L, et al. Cancer Res 2005;65(7):2554−2559.
- Dirican E, et al. Tumour Biol 2016;37(6):7033−7045.
- PIQRAY® (alpelisib) Summary of Product Characteristics. Novartis Pharma; 2020.
- Dumont A, et al. Chin J Cancer 2012;31(7):327−334.
- Juric D, et al. GS3-08. Presented at SABCS 2018; 4−8 December 2018; San Antonio, Texas, USA.
- Qin H, et al. Peer J 2018;6:e5092.
- Thorpe LM, et al. Nat Rev Cancer 2015;15(1):7–24.
- Fruman DA, Rommel C. Nat Rev Discov 2014;13(2)140−156.
- Miller TW, et al. J Clin Invest 2010;120(7):2406−2413.
- PIQRAY® (alpelisib) Core Data Sheet: Version 1.0. Novartis Pharma AG; November 2018.
- Goncalves M, et al. N Engl J Med 2018;379(21):2052−2062.
- Croessmann S, et al. Clin Cancer Res 2018;24(6):1426−1435.
- Faslodex® (fulvestrant) Summary of Product Characteristics. AstraZeneca UK Limited; November 2019.
- Mayer IA, et al. Clin Cancer Res 2017;23(1):26−34.