PIK3CA mutation inhibition in hormone receptor-positive breast cancer: time has come

Abstract

The phosphatidylinositol-3-kinase (PI3K) pathway is mutated and aberrantly activated in breast and other cancers and plays a key role in cancer cell proliferation and survival.1.Engelman J.A. Targeting PI3K signalling in cancer: opportunities, challenges and limitations.Nat Rev Cancer. 2009; 9: 550-562doi:10.1038/nrc2664Crossref PubMed Scopus (1974) Google Scholar, 2.Cantley L.C. The phosphoinositide 3-kinase pathway.http://www.ncbi.nlm.nih.gov/pubmed/12040186Science. 2002; 296: 1655-1657doi:10.1126/science.296.5573.1655Google Scholar The PI3K pathway is deregulated through a variety of mechanisms, including mutation or amplification of PI3K, loss or inactivation of the tumour suppressor phosphatase and tensin homolog deleted on chromosome 10 (PTEN), as well as activation of tyrosine kinase growth factor receptors or oncogenes upstream of PI3K.3.Yang J. Nie J. Ma X. et al.Targeting PI3K in cancer: mechanisms and advances in clinical trials.http://www.ncbi.nlm.nih.gov/pubmed/30782187Mol Cancer. 2019; 18 (26)doi:10.1186/s12943-019-0954-xGoogle Scholar, 4.Hanker A.B. Kaklamani V. Arteaga C.L. Challenges for the clinical development of PI3K inhibitors: strategies to improve their impact in solid tumors.http://www.ncbi.nlm.nih.gov/pubmed/30867161Cancer Discov. 2019; 9: 482-491doi:10.1158/2159-8290.CD-18-1175Google Scholar Activating mutations in PIK3CA, the gene encoding the alpha isoform (p110 α) catalytic subunit of PI3K, is present in up to 40% of patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancers5.Mollon L.E. Anderson E.J. Dean J.L. et al.A Systematic Literature Review of the Prognostic and Predictive Value of PIK3CA Mutations in HR+/HER2- Metastatic Breast Cancer.http://www.ncbi.nlm.nih.gov/pubmed/32234362Clin Breast Cancer. 2020; 20: e232-e243doi:10.1016/j.clbc.2019.08.011Google Scholar, 6.Mosele F. Stefanovska B. Lusque A. et al.Outcome and molecular landscape of patients with PIK3CA-mutated metastatic breast cancer.http://www.ncbi.nlm.nih.gov/pubmed/32067679Ann Oncol. 2020; 31: 377-386doi:10.1016/j.annonc.2019.11.006Google Scholar and represents a molecular target to personalise therapy of selected patients with breast cancer.2.Cantley L.C. The phosphoinositide 3-kinase pathway.http://www.ncbi.nlm.nih.gov/pubmed/12040186Science. 2002; 296: 1655-1657doi:10.1126/science.296.5573.1655Google Scholar Standard of care therapy for advanced HR-positive/HER2-negative breast cancers consists on endocrine therapy with or without the use of cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors.7.Cardoso F. Senkus E. Costa A. et al.4th ESO-ESMO International Consensus Guidelines for Advanced Breast Cancer (ABC 4)†.http://www.ncbi.nlm.nih.gov/pubmed/30032243Ann Oncol. 2018; 29: 1634-1657doi:10.1093/annonc/mdy192Google Scholar Therapy-resistance inevitably occurs in the majority of patients. The rationale of combining PI3K inhibitors and endocrine therapy is to synergistically inhibit both the PI3K and ER pathways.8.Vasan N. Toska E. Scaltriti M. Overview of the relevance of PI3K pathway in HR-positive breast cancer.Ann. Oncol. 2019; : 30:x3-x11Google Scholar Initial trials of pan-PI3K inhibitors plus endocrine therapy for patients with advanced breast cancer showed modest benefit with high rates of toxicity limiting their clinical drug development.9.Baselga J. Im S.-A. Iwata H. et al.Buparlisib plus fulvestrant versus placebo plus fulvestrant in postmenopausal, hormone receptor-positive, HER2-negative, advanced breast cancer (BELLE-2): a randomised, double-blind, placebo-controlled, phase 3 trial.http://www.ncbi.nlm.nih.gov/pubmed/28576675Lancet Oncol. 2017; 18: 904-916doi:10.1016/S1470-2045(17)30376-5Google Scholar, 10.Baselga J. Cortés J. DeLaurentiis M. et al.SANDPIPER: Phase III study of the PI3-kinase (PI3K) inhibitor taselisib (GDC-0032) plus fulvestrant in patients (pts) with estrogen receptor (ER)-positive, HER2-negative locally advanced or metastatic breast cancer (BC) enriched for pts with PIK3CA- mutant tumors.JCO. 2017; 35 (TPS1119)doi:10.1200/JCO.2017.35.15_suppl.TPS1119Google Scholar, 11.Di Leo A. Johnston S. Lee K.S. et al.Buparlisib plus fulvestrant in postmenopausal women with hormone-receptor-positive, HER2-negative, advanced breast cancer progressing on or after mTOR inhibition (BELLE-3): a randomised, double-blind, placebo-controlled, phase 3 trial.Lancet Oncol. 2018; 19: 87-100doi:10.1016/S1470-2045(17)30688-5Abstract Full Text Full Text PDF PubMed Scopus (259) Google Scholar Selective isoform-specific PI3K inhibitors, such as an α-specific PI3K inhibitor, have subsequently revealed activity with less toxicity.12.Mayer I.A. Abramson V.G. Formisano L. et al.A phase Ib study of Alpelisib (BYL719), a PI3Ka-Specific inhibitor, with letrozole in ERþ/HER2 metastatic breast cancer.Clin. Cancer Res. 2017; Crossref Scopus (214) Google Scholar, 13.Juric D. Janku F. Rodón J. et al.Alpelisib plus fulvestrant in PIK3CA-Altered and PIK3CA-Wild-Type estrogen receptor-positive advanced breast cancer: a phase 1B clinical trial.http://www.ncbi.nlm.nih.gov/pubmed/30543347JAMA Oncol. 2019; 5: e184475doi:10.1001/jamaoncol.2018.4475Google Scholar The phase III SOLAR-1 (Clinical Studies of Alpelisib in Breast Cancer 1) trial investigated the efficacy and safety of alpelisib, a α-specific class-I PI3Kinhibitor, plus fulvestrant versus placebo plus fulvestrant in patients with metastatic HR-positive/HER2-negative breast cancer who had received endocrine therapy beforehand.14.André F. Ciruelos E. Rubovszky G. et al.Alpelisib for PIK3CA-mutated, hormone receptor-positive advanced breast Cancer.http://www.ncbi.nlm.nih.gov/pubmed/31091374N Engl J Med. 2019; 380: 1929-1940doi:10.1056/NEJMoa1813904Google Scholar About 85.6% of patients had endocrine-resistance disease. Alpelisib plus fulvestrant met its the primary endpoint by significantly extending progression-free survival (PFS) versus placebo plus fulvestrant in the 341 patients of PIK3CA-mutant cohort at a median duration of follow-up of 20 months (HR 0.65; 95% CI 0.50 to 0.85; p=0.00065; median 11.0 vs 5.7 months). Overall response (26.6 vs 12.8%) and clinical benefit (61.5 vs 45.3%) also favoured alpelisib plus fulvestrant arm. Response rates in the mutation cohort with measurable disease were doubled (35.7% vs 16.2%; p=0.0002). In contrast, in the PIK3CA wild type cohort (n=231), alpelisib only modestly extended PFS (7.4 vs 5.6 months; HR 0.85; 95% CI 0.58 to 1.25). The most frequent adverse events in the alpelisib arm were increased incidences of hyperglycaemia, an on-target effect related with the activity of alpelisib and diarrhoea, nausea and rash compared with the placebo arm.14.André F. Ciruelos E. Rubovszky G. et al.Alpelisib for PIK3CA-mutated, hormone receptor-positive advanced breast Cancer.http://www.ncbi.nlm.nih.gov/pubmed/31091374N Engl J Med. 2019; 380: 1929-1940doi:10.1056/NEJMoa1813904Google Scholar In a subgroup analyses from the SOLAR-1 trial,15.Juric D. Ciruelos E. Rubovszky G. et al.Abstract GS3-08: Alpelisib + fulvestrant for advanced breast cancer: subgroup analyses from the phase III SOLAR-1 trial.Gen Sess Abstr American Association for Cancer Research. 2019; : :GS3-08-3Google Scholar a statistically significant benefit in PFS was also observed for alpelisib in patients with PIK3CA-mutant detected in the plasma cell-free tumour DNA (ctDNA), assessed as liquid biopsy (10.9 vs 3.6 months; HR 0.55; 95% CI 0.39 to 0.79; p=0.0005).15.Juric D. Ciruelos E. Rubovszky G. et al.Abstract GS3-08: Alpelisib + fulvestrant for advanced breast cancer: subgroup analyses from the phase III SOLAR-1 trial.Gen Sess Abstr American Association for Cancer Research. 2019; : :GS3-08-3Google Scholar, 16.De Mattos-Arruda L. Weigelt B. Cortes J. et al.Capturing intra-tumor genetic heterogeneity by de novo mutation profiling of circulating cell-free tumor DNA: a proof-of-principle.http://www.ncbi.nlm.nih.gov/pubmed/25009010Ann Oncol. 2014; 25: 1729-1735doi:10.1093/annonc/mdu239Google Scholar, 17.De Mattos-Arruda L. Caldas C. Cell-Free circulating tumour DNA as a liquid biopsy in breast cancer.http://www.ncbi.nlm.nih.gov/pubmed/26776681Mol Oncol. 2016; 10: 464-474doi:10.1016/j.molonc.2015.12.001Google Scholar The benefit of administering alpelisib was consistent across patient’s subgroups, including patients that had previously received neoadjuvant and adjuvant therapies, those receiving second-line therapy and patients that had less than three metastatic sites affected. These data suggest that PIK3CA mutations are relevant therapeutic targets in advanced or metastatic HR-positive/HER2-negative breast cancers with PI3K pathway dependence. On 28 May 2020, the European Medicine Agency granted marketing authorisation for alpelisib in combination with fulvestrant for the treatment of postmenopausal women and men, with HR-positive/HER2-negative, locally advanced or metastatic breast cancer with a PIK3CA mutation after disease progression following endocrine therapy as monotherapy. The approval of alpelisib in combination with fulvestrant for PIK3CA-mutant endocrine resistant patients with breast cancer is an important step towards Precision Medicine. However, this progress comes with a few challenges. First, the SOLAR-1 trial enrolled very few patients pretreated with the current first-line standard therapy—a small number of PIK3CA-mutant HR-positive/HER2-negative patients received prior therapy with CDK4/6 inhibitors (5.9%, 20 patients).15.Juric D. Ciruelos E. Rubovszky G. et al.Abstract GS3-08: Alpelisib + fulvestrant for advanced breast cancer: subgroup analyses from the phase III SOLAR-1 trial.Gen Sess Abstr American Association for Cancer Research. 2019; : :GS3-08-3Google Scholar For patients who have PIK3CA -mutant disease and progress on a CDK4/6 inhibitor-based therapy, alpelisib plus fulvestrant is a treatment option, and there is emerging clinical data available.18.HSRugo, FFLerebours, ECiruelos, et al. Alpelisib (ALP) + fulvestrant (FUL) in patients (PTS) with PIK3CA-mutated (mut) hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) advanced breast cancer (ABC) previously treated with cyclin-dependent kinase 4/6 inhibitor (CDKi) + aromatase inhibitor (AI): BYLieve study results. presented at: 2020 ASCO virtual scientific program; may 29-31, 2020. Abstract 1006.Google Scholar In the phase 2, non-comparative, 3-cohort BYLieve trial (ClinicalTrials.gov number, NCT03056755,18.HSRugo, FFLerebours, ECiruelos, et al. Alpelisib (ALP) + fulvestrant (FUL) in patients (PTS) with PIK3CA-mutated (mut) hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) advanced breast cancer (ABC) previously treated with cyclin-dependent kinase 4/6 inhibitor (CDKi) + aromatase inhibitor (AI): BYLieve study results. presented at: 2020 ASCO virtual scientific program; may 29-31, 2020. Abstract 1006.Google Scholar alpelisib plus endocrine therapy (fulvestrant or letrozole) is administered to patients with advanced PIK3CA-mutant HR-positive/HER2-negative breast cancers whose disease progressed on or after CDK4/6 inhibitor plus endocrine therapy. The results of one of the three cohorts (cohort A) of the BYLieve trial, in which patients with prior CDK4/6 inhibitor plus aromatase inhibitor received alpelisib plus fulvestrant, showed that 50.4% of patients were alive without progressive disease at 6 months. Median PFS was 7.3 months.18.HSRugo, FFLerebours, ECiruelos, et al. Alpelisib (ALP) + fulvestrant (FUL) in patients (PTS) with PIK3CA-mutated (mut) hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) advanced breast cancer (ABC) previously treated with cyclin-dependent kinase 4/6 inhibitor (CDKi) + aromatase inhibitor (AI): BYLieve study results. presented at: 2020 ASCO virtual scientific program; may 29-31, 2020. Abstract 1006.Google Scholar In addition, although the SOLAR-1 is a well-designed study, it does not answer a question that arises in the real life: would fulvestrant single agent be the choice as second-line endocrine therapy, knowing the efficacy of endocrine therapy plus everolimus, that works regardless of PIK3CA status? Fulvestrant plus alpelisib versus fulvestrant plus everolimus is yet to be compared. Second, the source of genetic material (tumour tissue and/or plasma ctDNA) and the technology for profiling PIK3CA mutation is undefined yet. The SOLAR-1 and BYLieve trials14.André F. Ciruelos E. Rubovszky G. et al.Alpelisib for PIK3CA-mutated, hormone receptor-positive advanced breast Cancer.http://www.ncbi.nlm.nih.gov/pubmed/31091374N Engl J Med. 2019; 380: 1929-1940doi:10.1056/NEJMoa1813904Google Scholar, 18.HSRugo, FFLerebours, ECiruelos, et al. Alpelisib (ALP) + fulvestrant (FUL) in patients (PTS) with PIK3CA-mutated (mut) hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) advanced breast cancer (ABC) previously treated with cyclin-dependent kinase 4/6 inhibitor (CDKi) + aromatase inhibitor (AI): BYLieve study results. presented at: 2020 ASCO virtual scientific program; may 29-31, 2020. Abstract 1006.Google Scholar profiled PIK3CA gene by polymerase-chain-reaction analysis of mutation hotspots in exons 7, 9 and 20. Patients could be profiled and selected for therapy if presented a PIK3CA mutation in tumour tissue specimens14.André F. Ciruelos E. Rubovszky G. et al.Alpelisib for PIK3CA-mutated, hormone receptor-positive advanced breast Cancer.http://www.ncbi.nlm.nih.gov/pubmed/31091374N Engl J Med. 2019; 380: 1929-1940doi:10.1056/NEJMoa1813904Google Scholar, 18.HSRugo, FFLerebours, ECiruelos, et al. Alpelisib (ALP) + fulvestrant (FUL) in patients (PTS) with PIK3CA-mutated (mut) hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) advanced breast cancer (ABC) previously treated with cyclin-dependent kinase 4/6 inhibitor (CDKi) + aromatase inhibitor (AI): BYLieve study results. presented at: 2020 ASCO virtual scientific program; may 29-31, 2020. Abstract 1006.Google Scholar and/or in ctDNA isolated from plasma specimens.15.Juric D. Ciruelos E. Rubovszky G. et al.Abstract GS3-08: Alpelisib + fulvestrant for advanced breast cancer: subgroup analyses from the phase III SOLAR-1 trial.Gen Sess Abstr American Association for Cancer Research. 2019; : :GS3-08-3Google Scholar The use of a liquid biopsy would be adequate to select patients for therapy. A liquid biopsy has the advantage of being a non-invasive, rapid, real-time assay and can be used to profile and serially monitor breast cancer patient’s progress.16.De Mattos-Arruda L. Weigelt B. Cortes J. et al.Capturing intra-tumor genetic heterogeneity by de novo mutation profiling of circulating cell-free tumor DNA: a proof-of-principle.http://www.ncbi.nlm.nih.gov/pubmed/25009010Ann Oncol. 2014; 25: 1729-1735doi:10.1093/annonc/mdu239Google Scholar, 19.Bettegowda C. Sausen M. Leary R.J. et al.Detection of circulating tumor DNA in early- and late-stage human malignancies.http://www.ncbi.nlm.nih.gov/pubmed/24553385Sci Transl Med. 2014; 6 (224ra24-224ra24)doi:10.1126/scitranslmed.3007094Google Scholar It may reveal each patient with breast cancer repertoire of mutations as an up-to-the-minute tool, reflecting the disease status and heterogeneity.20.De Mattos-Arruda L. Sammut S.-J. Ross E.M. et al.The genomic and immune landscapes of lethal metastatic breast cancer.http://www.ncbi.nlm.nih.gov/pubmed/31141692Cell Rep. 2019; 27: 2690-2708doi:10.1016/j.celrep.2019.04.098Google Scholar In addition, it may broaden the number of targetable biomarkers that can be used to develop a personalised therapeutic approach for each patient. Third, there is a number of single gene tests and multigene panels that differ across companies and academic institutions.21.Zehir A. Benayed R. Shah R.H. et al.Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients.Nat Med. 2017; 23: 703-713doi:10.1038/nm.4333Crossref PubMed Scopus (1814) Google Scholar, 22.Blakely C.M. Watkins T.B.K. Wu W. et al.Evolution and clinical impact of co-occurring genetic alterations in advanced-stage EGFR-mutant lung cancers.Nat Genet. 2017; 49: 1693-1704doi:10.1038/ng.3990Crossref PubMed Scopus (323) Google Scholar The best strategy is not standardised yet. Currently, next-generation DNA sequencing technology offers simultaneous testing for multiple genes, which has pros and cons in terms of turnaround time and possibility to detect PIK3CA and other concomitant mutations that could be associated with either increased sensitivity23.Vasan N. Razavi P. Johnson J.L. et al.Double PIK3CA mutations in cis increase oncogenicity and sensitivity to PI3Kα inhibitors.http://www.ncbi.nlm.nih.gov/pubmed/31699932Science. 2019; 366: 714-723doi:10.1126/science.aaw9032Google Scholar or resistance to PI3Kα inhibitors.12.Mayer I.A. Abramson V.G. Formisano L. et al.A phase Ib study of Alpelisib (BYL719), a PI3Ka-Specific inhibitor, with letrozole in ERþ/HER2 metastatic breast cancer.Clin. Cancer Res. 2017; Crossref Scopus (214) Google Scholar, 24.Janku F. Wheler J.J. Westin S.N. et al.Pi3K/Akt/mTOR inhibitors in patients with breast and gynecologic malignancies harboring PIK3CA mutations.http://www.ncbi.nlm.nih.gov/pubmed/22271473J Clin Oncol. 2012; 30: 777-782doi:10.1200/JCO.2011.36.1196Google Scholar, 25.Avivar-Valderas A. McEwen R. Taheri-Ghahfarokhi A. et al.Functional significance of co-occurring mutations in PIK3CA and MAP3K1 in breast cancer.http://www.ncbi.nlm.nih.gov/pubmed/29765551Oncotarget. 2018; 9: 21444-21458doi:10.18632/oncotarget.25118Google Scholar Double PIK3CA mutations in cis (ie, on the same allele) than single mutations have shown increased sensitivity to PI3Kα inhibitors.23.Vasan N. Razavi P. Johnson J.L. et al.Double PIK3CA mutations in cis increase oncogenicity and sensitivity to PI3Kα inhibitors.http://www.ncbi.nlm.nih.gov/pubmed/31699932Science. 2019; 366: 714-723doi:10.1126/science.aaw9032Google Scholar The hotspot mutation PIK3CA H1047R seemed to be associated with higher clinical benefit from alpelisib compared with helical domain mutations in a phase 1 trial, a finding not confirmed in other studies.12.Mayer I.A. Abramson V.G. Formisano L. et al.A phase Ib study of Alpelisib (BYL719), a PI3Ka-Specific inhibitor, with letrozole in ERþ/HER2 metastatic breast cancer.Clin. Cancer Res. 2017; Crossref Scopus (214) Google Scholar Patients with PIK3CA mutations and concomitant alterations in TP53, KRAS or FGFR1 did not benefit from alpelisib.12.Mayer I.A. Abramson V.G. Formisano L. et al.A phase Ib study of Alpelisib (BYL719), a PI3Ka-Specific inhibitor, with letrozole in ERþ/HER2 metastatic breast cancer.Clin. Cancer Res. 2017; Crossref Scopus (214) Google Scholar Concomitant mutations in the mitogen activated protein kinase pathway may mediate therapy resistance in patients having PIK3CA mutation.6.Mosele F. Stefanovska B. Lusque A. et al.Outcome and molecular landscape of patients with PIK3CA-mutated metastatic breast cancer.http://www.ncbi.nlm.nih.gov/pubmed/32067679Ann Oncol. 2020; 31: 377-386doi:10.1016/j.annonc.2019.11.006Google Scholar, 24.Janku F. Wheler J.J. Westin S.N. et al.Pi3K/Akt/mTOR inhibitors in patients with breast and gynecologic malignancies harboring PIK3CA mutations.http://www.ncbi.nlm.nih.gov/pubmed/22271473J Clin Oncol. 2012; 30: 777-782doi:10.1200/JCO.2011.36.1196Google Scholar In conclusion, PIK3CA mutations represent a target to guide therapy in endocrine resistance HR-positive/HER2-negative breast cancer. The role of administering alpelisib after CDK4/6 inhibitor-based therapy should be consolidated. Patients could take advantage of a liquid biopsy to uncover PIK3CA mutation for alpelisib eligibility if they are unfit or are otherwise unable to provide a tumour specimen. Although some PIK3CA-mutant patients derived prolonged clinical benefit with α-specific class-I PI3Kinhibitor, not all patients with PIK3CA mutations have similar benefit from PI3K inhibitors. Also, a small fraction of patients without PIK3CA hotspot mutations respond to PI3K inhibitors. Clinical trials are ongoing to evaluate new combinations of PI3K-targeted agents as well the role of other genomic alterations (eg, PIK3CA amplifications, PIK3R1 mutations) to better select and monitor patients under therapy.3.Yang J. Nie J. Ma X. et al.Targeting PI3K in cancer: mechanisms and advances in clinical trials.http://www.ncbi.nlm.nih.gov/pubmed/30782187Mol Cancer. 2019; 18 (26)doi:10.1186/s12943-019-0954-xGoogle Scholar, 26.Miled N. Yan Y. Hon W.-C. et al.Mechanism of two classes of cancer mutations in the phosphoinositide 3-kinase catalytic subunit.http://www.ncbi.nlm.nih.gov/pubmed/17626883Science. 2007; 317: 239-242doi:10.1126/science.1135394Google Scholar, 27.Sun M. Hillmann P. Hofmann B.T. et al.Cancer-Derived mutations in the regulatory subunit p85alpha of phosphoinositide 3-kinase function through the catalytic subunit p110alpha.http://www.ncbi.nlm.nih.gov/pubmed/20713702Proc Natl Acad Sci U S A. 2010; 107: 15547-15552doi:10.1073/pnas.1009652107Google Scholar Biomarkers of secondary resistance to PI3Kα inhibitors are should also be identified. The author is grateful to Dr Miguel Martin for critically reading this manuscript.