buparlisib and Breast-Neoplasms

The phosphatidylinositol 3-kinase (PI3K) signaling pathway is a promising treatment target for patients with breast cancer (BC). Our study aimed to evaluate the most effective and safe PI3K inhibitor for patients with BC, especially in PIK3CA mutation.. Electronics databases were systematically searched from their inception to June 2020 for published randomized controlled trials (RCTs) comparing PI3K inhibitor therapy versus non-PI3K inhibitor therapy in patients with BC that mentioned or reported data of PIK3CA-mutated patient subgroups. Eligible RCTs had to report at least one of the following clinical outcomes: objective response rate (ORR), progression-free survival (PFS), or adverse events (AE).. Nine eligible RCTs involving 3872 BC patients and four PI3K inhibitor therapy arms (i.e., alpelisib, buparlisib, pictilisib, and taselisib) were included. In evaluating ORR, beneficial significant results of PI3K inhibitors could be found in the PIK3CA mutated group (1.952, 1.012 to 3.766); analogous results could also be found in 6m-PFS (1.519, 1.144 to 2.018) and PFS from HR data (-0.346, -0.525 to -0.168). From pairwise and network meta-analyses, buparlisib showed the most favorable ORR, as it was significantly different from fulvestrant in the PIK3CA-mutated patient group (2.80, 1.56 to 5.03). Alpelisib ranked first in the assessment of 6m-PFS and was significantly different from fulvestrant in the PIK3CA-mutated group (2.33, 1.45 to 3.44). The above PI3K inhibitors had good safety with few serious AEs. PROSPERO registration CRD42020193932.. The PI3K inhibitors alpelisib and buparlisib appear to have superior efficacy and safety therapeutic choices for patients with BC, especially in PIK3CA-mutated patients.

Topics: Aminopyridines; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Class I Phosphatidylinositol 3-Kinases; Clinical Trials as Topic; Female; Humans; Morpholines; Mutation; Network Meta-Analysis; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Progression-Free Survival; Signal Transduction; Thiazoles; Treatment Outcome

The efficacy of neoadjuvant buparlisib for breast cancer remains controversial. We conduct a systematic review and meta-analysis to explore the influence of neoadjuvant buparlisib versus placebo for breast cancer.. We search PubMed, EMbase, Web of science, EBSCO, and Cochrane library databases through May 2019 for randomized controlled trials (RCTs) assessing the efficacy and safety of neoadjuvant buparlisib versus placebo for breast cancer. This meta-analysis is performed using the random-effect model.. Four RCTs are included in the meta-analysis. Overall, compared with control group for breast cancer, neoadjuvant buparlisib can substantially reduce progressive disease (risk ratios [RR] = 0.66; 95% confidence interval [CI] = 0.52-0.82; P = .0003) and improve stable disease (RR = 1.29; 95% CI = 1.02-1.64; P = .04), but has no notable influence on overall response rate (RR = 1.32; 95% CI = 0.84-2.06; P = .22), clinical benefit rate (RR = 1.06; 95% CI = 0.79-1.43; P = .69). Neoadjuvant buparlisib results in the increase in adverse grade 3/4 adverse events including increased alanine aminotransferase (ALT) (RR = 11.87; 95% CI = 5.65-24.90; P < .00001), increased aspartate aminotransferase (AST) (RR = 6.50; 95% CI = 4.14-10.21; P < .00001) and hyperglycaemia (RR = 36.65; 95% CI = 10.44-128.68; P < .00001), as well as serious adverse events (RR = 1.47; 95% CI = 1.23-1.76; P < .0001) compared to placebo. Deaths is found to be similar between two groups (RR = 0.88; 95% CI = 0.75-1.04; P = .13).. Neoadjuvant buparlisib may provide some efficacy for breast cancer, but leads to the increase in serious adverse events.

Topics: Aminopyridines; Breast Neoplasms; Humans; Morpholines; Neoadjuvant Therapy; Phosphoinositide-3 Kinase Inhibitors; Randomized Controlled Trials as Topic; Receptor, ErbB-2

Endocrine resistance remains a challenge and an unmet need for managing hormone receptor-positive breast cancer. The mechanisms of endocrine resistance are multifaceted and are likely to evolve over time following various single or combination therapies. The purpose of this review article is to provide general understanding of molecular basis of endocrine resistance of breast cancer and to offer comprehensive review on current treatment options and potential new treatment strategies for endocrine resistant breast cancers. Last but not the least, we discuss current challenges and future directions for management of endocrine resistant breast cancers.

Topics: Aminopyridines; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Breast Neoplasms; Drug Resistance, Neoplasm; ErbB Receptors; Estradiol; Everolimus; Female; Fulvestrant; Gene Expression Regulation, Neoplastic; Humans; Mitogen-Activated Protein Kinases; Molecular Targeted Therapy; Morpholines; Piperazines; Pyridines; Receptor, ErbB-2; Receptors, Estrogen; Signal Transduction

Aberrations in the PI3K signaling pathway are frequently observed in patients with breast cancer. Because of that, PI3K inhibitors are attractive options for the treatment of breast cancer because PI3K is the most proximal component of the pathway other than receptor tyrosine kinases. Buparlisib is a potent and highly specific oral pan-class I PI3K inhibitor, which is currently under investigation in patients with breast cancer. In this article, we describe the PI3K signaling pathway, the prognostic value of PI3K pathway mutations, as well as the mechanism of action of buparlisib. Lastly, we discuss preliminary results of preclinical and clinical studies showing the efficacy and safety profile of this agent in breast cancer patients.

Topics: Aminopyridines; Animals; Antineoplastic Agents; Breast Neoplasms; Female; Humans; Mice; Molecular Targeted Therapy; Morpholines; Phosphatidylinositol 3-Kinases; Signal Transduction

Deregulation of the phosphatidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) intracellular signaling pathway is common in breast cancer (BC) and has been found to be potentially implicated in resistance to endocrine and anti-HER2 therapies. Targeting the PI3K/Akt/mTOR pathway may remove this inhibition and restore sensitivity to these compounds. Buparlisib (BKM120) is a potent oral pan-class I PI3K inhibitor that is being extensively evaluated in multiple tumor types.. This review briefly summarizes the pharmacodynamics and pharmacokinetics of buparlisib, focusing on preclinical and clinical data in BC and on ongoing randomized trials.. Overall, buparlisib is a safe and tolerable drug and, despite its peculiar toxicity profile, it is suitable for studies in combination with other anticancer agents in BC. Early-phase clinical trials in BC have provided evidence of antitumor activity. Several trials are being conducted in all the biological subsets of BC, including combinations with endocrine therapy, anti-HER2 agents, PARP-inhibitors and chemotherapy. While clinical results are eagerly awaited, biological material suitable for both genomic and non-genomic analyses is being collected. The authors expect an intense investigation of the potential biomarkers that explain response or resistance to buparlisib and inspire strategies to rationally explore the therapeutic potential of this drug.

Topics: Aminopyridines; Animals; Antineoplastic Agents; Breast Neoplasms; Drug Resistance, Neoplasm; Female; Humans; Molecular Targeted Therapy; Morpholines; Phosphoinositide-3 Kinase Inhibitors; Signal Transduction

Buparlisib (formerly BKM 120), an oral 2,6-dimorpholino pyrimidine derivative is a potent pan-PI3K inhibitor causing inhibition of PI3K downstream signaling including downregulation of p-Akt and p-S6R and apoptosis of cancer cells. Buparlisib is rapidly absorbed, has more than 90% bioavailability, good blood-brain barrier penetration and half-life of 40 h. Phase I trials have shown good disease control rate with tolerable toxicity profile at the recommended doses of 100 mg. The most common adverse events noted with buparlisib are rash, hyperglycemia, derangement of liver functions and psychiatric events. Several clinical trials with buparlisib alone or in combination with chemotherapy and targeted therapies are underway. Buparlisib has not yet been approved for regular use. Further randomized trials are required before buparlisib is approved for treatment of breast cancer.

Topics: Aminopyridines; Animals; Antineoplastic Agents; Breast Neoplasms; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Drug Evaluation, Preclinical; Female; Humans; Morpholines; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Signal Transduction; TOR Serine-Threonine Kinases; Treatment Outcome

Buparlisib is an oral pan-class I phosphotidyinositol-3-kinase (PI3K) inhibitor. The present phase I study evaluated the safety, pharmacokinetics, and efficacy of buparlisib with capecitabine in patients with metastatic breast cancer.. Patients received buparlisib once daily (range, 50 to 100 mg) for 3 weeks with capecitabine twice daily (range, 1000 to 1250 mg/m. Of the 25 patients enrolled, 23 were evaluable for DLT and 17 were evaluable for response. The maximum tolerated dose of the combination was buparlisib 100 mg daily and capecitabine 1000 mg/m. The combination of buparlisib with capecitabine in patients with metastatic breast cancer was generally well-tolerated, with several patients demonstrating prolonged responses. Unexpectedly low rates of PIK3CA mutations (3 of 17) were seen, and only 2 of 7 tumors with subtyping were luminal, making exploration of these putative predictive markers impossible. Further study of the combination is not unreasonable, with expanded pharmacokinetics and sequencing analysis to better elucidate potential drug-drug interactions and more accurate predictive biomarkers of response.

Topics: Adult; Aminopyridines; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Capecitabine; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Maximum Tolerated Dose; Middle Aged; Morpholines; Mutation; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Protein Kinase Inhibitors; Treatment Outcome

A Phase Ib study in patients with trastuzumab-resistant, human epidermal growth factor receptor-2- (HER2)-positive advanced breast cancer defined the recommended Phase II dose of buparlisib as 100 mg/day in combination with 2 mg/kg weekly trastuzumab, and reported preliminary signs of clinical activity. Here we present results from the Phase II portion.. Patients with trastuzumab-resistant, HER2-positive advanced breast cancer received buparlisib plus trastuzumab. Study endpoints included safety/tolerability and antitumour activity. The study was extended to include a Phase Ib dose-escalation phase, in which patients with progressive brain metastases also received capecitabine.. In the Phase II portion, of 50 patients treated with buparlisib and trastuzumab, the most common (≥ 30%) all-grade adverse events (AEs) were diarrhoea (54%), nausea (48%), decreased appetite, increased alanine aminotransferase (36% each), increased aspartate aminotransferase (34%), fatigue, rash (32% each), cough and hyperglycemia (30% each). One (2%) patient achieved complete response and four (8%) patients had confirmed partial responses [PR; including two patients with phosphatidylinositol 3-kinase (PI3 K) pathway-activated tumours]. Overall response rate (ORR) was 10%: the primary endpoint (ORR ≥ 25%) was therefore not met. In the Phase Ib portion, all patients with measurable brain lesions at baseline showed tumour shrinkage to some degree; due to low enrollment, maximum tolerated dose of buparlisib in combination with trastuzumab and capecitabine was not determined.. Buparlisib plus trastuzumab, as a chemotherapy-free regimen, demonstrated an acceptable safety profile but limited efficacy in patients with heavily pretreated, trastuzumab-resistant HER2-positive breast cancer, and in patients with progressive brain metastases also receiving capecitabine.

Topics: Adult; Aged; Aminopyridines; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Brain Neoplasms; Breast Neoplasms; Capecitabine; Disease Progression; Drug Resistance, Neoplasm; Female; Humans; Maximum Tolerated Dose; Middle Aged; Morpholines; Receptor, ErbB-2; Response Evaluation Criteria in Solid Tumors; Trastuzumab

Activation of the PI3K/AKT/mTOR pathway occurs frequently in breast cancer that is resistant to endocrine therapy. Approved mTOR inhibitors effectively inhibit cell growth and proliferation but elicit AKT phosphorylation via a feedback activation pathway, potentially leading to resistance to mTOR inhibitors. We evaluated the efficacy and safety of buparlisib plus fulvestrant in patients with advanced breast cancer who were pretreated with endocrine therapy and mTOR inhibitors.. BELLE-3 was a randomised, double-blind, placebo-controlled, multicentre, phase 3 study. Postmenopausal women aged 18 years or older with histologically or cytologically confirmed hormone-receptor-positive, HER2-negative, locally advanced or metastatic breast cancer, who had relapsed on or after endocrine therapy and mTOR inhibitors, were recruited from 200 trial centres in 22 countries. Eligible patients were randomly assigned (2:1) via interactive response technology (block size of six) to receive oral buparlisib (100 mg per day) or matching placebo starting on day 1 of cycle 1, plus intramuscular fulvestrant (500 mg) on days 1 and 15 of cycle 1 and on day 1 of subsequent 28-day cycles. Randomisation was stratified by visceral disease status. The primary endpoint was progression-free survival by local investigator assessment as per the Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1 in the full analysis population (all randomised patients, by intention-to-treat). Safety was analysed in all patients who received at least one dose of treatment and at least one post-baseline safety assessment. This study is registered with ClinicalTrials.gov, number NCT01633060, and is ongoing but no longer enrolling patients.. Between Jan 15, 2013, and March 31, 2016, 432 patients were randomly assigned to the buparlisib (n=289) or placebo (n=143) groups. Median progression-free survival was significantly longer in the buparlisib versus placebo group (3·9 months [95% CI 2·8-4·2] vs 1·8 months [1·5-2·8]; hazard ratio [HR] 0·67, 95% CI 0·53-0·84, one-sided p=0·00030). The most frequent grade 3-4 adverse events in the buparlisib versus placebo group were elevated alanine aminotransferase (63 [22%] of 288 patients vs four [3%] of 140), elevated aspartate aminotransferase (51 [18%] vs four [3%]), hyperglycaemia (35 [12%] vs none), hypertension (16 [6%] vs six [4%]), and fatigue (ten [3%] vs two [1%]). Serious adverse events were reported in 64 (22%) of 288 patients in the buparlisib group versus 23 (16%) of 140 in the placebo group; the most frequent serious adverse events (affecting ≥2% of patients) were elevated aspartate aminotransferase (six [2%] vs none), dyspnoea (six [2%] vs one [1%]), and pleural effusion (six [2%] vs none). On-treatment deaths occurred in ten (3%) of 288 patients in the buparlisib group and in six (4%) of 140 in the placebo group; most deaths were due to metastatic breast cancer, and two were considered treatment-related (cardiac failure [n=1] in the buparlisib group and unknown reason [n=1] in the placebo group).. The safety profile of buparlisib plus fulvestrant does not support its further development in this setting. Nonetheless, the efficacy of buparlisib supports the rationale for the use of PI3K inhibitors plus endocrine therapy in patients with PIK3CA mutations.. Novartis Pharmaceuticals Corporation.

Topics: Aged; Aminopyridines; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Breast Neoplasms; Disease Progression; Disease-Free Survival; Double-Blind Method; Estradiol; Estrogen Receptor Antagonists; Female; Fulvestrant; Humans; Middle Aged; Morpholines; Phosphatidylinositol 3-Kinase; Phosphoinositide-3 Kinase Inhibitors; Protein Kinase Inhibitors; Receptor, ErbB-2; Receptors, Estrogen; Receptors, Progesterone; Time Factors; TOR Serine-Threonine Kinases; Treatment Outcome

Buparlisib, a pan-phosphatidylinositol 3-kinase (PI3K) inhibitor, plus fulvestrant in the BELLE-2 study significantly improved progression-free survival (PFS) in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer.. In this phase III study, patients were randomised 1:1 to buparlisib (100 mg/day; continuously in 28-day cycles) or placebo, plus fulvestrant (500 mg on cycle 1 day 15, and day 1 of subsequent cycles). Overall survival (OS) was assessed in the overall population and patients with known PI3K pathway status (both had shown significant PFS improvements). OS by PIK3CA status in circulating tumour DNA (ctDNA) was an exploratory end-point.. A total of 2025 patients were screened for eligibility between 7th September 2012 and 10th September 2014, and 1178 received fulvestrant (500 mg) during a run-in phase; 31 discontinued. Of 1147 patients (median age 62 years), 98% had the Eastern Cooperative Oncology Group performance status ≤1, and 59% had visceral disease. Median follow-up from randomisation to data cut-off (23rd December 2016) was 37.6 months. Median OS trended in favour of the buparlisib arm in the overall population (33.2 versus 30.4 months; P = 0.045) and among patients with known PI3K pathway status (30.9 versus 28.9 months; P = 0.144); neither outcome was statistically significant. Median OS also trended in favour of buparlisib among patients with PIK3CA-mutant ctDNA (26.0 versus 24.8 months). Grade III/IV adverse events with ≥10% difference between the buparlisib versus placebo arms were elevated alanine aminotransferase (26% versus 1%), elevated aspartate aminotransferase (18% versus 3%) and hyperglycemia (15% versus <1%).. OS results were in favour of buparlisib plus fulvestrant versus placebo plus fulvestrant; however, there is no statistical significance and more frequent grade III/IV adverse events were reported. Use of more selective PI3K inhibitors might provide the greatest clinical benefit and tolerable safety profile in this setting. Further evaluation of the predictive benefit of PIK3CA-mutant ctDNA is warranted.. NCT01610284.

Topics: Aminopyridines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Double-Blind Method; Female; Fulvestrant; Humans; Middle Aged; Morpholines; Postmenopause; Survival Analysis

Phosphatidylinositol 3-kinase (PI3K) pathway activation is a hallmark of endocrine therapy-resistant, hormone receptor-positive breast cancer. This phase 3 study assessed the efficacy of the pan-PI3K inhibitor buparlisib plus fulvestrant in patients with advanced breast cancer, including an evaluation of the PI3K pathway activation status as a biomarker for clinical benefit.. The BELLE-2 trial was a randomised, double-blind, placebo-controlled, multicentre study. Postmenopausal women aged 18 years or older with histologically confirmed, hormone receptor-positive and human epidermal growth factor (HER2)-negative inoperable locally advanced or metastatic breast cancer whose disease had progressed on or after aromatase inhibitor treatment and had received up to one previous line of chemotherapy for advanced disease were included. Eligible patients were randomly assigned (1:1) using interactive voice response technology (block size of 6) on day 15 of cycle 1 to receive oral buparlisib (100 mg/day) or matching placebo, starting on day 15 of cycle 1, plus intramuscular fulvestrant (500 mg) on days 1 and 15 of cycle 1, and on day 1 of subsequent 28-day cycles. Patients were assigned randomisation numbers with a validated interactive response technology; these numbers were linked to different treatment groups which in turn were linked to treatment numbers. PI3K status in tumour tissue was determined via central laboratory during a 14-day run-in phase. Randomisation was stratified by PI3K pathway activation status (activated vs non-activated vs and unknown) and visceral disease status (present vs absent). Patients, investigators, local radiologists, study team, and anyone involved in the study were masked to the identity of the treatment until unblinding. The primary endpoints were progression-free survival by local investigator assessment per Response Evaluation Criteria In Solid Tumors (version 1.1) in the total population, in patients with known (activated or non-activated) PI3K pathway status, and in PI3K pathway-activated patients. Efficacy analyses were done in the intention-to-treat population. Safety was analysed in all patients who received at least one dose of study drug and had at least one post-baseline safety assessment according to the treatment they received. This trial is registered with ClinicalTrials.gov, number NCT01610284, and is currently ongoing but not recruiting participants.. Between Sept 7, 2012, and Sept 10, 2014, 1147 patients from 267 centres in 29 countries were randomly assigned to receive buparlisib (n=576) or placebo plus fulvestrant (n=571). In the total patient population (n=1147), median progression-free survival was 6·9 months (95% CI 6·8-7·8) in the buparlisib group versus 5·0 months (4·0-5·2) in the placebo group (hazard ratio [HR] 0·78 [95% CI 0·67-0·89]; one-sided p=0·00021). In patients with known PI3K status (n=851), median progression-free survival was 6·8 months (95% CI 5·0-7·0) in the buparlisib group vs 4·5 months (3·3-5·0) in the placebo group (HR 0·80 [95% CI 0·68-0·94]; one-sided p=0·0033). In PI3K pathway-activated patients (n=372), median progression-free survival was 6·8 months (95% CI 4·9-7·1) in the buparlisib group versus 4·0 months (3·1-5·2) in the placebo group (HR 0·76 [0·60-0·97], one-sided p=0·014). The most common grade 3-4 adverse events in the buparlisib group versus the placebo group were increased alanine aminotransferase (146 [25%] of 573 patients vs six [1%] of 570), increased aspartate aminotransferase (103 [18%] vs 16 [3%]), hyperglycaemia (88 [15%] vs one [<1%]), and rash (45 [8%] vs none). Serious adverse events were reported in 134 (23%) of 573 patients in the buparlisib group compared with 90 [16%] of 570 patients in the placebo group; the most common serious adverse events (affecting ≥2% of patients) were increased alanine aminotransferase (17 [3%] of 573 vs one [<1%] of 570) and increased aspartate aminotransferase (14 [2%] vs one [<1%]). No treatment-related deaths occurred.. The results from this study show that PI3K inhibition combined with endocrine therapy is effective in postmenopausal women with endocrine-resistant, hormone receptor-positive and HER2-negative advanced breast cancer. Use of more selective PI3K inhibitors, such as α-specific PI3K inhibitor, is warranted to further improve safety and benefit in this setting. No further studies are being pursued because of the toxicity associated with this combination.. Novartis Pharmaceuticals Corporation.

Topics: Aged; Alanine Transaminase; Aminopyridines; Antineoplastic Combined Chemotherapy Protocols; Aspartate Aminotransferases; Biomarkers, Tumor; Breast Neoplasms; Class I Phosphatidylinositol 3-Kinases; Disease-Free Survival; DNA Mutational Analysis; DNA, Neoplasm; Double-Blind Method; Drug Eruptions; Estradiol; Exanthema; Female; Fulvestrant; Humans; Hyperglycemia; Middle Aged; Morpholines; Neoplasm Metastasis; Phosphatidylinositol 3-Kinases; Postmenopause; Receptor, ErbB-2; Receptors, Estrogen; Receptors, Progesterone; Response Evaluation Criteria in Solid Tumors; Retreatment; Signal Transduction; Survival Rate

The Neoadjuvant PI3K inhibition in HER2 OverExpressing Breast cancEr (NeoPHOEBE) trial evaluated the efficacy and safety of buparlisib, a pan-phosphatidylinositol 3-kinase (PI3K) inhibitor, plus trastuzumab and paclitaxel as neoadjuvant treatment for human epidermal growth factor receptor-2 positive (HER2+) breast cancer.. NeoPHOEBE was a neoadjuvant, phase II, randomised, double-blind study. Women with HER2+ breast cancer were randomised within two independent cohorts by PIK3CA mutation status and, in each cohort stratified by oestrogen receptor (ER) status to receive buparlisib or placebo plus trastuzumab (first 6 weeks) followed by buparlisib or placebo with trastuzumab and paclitaxel. Primary end-point was pathological complete response (pCR) rate; key secondary end-point was objective response rate (ORR) at 6 weeks. Exploratory end-points were evaluation of Ki67 levels and change in tumour infiltrating lymphocytes (TILs) in intermediate biopsies at day 15.. Addition of the pan-PI3K inhibitor buparlisib to taxane-trastuzumab-based therapy in HER2+ early breast cancer was not feasible. However, the higher ORR and Ki67 reduction in the ER+, HER2+ subgroup indicates a potential role for PI3K-targeted therapy in this setting and may warrant further investigation with better-tolerated second-generation PI3K inhibitors.. NCT01816594.

Topics: Adult; Aged; Aminopyridines; Antineoplastic Combined Chemotherapy Protocols; Australia; Biomarkers, Tumor; Biopsy; Breast Neoplasms; Chemical and Drug Induced Liver Injury; Chemotherapy, Adjuvant; Class I Phosphatidylinositol 3-Kinases; Double-Blind Method; Early Termination of Clinical Trials; Europe; Female; Humans; Ki-67 Antigen; Lymphocytes, Tumor-Infiltrating; Middle Aged; Morpholines; Mutation; Neoadjuvant Therapy; Paclitaxel; Protein Kinase Inhibitors; Receptor, ErbB-2; Time Factors; Trastuzumab; Treatment Outcome

Phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin pathway is frequently activated in HER2-positive breast cancer and may play a major role in resistance to trastuzumab. Buparlisib is a pan-class-I PI3K inhibitor with potent and selective activity against wild-type and mutant PI3K p110 isoforms.. PIKHER2 phase IB study aimed primarily to determine a maximum tolerated dose (MTD) and propose a recommended phase II dose (RP2D) for buparlisib in combination with lapatinib in HER2-positive, trastuzumab-resistant, advanced breast cancer. Oral buparlisib (40, 60 or 80 mg) and lapatinib (750, 1000 or 1250 mg) were administered daily. A modified continuous reassessment method using an adaptive Bayesian model guided the dose escalation of both agents. Secondary end-points included antitumour activity and pharmacokinetic (PK) assessments.. A total of 24 patients were treated across five dose levels. Dose-limiting toxicities included transaminases elevation, vomiting, stomatitis, hyperglycemia and diarrhoea. MTD was declared at buparlisib 80 mg/d + lapatinib 1250 mg/d, but toxicities and early treatment discontinuation rate beyond cycle 1 led to select buparlisib 80 mg + lapatinib 1000 mg/d as the RP2D. Main drug-related adverse events included diarrhoea, nausea, skin rash, asthenia, depression, anxiety and transaminases increase. There was no significant evidence for drug-drug PK interaction. Disease control rate was 79% [95% confidence interval [CI] 57-92%], one patient obtained a complete remission, and six additional patients experienced stable disease for ≥ 24 weeks (clinical benefit rate of 29% [95% CI 12-51%]).. Combining buparlisib and lapatinib in HER2-positive trastuzumab-resistant advanced breast cancer was feasible. Preliminary evidence of antitumour activity was observed in this heavily pre-treated population.. NCT01589861.

Topics: Administration, Oral; Adult; Aged; Aminopyridines; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Drug Administration Schedule; Drug Dosage Calculations; Drug Resistance, Neoplasm; Female; France; Humans; Lapatinib; Maximum Tolerated Dose; Middle Aged; Morpholines; Phosphatidylinositol 3-Kinase; Phosphoinositide-3 Kinase Inhibitors; Protein Kinase Inhibitors; Quinazolines; Receptor, ErbB-2; Trastuzumab; Treatment Outcome

Phosphatidylinositol 3-kinase (PI3K) pathway activation in preclinical models of breast cancer is associated with tumor growth and resistance to anticancer therapies, including paclitaxel. Effects of the pan-Class I PI3K inhibitor buparlisib (BKM120) appear synergistic with paclitaxel in preclinical and clinical models.. BELLE-4 was a 1:1 randomized, double-blind, placebo-controlled, adaptive phase II/III study investigating the combination of buparlisib or placebo with paclitaxel in women with human epidermal growth factor receptor 2-negative locally advanced or metastatic breast cancer with no prior chemotherapy for advanced disease. Patients were stratified by PI3K pathway activation and hormone receptor status. The primary endpoint was progression-free survival (PFS) in the full and PI3K pathway-activated populations. An adaptive interim analysis was planned following the phase II part of the study, after ≥125 PFS events had occurred in the full population, to decide whether the study would enter phase III (in the full or PI3K pathway-activated population) or be stopped for futility.. As of August 2014, 416 patients were randomized to receive buparlisib (207) or placebo (209) with paclitaxel. At adaptive interim analysis, there was no improvement in PFS with buparlisib versus placebo in the full (median PFS 8.0 versus 9.2 months, hazard ratio [HR] 1.18), or PI3K pathway-activated population (median PFS 9.1 versus 9.2 months, HR 1.17). The study met protocol-specified criteria for futility in both populations, and phase III was not initiated. Median duration of study treatment exposure was 3.5 months in the buparlisib arm versus 4.6 months in the placebo arm. The most frequent adverse events with buparlisib plus paclitaxel (≥40% of patients) were diarrhea, alopecia, rash, nausea, and hyperglycemia.. Addition of buparlisib to paclitaxel did not improve PFS in the full or PI3K pathway-activated study population. Consequently, the trial was stopped for futility at the end of phase II.

Topics: Adult; Aged; Aged, 80 and over; Aminopyridines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Disease-Free Survival; Double-Blind Method; Female; Humans; Kaplan-Meier Estimate; Middle Aged; Morpholines; Paclitaxel; Phosphoinositide-3 Kinase Inhibitors; Proportional Hazards Models; Receptor, ErbB-2; Treatment Outcome; Young Adult

Based upon preclinical synergy in murine models, we carried out a phase I trial to determine the maximum tolerated dose (MTD), toxicities, pharmacokinetics, and biomarkers of response for the combination of BKM120, a PI3K inhibitor, and olaparib, a PARP inhibitor.. Olaparib was administered twice daily (tablet formulation) and BKM120 daily on a 28-day cycle, both orally. A 3 + 3 dose-escalation design was employed with the primary objective of defining the combination MTD, and secondary objectives were to define toxicities, activity, and pharmacokinetic profiles. Eligibility included recurrent breast (BC) or ovarian cancer (OC); dose-expansion cohorts at the MTD were enrolled for each cancer.. In total, 69 of 70 patients enrolled received study treatment; one patient never received study treatment because of ineligibility. Twenty-four patients had BC; 46 patients had OC. Thirty-five patients had a germline BRCA mutation (gBRCAm). Two DLTs (grade 3 transaminitis and hyperglycemia) were observed at DL0 (BKM120 60 mg/olaparib and 100 mg b.i.d.). The MTD was determined to be BKM120 50 mg q.d. and olaparib 300 mg b.i.d. (DL8). Additional DLTs included grade 3 depression and transaminitis, occurring early in cycle 2 (DL7). Anticancer activity was observed in BC and OC and in gBRCAm and gBRCA wild-type (gBRCAwt) patients.. BKM120 and olaparib can be co-administered, but the combination requires attenuation of the BKM120 dose. Clinical benefit was observed in both gBRCAm and gBRCAwt pts. Randomized phase II studies will be needed to further define the efficacy of PI3K/PARP-inhibitor combinations as compared with a PARP inhibitor alone.

Topics: Adult; Aged; Aminopyridines; BRCA1 Protein; BRCA2 Protein; Breast Neoplasms; Dose-Response Relationship, Drug; Female; Germ-Line Mutation; Humans; Middle Aged; Morpholines; Neoplasm Grading; Neoplasm Recurrence, Local; Ovarian Neoplasms; Phosphoinositide-3 Kinase Inhibitors; Phthalazines; Piperazines; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases

Buparlisib, an oral reversible inhibitor of all class I phosphoinositide-3-kinases, has shown antitumoral activity against estrogen receptor (ER)-positive breast cancer cell lines and xenografts, alone and with endocrine therapy. This phase Ib study evaluated buparlisib plus letrozole's safety, tolerability, and preliminary activity in patients with metastatic ER-positive breast cancer refractory to endocrine therapy.. Patients received letrozole and buparlisib in two different administration schedules. Outcomes were assessed by standard solid-tumor phase I methods. [(18)F]fluorodeoxyglucose-positron emission tomography/computed tomography ([(18)F]FDG-PET/CT) scans were done at baseline and 2 weeks after treatment initiation. Tumor blocks were collected for phosphoinositide-3-kinase pathway mutation analysis.. Fifty-one patients were allocated sequentially to continuous or intermittent (five on/two off days) buparlisib administration on an every-4-week schedule. Buparlisib's maximum-tolerated dose (MTD) was 100 mg/d. Common drug-related adverse events included ≤ grade 2 hyperglycemia, nausea, fatigue, transaminitis, and mood disorders. The clinical benefit rate (lack of progression ≥ 6 months) among all patients treated at the MTD was 31%, including two objective responses in the continuous dose arm. Of seven patients remaining on treatment ≥ 12 months, three had tumors with PIK3CA hot-spot mutation. Patients exhibiting metabolic disease progression by [(18)F]FDG-PET/CT scan at 2 weeks progressed rapidly on therapy.. The letrozole and buparlisib combination was safe, with reversible toxicities regardless of schedule administration. Clinical activity was observed independent of PIK3CA mutation status. No metabolic response by [(18)F]FDG-PET/CT scan at 2 weeks was associated with rapid disease progression. Phase III trials of buparlisib and endocrine therapy in patients with ER-positive breast cancer are ongoing.

Topics: Adult; Aged; Aminopyridines; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cell Line, Tumor; Class I Phosphatidylinositol 3-Kinases; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Fluorodeoxyglucose F18; Humans; Letrozole; Middle Aged; Morpholines; Multimodal Imaging; Nitriles; Phosphoinositide-3 Kinase Inhibitors; Positron-Emission Tomography; Protein Kinase Inhibitors; Radiopharmaceuticals; Receptor, ErbB-2; Receptors, Estrogen; Tomography, X-Ray Computed; Triazoles

Estrogen receptor-positive (ER(+)) breast cancers adapt to hormone deprivation and become resistant to antiestrogen therapy. Here, we performed deep sequencing on ER(+) tumors that remained highly proliferative after treatment with the aromatase inhibitor letrozole and identified a D189Y mutation in the inhibitory SH2 domain of the SRC family kinase (SFK) LYN. Evaluation of 463 breast tumors in The Cancer Genome Atlas revealed four LYN mutations, two of which affected the SH2 domain. In addition, LYN was upregulated in multiple ER(+) breast cancer lines resistant to long-term estrogen deprivation (LTED). An RNAi-based kinome screen revealed that LYN is required for growth of ER(+) LTED breast cancer cells. Kinase assays and immunoblot analyses of SRC substrates in transfected cells indicated that LYN(D189Y) has higher catalytic activity than WT protein. Further, LYN(D189Y) exhibited reduced phosphorylation at the inhibitory Y507 site compared with LYN(WT). Other SH2 domain LYN mutants, E159K and K209N, also exhibited higher catalytic activity and reduced inhibitory site phosphorylation. LYN(D189Y) overexpression abrogated growth inhibition by fulvestrant and/or the PI3K inhibitor BKM120 in 3 ER(+) breast cancer cell lines. The SFK inhibitor dasatinib enhanced the antitumor effect of BKM120 and fulvestrant against estrogen-deprived ER(+) xenografts but not LYN(D189Y)-expressing xenografts. These results suggest that LYN mutations mediate escape from antiestrogens in a subset of ER(+) breast cancers.

Topics: Amino Acid Substitution; Aminopyridines; Animals; Breast Neoplasms; Dasatinib; Drug Resistance, Neoplasm; Drug Synergism; Estrogen Receptor Modulators; Female; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Humans; Mice; Mice, Nude; Morpholines; Mutation, Missense; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Phosphorylation; Protein Kinase Inhibitors; Pyrimidines; Receptors, Estrogen; src Homology Domains; src-Family Kinases; Thiazoles; Xenograft Model Antitumor Assays

This study reports the MTD, recommended phase 2 dose (RP2D), and preliminary efficacy of alpelisib or buparlisib used in combination with tamoxifen plus goserelin in premenopausal patients with hormone receptor-positive (HR. This study enrolled premenopausal women with HR. The criteria for MTD were not met for both alpelisib and buparlisib. The RP2D of alpelisib and buparlisib in combination with tamoxifen and goserelin were 350 mg and 100 mg, respectively. Both combinations met protocol-specified criteria for tolerability. The most common grade 3/4 treatment-emergent adverse events (TEAE) were hypokalemia (12.5%), hyperglycemia (6.3%), and rash (6.3%) for alpelisib and alanine aminotransferase increase (30.8%), aspartate aminotransferase increase (23.1%), and anxiety (15.4%) for buparlisib. TEAEs led to treatment discontinuation in 18.8% and 53.8% of alpelisib- and buparlisib-treated patients, respectively. Progression-free survival was 25.2 months in the alpelisib group and 20.6 months in the buparlisib group.. The RP2Ds of alpelisib and buparlisib were 350 mg and 100 mg, respectively. No unexpected safety findings were reported. Although an early-phase study, data suggest that alpelisib plus endocrine therapy may be a potentially efficacious treatment that warrants further evaluation for premenopausal patients with HR

Topics: Aminopyridines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cyclin-Dependent Kinase 4; Female; Goserelin; Humans; Morpholines; Phosphatidylinositol 3-Kinases; Receptor, ErbB-2; Tamoxifen; Thiazoles

In this open-label, multicenter, phase Ib study, 70 postmenopausal women with HR. The recommended phase II dose (RP2D) of ribociclib was confirmed to be 600 mg (3 weeks on, 1 week off) and 400 mg (continuous dosing) plus fulvestrant 500 mg. For the triple combination with buparlisib, the RP2D was ribociclib 400 mg plus buparlisib 30 mg plus fulvestrant 500 mg. Enrollment for the triple combinations was stopped due to unexpected toxicity. No RP2D was determined for the alpelisib combination. The safety profiles of the ribociclib plus fulvestrant combinations were consistent with those in previous studies. There was no marked difference in ribociclib exposure in the presence of triple-combination partners. The highest overall response rate was seen in the buparlisib triple combination (25.0%; 95% confidence interval, 9.8-46.7).. Ribociclib plus fulvestrant demonstrated safety in the treatment of patients with HR

Topics: Aminopyridines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cyclin-Dependent Kinase 4; Female; Fulvestrant; Humans; Morpholines; Phosphatidylinositol 3-Kinases; Purines; Receptors, Estrogen; Thiazoles

PI3K and CDK4/6 inhibitors (CDK4/6i) are targeted therapies approved to treat advanced breast cancer; CDK4/6is are more widely used. Here, we discuss trials that examine PI3K inhibitors with novel drug combinations, including a CDK4/6i, given data implicating the pathway in CDK 4/6 resistance.

Topics: Aminopyridines; Breast Neoplasms; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Female; Goserelin; Humans; Morpholines; Phosphatidylinositol 3-Kinases; Tamoxifen; Thiazoles

Topics: Aminopyridines; Animals; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cell Line, Tumor; Drug Resistance, Neoplasm; Female; Gain of Function Mutation; Humans; Mice, Nude; Molecular Docking Simulation; Molecular Dynamics Simulation; Morpholines; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Protein Multimerization; Quinolines; Receptor, ErbB-2; Receptor, ErbB-3; Trastuzumab; Xenograft Model Antitumor Assays

Metaplastic carcinoma of the breast (MCB) is a rare cancer characterized by the histologic presence of two or more histological cell types originating from epithelial and mesenchymal stem cells. Patients with metastatic MCB have a low response rate to conventional chemotherapy and poor survival. Optimal treatment strategies for metastatic MCB are urgently needed.. We retrospectively reviewed a patient who had enrolled in the phase II/III seamless study, BELLE-4 (NCT01572727). The patient's response to the study drug assessed by an investigator per protocol and clinical course were examined and compared with those of the main cohorts in the BELLE-4 study.. Buparlisib plus weekly paclitaxel might be a new treatment option for patients with metastatic MCB harboring a PIK3CA mutation. Additional prospective studies for investigating the efficacy of the proposed combination are warranted.

Topics: Aged, 80 and over; Aminopyridines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Carcinoma; Female; Humans; Metaplasia; Morpholines; Paclitaxel; Phosphoinositide-3 Kinase Inhibitors; Randomized Controlled Trials as Topic; Tomography, X-Ray Computed; Treatment Outcome

Chemoradiation is an effective combined modality therapeutic approach that utilizes principles of spatial cooperation to combat the adaptability associated with cancer and to potentially expand the therapeutic window. Optimal therapeutic efficacy requires intelligent selection and refinement of radiosynergistic pharmaceutical agents, enhanced delivery methods, and temporal consideration. Here, a monodisperse sub-20 nm mixed poloxamer micelle (MPM) system was developed to deliver hydrophobic drugs intravenously, in tandem with ionizing radiation. This report demonstrates in vitro synergy and enhanced radiosensitivity when two molecularly targeted DNA repair inhibitors, talazoparib and buparlisib, are encapsulated and combined with radiation in a 4T1 murine breast cancer model. Evaluation of in vivo biodistribution and toxicity exhibited no reduction in particle accumulation upon radiation and a lack of both acute and chronic toxicities. In vivo efficacy studies suggested the promise of combining talazoparib, buparlisib, and radiation to enhance survival and control tumor growth. Tissue analysis suggests enhanced DNA damage leading to apoptosis, thus increasing efficacy. These findings highlight the challenges associated with utilizing clinically relevant inclusion criteria and treatment protocols because complete tumor regression and extended survival were masked by an aggressively metastasizing model. As with clinical treatment regimens, the findings here establish a need for further optimization of this multimodal platform.

Topics: Aminopyridines; Animals; Breast Neoplasms; Cell Line, Tumor; Chemoradiotherapy; DNA Damage; Female; Humans; Mice; Mice, Inbred BALB C; Micelles; Morpholines; Phthalazines; Xenograft Model Antitumor Assays

Mutations and activation of the PI3K signaling pathway in breast cancer cells have been linked to brain metastases. However, here we describe that in some breast cancer brain metastases samples the protein expression of PI3K signaling components is restricted to the metastatic microenvironment. In contrast to the therapeutic effects of PI3K inhibition on the breast cancer cells, the reaction of the brain microenvironment is less understood. Therefore we aimed to quantify the PI3K pathway activity in breast cancer brain metastasis and investigate the effects of PI3K inhibition on the central nervous system (CNS) microenvironment. First, to systematically quantify the PI3K pathway activity in breast cancer brain metastases, we performed a prospective biomarker study using a reverse phase protein array (RPPA). The majority, namely 30 out of 48 (62.5%) brain metastatic tissues examined, revealed high PI3K signaling activity that was associated with a median overall survival (OS) of 9.41 months, while that of patients, whose brain metastases showed only moderate or low PI3K activity, amounted to only 1.93 and 6.71 months, respectively. Second, we identified PI3K as a master regulator of metastasis-promoting macrophages/microglia during CNS colonization; and treatment with buparlisib (BKM120), a pan-PI3K Class I inhibitor with a good blood-brain-barrier penetrance, reduced their metastasis-promoting features. In conclusion, PI3K signaling is active in the majority of breast cancer brain metastases. Since PI3K inhibition does not only affect the metastatic cells but also re-educates the metastasis-promoting macrophages/microglia, PI3K inhibition may hold considerable promise in the treatment of brain metastasis and the respective microenvironment.

Topics: Adult; Aged; Aminopyridines; Animals; Brain Neoplasms; Breast Neoplasms; Calcium-Binding Proteins; Disease Models, Animal; Enzyme Inhibitors; Female; Gene Expression Regulation, Neoplastic; Glial Fibrillary Acidic Protein; Humans; Macrophages; Mice; Mice, Inbred BALB C; Microfilament Proteins; Microglia; Middle Aged; Morpholines; Phosphatidylinositol 3-Kinases; Signal Transduction; TOR Serine-Threonine Kinases

PI3K/Akt/mTOR and hedgehog (Hh) signalings are two important pathways in breast cancer, which are usually connected with the drug resistance and cancer migration. Many studies indicated that PI3K/Akt/mTOR inhibitors and Hh inhibitors displayed synergistic effects, and the combination of the two signaling drugs could delay drug resistance and inhibit cancer migration in breast cancer. Therefore, the development of molecules simultaneously inhibiting these two pathways is urgent needed. Based on the structures of PI3K inhibitor buparlisib and Hh inhibitor vismodegib, a series of hybrid structures were designed and synthesized utilizing rational drug design and computer-based drug design. Several compounds displayed excellent antiproliferative activities against several breast cancer cell lines, including triple-negative breast cancer (TNBC) MDA-MB-231 cell. Further mechanistic studies demonstrated that the representative compound 9i could inhibit both PI3K/Akt/mTOR and hedgehog (Hh) signalings by inhibiting the phosphorylation of S6K and Akt as well as decreasing the SAG elevated expression of Gli1. Compound 9i could also induce apoptosis remarkably in T47D and MDA-MB-231 cells. In the transwell assay, 9i showed significant inhibition on the migration of MDA-MB-231.

Topics: Antineoplastic Agents; Breast Neoplasms; Cell Proliferation; Dose-Response Relationship, Drug; Drug Discovery; Drug Screening Assays, Antitumor; Female; Hedgehog Proteins; Humans; Molecular Structure; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Signal Transduction; Structure-Activity Relationship; TOR Serine-Threonine Kinases; Tumor Cells, Cultured; Urea

Although phase I clinical trials are the gateway to progress in cancer therapies, this setting poses ethical challenges to ensure that patients provide consent free from misunderstandings of therapeutic intent or unrealistic expectations of benefit. The design of phase I oncology trials has evolved rapidly over time and today includes more targeted agents and combinations of experimental drugs with standard drugs, which may further complicate how patients understand phase I research participation.. We conducted semistructured interviews regarding motivations, decision making, and understanding of trial purpose nested within a phase I clinical trial of a novel PI3kinase inhibitor combined with a standard oral chemotherapy in 18 participants.. Fewer than half of patients correctly identified the safety and dosing objectives. The inclusion of a targeted agent was attractive to participants and was perceived as an indicator of less toxic or more efficacious therapy, with less appreciation for added risks. The significance of a cellular drug target, without a known predictive biomarker of response, was unclear to patients. The inclusion of a standard drug in the regimen attracted patients with more treatment options than traditional first-in-human participants. Patients frequently expressed a realistic understanding of prognosis and uncertainty of benefit, but simultaneous hopes for extraordinary outcomes.. Novel phase I oncology trial designs may attract patients with less constrained treatment options, but the inclusion of targeted drugs and combinations including standard chemotherapies is likely to complicate understanding of safety and dosing objectives and likelihood of personal benefit for purposes of informed consent.

Topics: Aminopyridines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Capecitabine; Clinical Trials, Phase I as Topic; Decision Making; Female; Humans; Informed Consent; Morpholines; Motivation; Neoplasm Metastasis; Protein Kinase Inhibitors; Qualitative Research; Research Subjects

Breast cancer is the most frequent cancer in women. Despite a decline in breast cancer mortality, prognosis of advanced breast cancer remains poor. In a desperate need to improve breast cancer outcomes, newer agents that target molecular pathways are being tested. Deregulation of the phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) is frequently found in breast cancer. This can lead to resistance of endocrine therapy and anti-HER2 therapies. Targeting this pathway may restore sensitivity to these compounds. Buparlisib (BKM-120) is an orally active pan-PI3K inhibitor evaluated in different tumor types. Areas covered: Buparlisib is one of the most investigated PI3K inhibitors. Preclinical and clinical studies of buparlisib in breast cancer are analyzed and discussed. This article reviews the status of buparlisib, completed and ongoing trials, and its safety. Expert opinion: PI3K inhibitors show promising results in breast cancer. However, we raise a number of issues including the identification of biomarkers to predict treatment response and strategies to counteract resistance. Moreover, its toxicity profile could limit its extensive use.

Topics: Aminopyridines; Breast Neoplasms; Clinical Trials as Topic; Female; Half-Life; Humans; Morpholines; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Protein Kinase Inhibitors; TOR Serine-Threonine Kinases

Data from the BELLE-3 trial suggest that adding the investigational PI3K inhibitor buparlisib to endocrine therapy may improve outcomes for patients with hormone receptor-positive advanced breast cancer whose tumors become resistant to mTOR inhibition. However, experts remain concerned about a high rate of serious adverse events seen during the trial.

Topics: Aminopyridines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Clinical Trials, Phase III as Topic; Disease-Free Survival; Estradiol; Female; Fulvestrant; Humans; Morpholines; Postmenopause; Protein Kinase Inhibitors; Survival Analysis; Treatment Outcome

Autophagy is the process of lysosome-mediated degradation and recycling that functions as an adaptive survival mechanism during anti-cancer therapy. Aberrant activation of the phosphoinositide-3-kinase (PI3K) pathway frequently occurs in solid tumors, including cervical cancer. However, single-agent PI3K inhibitors show modest anti-tumor efficacy in clinics. To see whether autophagy inhibition improves the efficacy of PI3K inhibitor in PIK3CA-mutant cancer cells, cells were treated with BKM120, a pan-PI3K inhibitor, and the autophagy inhibitor hydroxychloroquine (HCQ). Autophagy inhibition augmented the efficacy of BKM120 depending on PIK3CA-mutant cancer cell type. BKM120 treatment led to the nuclear accumulation of forkhead box O3 (FOXO3a) in Caski and T47D cells, which showed a synergistic effect of BKM120 and HCQ and the strong induction of autophagy. However, most FOXO3a remained in cytoplasm in C33A and ME180 cells, which did not exhibit synergy. These data suggest that BKM120-induced nuclear translocation of FOXO3a might elicit autophagy and be a critical factor determining the synergistic activity of BKM120 and HCQ in PIK3CA-mutant cancer cells. The release of FOXO3a from 14-3-3 by BV02 or 14-3-3 knockdown induced autophagy by BKM120 in C33A cells and sensitized the cells to the combined BKM120 and HCQ treatment, suggesting that cytoplasmic retention of FOXO3a by 14-3-3 even in the presence of BKM120 inhibit autophagy induction and synergistic effect of BKM120 and HCQ combination. Taken together, our study shows that subcellular localization of FOXO3a might be a potential biomarker for predicting response to the combination treatment with PI3K and autophagy inhibitors in PIK3CA-mutant cervical cancer patients.

Topics: 14-3-3 Proteins; Active Transport, Cell Nucleus; Aminopyridines; Antineoplastic Combined Chemotherapy Protocols; Autophagy; Biomarkers, Tumor; Breast Neoplasms; Class I Phosphatidylinositol 3-Kinases; Cytoplasm; Dose-Response Relationship, Drug; Female; Forkhead Box Protein O3; Gene Expression Regulation, Neoplastic; HeLa Cells; Humans; Hydroxychloroquine; Morpholines; Mutation; Protein Kinase Inhibitors; RNA Interference; Signal Transduction; Time Factors; Transfection; Uterine Cervical Neoplasms

This trial was conducted to determine the maximum tolerated dose (MTD) and preliminary efficacy of buparlisib, an oral pan-class I PI3K inhibitor, plus fulvestrant in postmenopausal women with metastatic estrogen receptor positive (ER(+)) breast cancer.. Phase IA employed a 3+3 design to determine the MTD of buparlisib daily plus fulvestrant. Subsequent cohorts (phase IB and cohort C) evaluated intermittent (5/7-day) and continuous dosing of buparlisib (100 mg daily). No more than 3 prior systemic treatments in the metastatic setting were allowed in these subsequent cohorts.. Thirty-one patients were enrolled. MTD was defined as buparlisib 100 mg daily plus fulvestrant. Common adverse events (AE) included fatigue (38.7%), transaminases elevation (35.5%), rash (29%), and diarrhea (19.4%). C-peptide was significantly increased during treatment, consistent with on-target effect of buparlisib. Compared with intermittent dosing, daily buparlisib was associated with more frequent early onset AEs and higher buparlisib plasma concentrations. Among the 29 evaluable patients, the clinical benefit rate was 58.6% (95% CI, 40.7%-74.5%). Response was not associated with PIK3CA mutation or treatment cohort; however, loss of PTEN, progesterone receptor (PgR) expression, or mutation in TP53 was most common in resistant cases, and mutations inAKT1 and ESR1 did not exclude treatment response.. Buparlisib plus fulvestrant is clinically active with manageable AEs in patients with metastatic ER(+)breast cancer. Weekend breaks in buparlisib dosing reduced toxicity. Patients with PgR negative and TP53 mutation did poorly, suggesting buparlisib plus fulvestrant may not be adequately effective against tumors with these poor prognostic molecular features.

Topics: Adult; Aged; Aminopyridines; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Breast Neoplasms; Estradiol; Female; Fulvestrant; Humans; Middle Aged; Morpholines; Neoplasm Metastasis; Phosphoinositide-3 Kinase Inhibitors; Postmenopause; PTEN Phosphohydrolase; Receptors, Estrogen; Receptors, Progesterone; Treatment Outcome

Adding a PI3K inhibitor to anti-estrogen receptor therapy may be a viable treatment option for women with advanced hormone receptor-positive breast cancer that becomes resistant to endocrine therapy, according to findings from the phase III BELLE-2 trial, presented at the 2015 San Antonio Breast Cancer Symposium.

Topics: Aminopyridines; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Clinical Trials, Phase III as Topic; Congresses as Topic; Disease-Free Survival; Drug Resistance, Neoplasm; Estradiol; Female; Fulvestrant; Humans; Morpholines; Phosphatidylinositol 3-Kinase; Phosphoinositide-3 Kinase Inhibitors; Treatment Outcome

Brain metastases represent the greatest clinical challenge in treating HER2-positive breast cancer. We report the development of orthotopic patient-derived xenografts (PDXs) of HER2-expressing breast cancer brain metastases (BCBM), and their use for the identification of targeted combination therapies. Combined inhibition of PI3K and mTOR resulted in durable tumor regressions in three of five PDXs, and therapeutic response was correlated with a reduction in the phosphorylation of 4EBP1, an mTORC1 effector. The two nonresponding PDXs showed hypermutated genomes with enrichment of mutations in DNA-repair genes, which suggests an association of genomic instability with therapeutic resistance. These findings suggest that a biomarker-driven clinical trial of PI3K inhibitor in combination with an mTOR inhibitor should be conducted for patients with HER2-positive BCBM.

Topics: Adaptor Proteins, Signal Transducing; Aminopyridines; Animals; Antineoplastic Agents; Apoptosis; Brain Neoplasms; Breast Neoplasms; Carrier Proteins; Caspase 3; Cell Cycle Proteins; DNA Repair; Drug Resistance, Neoplasm; Drug Therapy, Combination; Eukaryotic Initiation Factors; Everolimus; Female; Gene Expression Profiling; Genomic Instability; Humans; Immunohistochemistry; Ki-67 Antigen; Magnetic Resonance Imaging; Mechanistic Target of Rapamycin Complex 1; Mice; Mice, SCID; Molecular Targeted Therapy; Morpholines; Multiprotein Complexes; Neoplasm Transplantation; Phosphoinositide-3 Kinase Inhibitors; Phosphoproteins; Phosphorylation; Receptor, ErbB-2; Remission Induction; TOR Serine-Threonine Kinases; Xenograft Model Antitumor Assays

Breast cancer is one of the leading causes of death for women worldwide. Among various subtypes of breast cancer, human epidermal growth factor receptor 2 (HER2)-positive and phosphatase and tensin homolog (PTEN) loss breast cancer is a cause of great concern in terms of its resistance to HER2-targeted therapies and its poor prognosis. Phosphatidylinositol 3-kinase (PI3K)/AKT hyperphosphorylation is considered one of key mechanisms leading to this resistance, thus combination therapy of PI3K inhibitors and HER2 antibodies is promising for overcoming this problem, and more specific regimens should be designed in this age of precision medicine. In this study, we established an HER2-positive and PTEN loss cell line and confirmed it by western blot analysis. This cell line and its orthotopic xenograft models were exposed to p110α-specific inhibitor BYL719, p110β-specific inhibitor AZD6482, or pan-PI3K inhibitor BKM120, respectively, and the results showed sensitivity to both BYL719 and BKM120 but not AZD6482, which indicated a p110α-reliance for HER2-positive-PTEN-loss breast cancer. Then, the addition of BYL719 to HER2 antibody greatly reduced tumor growth both in vitro and in vivo, accompanied by inhibited PI3K effector phosphorylation. Therefore, our findings suggest that the combination of p110α-selective inhibitor BYL719 with HER2 antibody could be a potential strategy for more personalized treatment of HER2-posistive-PTEN-loss breast cancer; and in addition, the optimal schedule of this combination therapy needs to be further explored.

Topics: Aminopyridines; Animals; Antibodies; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Cell Survival; Female; Humans; Lapatinib; Mice; Morpholines; ortho-Aminobenzoates; Phosphoinositide-3 Kinase Inhibitors; Phosphorylation; PTEN Phosphohydrolase; Pyrimidinones; Quinazolines; Receptor, ErbB-2; Thiazoles; Xenograft Model Antitumor Assays

The polycomb protein MEL-18 has been proposed as a tumor suppressor in breast cancer; however, its functional relevance to the hormonal regulation of breast cancer remains unknown. Here, we demonstrated that MEL-18 loss contributes to the hormone-independent phenotype of breast cancer by modulating hormone receptor expression. In multiple breast cancer cohorts, MEL-18 was markedly downregulated in triple-negative breast cancer (TNBC). MEL-18 expression positively correlated with the expression of luminal markers, including estrogen receptor-α (ER-α, encoded by ESR1). MEL-18 loss was also associated with poor response to antihormonal therapy in ER-α-positive breast cancer. Furthermore, whereas MEL-18 loss in luminal breast cancer cells resulted in the downregulation of expression and activity of ER-α and the progesterone receptor (PR), MEL-18 overexpression restored ER-α expression in TNBC. Consistently, in vivo xenograft experiments demonstrated that MEL-18 loss induces estrogen-independent growth and tamoxifen resistance in luminal breast cancer, and that MEL-18 overexpression confers tamoxifen sensitivity in TNBC. MEL-18 suppressed SUMOylation of the ESR1 transactivators p53 and SP1, thereby driving ESR1 transcription. MEL-18 facilitated the deSUMOylation process by inhibiting BMI-1/RING1B-mediated ubiquitin-proteasomal degradation of SUMO1/sentrin-specific protease 1 (SENP1). These findings demonstrate that MEL-18 is a SUMO-dependent regulator of hormone receptors and suggest MEL-18 expression as a marker for determining the antihormonal therapy response in patients with breast cancer.

Topics: Aminopyridines; Animals; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Breast Neoplasms; Carcinoma, Ductal, Breast; Cysteine Endopeptidases; Drug Resistance, Neoplasm; Endopeptidases; Estrogen Receptor alpha; Estrogens; Female; Humans; Kaplan-Meier Estimate; Mice; Morpholines; Neoplasm Proteins; Neoplasm Transplantation; Neoplasms, Hormone-Dependent; Polycomb Repressive Complex 1; Progesterone; Proportional Hazards Models; Proteasome Endopeptidase Complex; Protein Processing, Post-Translational; Receptor, ErbB-2; Receptors, Progesterone; RNA, Messenger; RNA, Neoplasm; Sp1 Transcription Factor; Sumoylation; Tamoxifen; Triple Negative Breast Neoplasms; Tumor Suppressor Protein p53

The multidrug resistance (MDR) phenotype often accompanies activation of the phosphatidylinositol 3-kinase (PI3K)/AKT pathway, which renders a survival signal to withstand cytotoxic anticancer drugs and enhances cancer stem cell (CSC) characteristics. As a result, PI3K/AKT-blocking approaches have been proposed as antineoplastic strategies, and inhibitors of PI3K/AKT are currently being trailed clinically in breast cancer patients. However, the effects of PI3K inhibitors on MDR breast cancers have not yet been elucidated. In the present study, the tumorigenic properties of three MDR breast cancer cell lines to a selective inhibitor of PI3K, NVP-BKM120 (BKM120), were assessed. We found that BKM120 showed a significant cytotoxic activity on MDR breast cancer cells both in vitro and in vivo. When doxorubicin (DOX) was combined with BKM120, strong synergistic antiproliferative effect was observed. BKM120 activity induced the blockage of PI3K/AKT signaling and NF-κB expression, which in turn led to activate caspase-3/7 and caspase-9 and changed the expression of several apoptosis-related gene expression. Furthermore, BKM120 effectively eliminated CSC subpopulation and reduced sphere formation of these drug-resistant cells. Our findings indicate that BKM120 partially overcomes the MDR phenotype in chemoresistant breast cancer through cell apoptosis induction and CSC abolishing, which appears to be mediated by the inhibition of the PI3K/AKT/NF-κB axis. This offers a strong rationale to explore the therapeutic strategy of using BKM120 alone or in combination for chemotherapy-nonresponsive breast cancer patients.

Topics: Aminopyridines; Animals; Breast Neoplasms; Cell Line, Tumor; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Female; Humans; Mice; Mice, Nude; Morpholines; Neoplastic Stem Cells; Phosphatidylinositol 3-Kinase; Phosphoinositide-3 Kinase Inhibitors; Protein Kinase Inhibitors; Signal Transduction

Despite multiple advances in the treatment of HER2+ breast cancers, resistance develops even to combinations of HER2 targeting agents. Inhibition of PI3K pathway signaling is critical for the efficacy of HER2 inhibitors. Activating mutations in PIK3CA can overlap with HER2 amplification and have been shown to confer resistance to HER2 inhibitors in preclinical studies.. Lapatinib-resistant cells were profiled for mutations in the PI3K pathway with the SNaPshot assay. Hotspot PIK3CA mutations were retrovirally transduced into HER2-amplified cells. The impact of PIK3CA mutations on the effect of HER2 and PI3K inhibitors was assayed by immunoblot, proliferation and apoptosis assays. Uncoupling of PI3K signaling from HER2 was investigated by ELISA for phosphoproteins in the HER2-PI3K signaling cascade. The combination of HER2 inhibitors with PI3K inhibition was studied in HER2-amplified xenograft models with wild-type or mutant PIK3CA.. Here we describe the acquisition of a hotspot PIK3CA mutation in cells selected for resistance to the HER2 tyrosine kinase inhibitor lapatinib. We also show that the gain of function conferred by these PIK3CA mutations partially uncouples PI3K signaling from the HER2 receptor upstream. Drug resistance conferred by this uncoupling was overcome by blockade of PI3K with the pan-p110 inhibitor BKM120. In mice bearing HER2-amplified wild-type PIK3CA xenografts, dual HER2 targeting with trastuzumab and lapatinib resulted in tumor regression. The addition of a PI3K inhibitor further improved tumor regression and decreased tumor relapse after discontinuation of treatment. In a PIK3CA-mutant HER2+ xenograft, PI3K inhibition with BKM120 in combination with lapatinib and trastuzumab was required to achieve tumor regression.. These results suggest that the combination of PI3K inhibition with dual HER2 blockade is necessary to circumvent the resistance to HER2 inhibitors conferred by PIK3CA mutation and also provides benefit to HER2+ tumors with wild-type PIK3CA tumors.

Topics: Aminopyridines; Animals; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Biomarkers, Tumor; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Class I Phosphatidylinositol 3-Kinases; Drug Resistance, Neoplasm; Female; Humans; Lapatinib; Mice; Mice, Nude; Morpholines; Mutation; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Protein Kinase Inhibitors; Quinazolines; Receptor, ErbB-2; Trastuzumab; Xenograft Model Antitumor Assays

ARID1A mutations are observed in various tumors, including ovarian clear cell (OCCC) and endometrioid carcinomas, endometrial, and breast carcinomas. They commonly result in loss of ARID1A-protein expression and frequently co-occur with PI3K/AKT-pathway activating mechanisms. The aim of this study was to test the hypothesis as to whether PI3K/AKT-pathway activation is a critical mechanism in ARID1A-mutated tumors and if consequently ARID1A-deficient tumors show increased sensitivity to treatment with PI3K- and AKT-inhibitors. Upon ARID1A knockdown, MCF7 breast cancer cells and primary MRC5 cells exhibited a significantly increased sensitivity towards the AKT-inhibitors MK-2206 and perifosine, as well as the PI3K-inhibitor buparlisib. Knockdown of ARID1A in MCF7 led to an increase of pAKT-Ser473. AKT-inhibition with MK-2206 led to increased apoptosis and to a decrease of pS6K in ARID1A-depleted MCF7 cells but not in the controls. In five OCCC cell lines ARID1A-deficiency correlated with increased pAKT-Ser473 levels and with sensitivity towards treatment with the AKT-inhibitor MK-2206. In conclusion, ARID1A-deficient cancer cells demonstrate an increased sensitivity to treatment with small molecule inhibitors of the PI3K/AKT-pathway. These findings suggest a specific requirement of the PI3K/AKT pathway in ARID1A-deficient tumors and reveal a synthetic lethal interaction between loss of ARID1A expression and inhibition of the PI3K/AKT pathway.

Topics: Aminopyridines; Apoptosis; Breast Neoplasms; DNA-Binding Proteins; Female; Gene Knockdown Techniques; Heterocyclic Compounds, 3-Ring; Humans; MCF-7 Cells; Morpholines; Nuclear Proteins; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Phosphorylation; Phosphorylcholine; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Ribosomal Protein S6 Kinases, 70-kDa; RNA, Small Interfering; Signal Transduction; Transcription Factors; Transfection

The PI3K signaling pathway regulates diverse cellular processes, including proliferation, survival, and metabolism, and is aberrantly activated in human cancer. As such, numerous compounds targeting the PI3K pathway are currently being clinically evaluated for the treatment of cancer, and several have shown some early indications of efficacy in breast cancer. However, resistance against these agents, both de novo and acquired, may ultimately limit the efficacy of these compounds. Here, we have taken a systematic functional approach to uncovering potential mechanisms of resistance to PI3K inhibitors and have identified several genes whose expression promotes survival under conditions of PI3K/mammalian target of rapamycin (PI3K/mTOR) blockade, including the ribosomal S6 kinases RPS6KA2 (RSK3) and RPS6KA6 (RSK4). We demonstrate that overexpression of RSK3 or RSK4 supports proliferation upon PI3K inhibition both in vitro and in vivo, in part through the attenuation of the apoptotic response and upregulation of protein translation. Notably, the addition of MEK- or RSK-specific inhibitors can overcome these resistance phenotypes, both in breast cancer cell lines and patient-derived xenograft models with elevated levels of RSK activity. These observations provide a strong rationale for the combined use of RSK and PI3K pathway inhibitors to elicit favorable responses in breast cancer patients with activated RSK.

Topics: Aminopyridines; Animals; Antineoplastic Agents; Apoptosis; Breast Neoplasms; Cell Survival; Drug Resistance, Neoplasm; Drug Synergism; Female; Gene Expression; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Heterocyclic Compounds, 3-Ring; Humans; Imidazoles; MCF-7 Cells; Mice; Mice, Nude; Molecular Targeted Therapy; Morpholines; Open Reading Frames; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Quinolines; Ribosomal Protein S6 Kinases, 90-kDa; Signal Transduction; Transcriptome; Tumor Burden; Xenograft Model Antitumor Assays

Everolimus, an mTOR inhibitor, showed great clinical efficacy in combination with tamoxifen, letrozole, or exemestane for the treatment of estrogen receptor-positive (ER+) breast cancer. However, its antitumor activity was shown to be compromised by a compensatory process involving AKT activation. Here, it was determined whether combining an additional PI3K inhibitor can reverse this phenomenon and improve treatment efficacy. In breast cancer cells (MCF-7 and BT474), everolimus inhibited the mTOR downstream activity by limiting phosphorylation of p70S6K and 4EBP1, which resulted in p-Ser473-AKT activation. However, addition of a LY294002, a PI3K inhibitor, to tamoxifen and everolimus treatment improved the antitumor effect compared with tamoxifen alone or the other two agents in combination. Moreover, LY294002 suppressed the activity of the PI3K/AKT/mTOR axis and mitigated the p-Ser473-AKT activation feedback loop in both cell lines. Critically, this combination scheme also significantly inhibited the expression of HIF-1a, an angiogenesis marker, under hypoxic conditions and reduced blood vessel sprout formation in vitro. Finally, it was shown that the three-agent cocktail had the greatest efficacy in inhibiting MCF-7 xenograft tumor growth and angiogenesis. Taken together, these results suggest that inhibition of PI3K and mTOR may further improve therapy in ER(+) breast cancer cells.. Combinatorial inhibition of the PI3K/AKT/mTOR signaling axis may enhance endocrine-based therapy in breast cancer.

Topics: Aminopyridines; Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Chromones; Everolimus; Female; Humans; Imidazoles; Mammary Neoplasms, Experimental; Mice; Mice, Nude; Morpholines; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Quinolines; Signal Transduction; Sirolimus; Tamoxifen; TOR Serine-Threonine Kinases; Xenograft Model Antitumor Assays

The PTEN hamartoma tumor syndrome (PHTS) is a complex disorder caused by germline inactivating mutations of the tumor suppressor gene PTEN. Loss of PTEN function leads to unimpeded phosphatidylinositol-3'-kinase (PI3K) activity and PI3K-driven cell division. Individuals with PHTS develop benign hamartomas in various tissues and have an increased risk of developing malignant diseases. Notably, no effective therapy currently exists for this disorder. Using both genetic mouse models and pharmacological approaches, we recently demonstrated that PI3K p110α and p110β isoforms play spatially distinct but concerted roles in the skin that are required for the development and maintenance of PHTS. We also show that treatment with a pan-PI3K inhibitor prevents the development of skin PHTS and reverses advanced-stage skin hamartomas in vivo. Here, we report that genetic ablation of only 3 out of 4 p110 alleles is sufficient to block the development of skin hamartomas resulting from the complete loss of Pten in mice. Similar to our findings in skin, we now also show that mammary gland neoplastic lesions can be prevented or reversed upon PI3K inhibition in our PHTS mouse model. Our data suggest a possible route to chemoprevention using reduced doses of PI3K inhibitors for PTEN-deficient carrier patients.

Topics: Alleles; Aminopyridines; Animals; Breast Neoplasms; Class Ia Phosphatidylinositol 3-Kinase; Disease Models, Animal; Female; Gene Dosage; Genotype; Hamartoma Syndrome, Multiple; Mice; Morpholines; Phosphoinositide-3 Kinase Inhibitors; Proto-Oncogene Proteins c-akt; PTEN Phosphohydrolase; Skin Neoplasms

Inhibition of phosphatidylinositol-3-kinase (PI3K) induces apoptosis when combined with estrogen deprivation in estrogen receptor (ER)-positive breast cancer. The aims of the present study were to identify effective PI3K pathway inhibitor and endocrine therapy combinations, to evaluate the effect of PI3K pathway mutations and estrogen dependency on tumor response, and to determine the relevance of PIK3CA mutation in recurrent disease.. The PI3K catalytic subunit inhibitor BKM120, the mammalian target of rapamycin (mTOR) inhibitor RAD001 and the dual PI3K/mTOR inhibitor BGT226 were tested against ER-positive breast cancer cell lines before and after long-term estrogen deprivation (LTED). The impact of estradiol deprivation and the ER downregulator fulvestrant on PI3K pathway inhibitor-induced apoptosis was assessed. PIK3CA hotspot mutation analysis was performed in 51 recurrent or metastatic breast cancers and correlated with ER status and survival.. Drug-induced apoptosis was most marked in short-term estrogen-deprived cells with PIK3CA mutation and phosphatase and tensin homolog loss. Apoptosis was most highly induced by BGT226, followed by BKM120, and then RAD001. Estradiol antagonized PI3K inhibitor-induced apoptosis following short-term estrogen deprivation, emphasizing a role for estrogen-deprivation therapy in promoting PI3K inhibitor activity in the first-line setting. ER-positive MCF7 LTED cells exhibited relative resistance to PI3K pathway inhibition that was reversed by fulvestrant. In contrast, T47D LTED cells exhibited ER loss and ER-independent PI3K agent sensitivity. PIK3CA mutation was prevalent in relapsed ER-positive disease (48%) and was associated with persistent ER positivity and a late relapse pattern.. Estrogen deprivation increased the apoptotic effects of PI3K and dual PI3K/mTOR inhibitors in ER-positive disease, providing a rationale for PI3K/aromatase inhibitor combinations as first-line therapy. In LTED cells, differential effects on ER expression may be a relevant consideration. When ER was persistently expressed, fulvestrant strongly promoted PI3K drug activity. When ER was lost, PI3K inhibitor monotherapy was sufficient to induce high-level apoptosis. Although tumors with PIK3CA mutation had a late recurrence pattern, these mutations were common in metastatic disease and were most often associated with persistent ER expression. Targeting PIK3CA mutant tumors with a PI3K pathway inhibitor and fulvestrant is therefore a feasible strategy for aromatase-inhibitor-resistant ER-positive relapsed breast cancer.

Topics: Aminopyridines; Antineoplastic Agents, Hormonal; Apoptosis; Aromatase Inhibitors; Breast Neoplasms; Cell Line, Tumor; Class I Phosphatidylinositol 3-Kinases; Estradiol; Estrogens; Everolimus; Female; Fulvestrant; Humans; Imidazoles; Morpholines; Mutation; Neoplasm Recurrence, Local; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; PTEN Phosphohydrolase; Quinolines; Receptors, Estrogen; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases