Development of PI3K Inhibitors in Breast Cancer

Abstract

The PI3K pathway is the most frequently altered pathway in cancer, and its activation has been shown to confer resistance to endocrine and HER2-targeted therapies preclinically. Conflicting data have been published regarding the prognostic significance, hormone receptor association, and treatment implications of PIK3CA mutations. Given the high frequency of these mutations and their prognostic implications in breast cancers, an increasing focus has been placed on the development of inhibitors of the PI3K pathway. Emerging clinical data in ER+ and HER2-amplified breast cancers suggest preliminary clinical activity from PI3K inhibitors in combination with endocrine therapy and HER2-targeted therapy, respectively. This manuscript will review the rationale for exploring PI3K inhibitors in ER+ and HER2-amplified breast cancers.

Introduction

The phosphoinositide-3 kinase (PI3K)/AKT signaling network is the most frequently mutated pathway in breast cancer. Of the somatic alterations in the PI3K/AKT pathway, the mutation of the genes encoding the PI3K catalytic subunits p110α (PIK3CA) are the most common genetic alteration of this pathway, where ≥80% occur within the helical (E542K, E545K) and kinase (H1047R) domains of p110α.¹ PIK3CA mutations induce a transformed phenotype in vitro and in vivo, including enhanced cell proliferation and survival, growth factor independence, protection from apoptosis, and drug resistance. ^2-5

PI3K Inhibitors

Data surrounding the association of PIK3CA mutations with estrogen/progesterone receptor expression (ER/PR+) or human epidermal growth factor receptor-2 gene (HER2) amplification have been variable. Given the high frequency of these mutations and their prognostic implications, an increasing focus has been placed on the development of inhibitors of the PI3K pathway. In this manuscript, we will review the rationale for exploring PI3K inhibitors in breast cancer.Numerous PI3K inhibitors (ATP-mimetics that bind competitively and reversibly to the ATP-binding pocket of p110α subunit) have been developed and are in varying stages of clinical testing (Table 1). These include pan-PI3K inhibitors, isoform specific inhibitors (that allow higher doses of anti-p110a and anti-p110b drugs to be delivered without incurring side effects caused by pan-PI3K inhibitors), and combined PI3K/mTOR inhibitors (which aim to overcome the loss of feedback inhibition of PI3K activation seen with the analogues of rapamycin). Janku et al showed a favorable response to PI3K/AKT/mTOR inhibitors in patients with PIK3CA mutant tumors who had failed conventional therapy.⁶

Table 1. Select PI3K Inhibitors in Clinical Development

ER+ Breast Cancer

Overall, toxic effects from PI3K inhibitors have been primarily mild to moderate, and manageable with supportive medication. Several of the toxic effects seen are “off-target” effects, but others seem to be directly related to PI3K target engagement and mechanisms of action, such as hyperglycemia, which is more commonly seen upon more sustained inhibition of p110α.⁷ Dose-limiting toxic effects reported with multiple agents include hyperglycemia, maculo-papular rash, gastrointestinal intolerance (anorexia, nausea, vomiting, dyspepsia, diarrhea), and stomatitis. Of note, the only pan-PI3K inhibitor that can cross the blood-brain barrier (buparlisib [BKM120], Novartis, data on file) potentially inhibits PI3K in the central nervous system,^8,9 and was commonly associated with mood alteration (anxiety, irritability, or depression) in phase I clinical trials.^7,10 The mood alteration is mild overall, and responsive to dose reductions/interruptions (suggesting dose dependency), as well as treatment with selective serotonin reuptake inhibitors and anxiolytics.ER+ Breast Cancer and PI3K Pathway

The ER signaling pathway and PI3K pathway have significant cross-talk. PI3K has been shown to interact with ER directly and indirectly, resulting in ER phosphorylation and an increase in ER transcription.^11,12 Conversely, ER also upregulates the PI3K pathway by promoting transcription of genes involved in the PI3K pathway, including receptor ligands, RTKs, and signaling adaptors.¹³ Interestingly, estrogen deprivation has been shown to downregulate PI3K and phosho-mTOR,¹⁴ suggesting that part of the antitumoral activity seen with endocrine therapies may stem from abrogation of cell survival, via downregulation of the PI3K/ AKT/mTOR pathway.

PIK3CA is mutated in about 40% of ER+ breast cancers,^15-17 but its prognostic significance is still unclear. Some series have found an association of PIK3CA mutations and poor prognostic features.^18,19 In contrast, other series have shown an association between PIK3CA mutations and improved recurrence-free survival.^15,20-24 Despite the conflicting prognostic significance of PIK3CA mutations, activation of the PI3K/AKT pathway has been shown to confer resistance to antiestrogens in various experimental models.²⁵ PI3K signaling has been shown to promote estrogen-independent growth of ER+ breast cancer cells,^26,27 and tumor cells with acquired endocrine resistance have been shown to upregulate PI3K/KT/mTOR activity,²⁶ one of the main mechanisms of adaptation of ER+ cells to estrogen deprivation. Interestingly, this estrogen-independent growth can be inhibited by the addition of PI3K inhibitors to antiestrogens, as shown in ER+ cell lines and xenograft models,²⁸ suggesting that PI3K inhibition may overcome endocrine resistance. ²⁹ Additionally, PI3K inhibition of long term estrogendeprived breast cancer cell lines has been shown to also induce apoptosis.^26,27 However, the addition of exogenous estrogen negated the PI3K inhibitor—induced apoptosis on these ER positive cells,²⁷ implying that PI3K inhibitors still require estrogen deprivation to be effective, providing a synergistic rationale for combinations of antiestrogens with PI3K pathway inhibitors.

PI3K Inhibitors in ER+ Breast Cancer

Strong clinical evidence of the relevance of the PI3K pathway in ER+ breast cancer has already been shown in clinical trials incorporating the mTOR (TORC1) inhibitor everolimus. The combination of everolimus with the aromatase inhibitor exemestane is already a US Food and Drug Administration strategy for patients with ER+ metastatic breast cancer refractory to prior aromatase inhibitor use, in view of the significant increase in progression-free survival in that group (BOLERO-2).³⁰ Within the BOLERO-2 trial, exon sequence and gene copy number variations were analyzed by next-generation sequencing (NGS) in a subset of patients. The treatment benefit of everolimus over placebo was maintained in the subgroups defined by genes with a mutation rate >10% (such as PIK3CA, FGFR1, and CCND1).

However, patients with 0 or 1 genetic alterations in PI3K or FGFR pathways or CCND1 had a greater treatment effect from everolimus (hazard ratio [HR] = 0.27; 95% CI, 0.18-0.41, adjusted by covariates, in 76% of the NGS population), indicating the value of these pathways for predicting sensitivity to everolimus in this setting. Nevertheless, until further confirmation, there are no biomarkers that reliably predict benefit (or lack thereof) from PI3K/mTOR inhibitors, that can be used for either clinical trial development or individual therapeutic decisions. Therefore, the optimal patient selection for current and future clinical trials with PI3K inhibitors is still a topic of controversy.

The first reported clinic trial of a PI3K inhibitor in combination with endocrine therapy was a phase Ib study of the oral reversible inhibitor of all class I PI3K buparlisib (BKM120) with letrozole in post menopausal patients with ER+ metastatic breast cancer.10 Common drug-related adverse events included ≤grade 2 hyperglycemia, nausea, fatigue, transaminitis, and mood disorders, and were similar to what was seen in the single-agent buparlisib trial.7 Two of the patients had objective responses to treatment, and about 30% of patients in the trial remained free of progression for 6 more months. Of note, PIK3CA mutation status did not predict clinical activity in this cohort of patients. Buparlisib is now part of 2 ongoing phase III trials, in combination with fulvestrant or placebo, in postmenopausal ER+/HER2-negative metastatic breast cancer refractory to aromatase inhibitors (BELLE-2; NCT01610284) and aromatase inhibitors and mTOR inhibitors (BELLE-3; NCT01633060).

HER2+ Breast Cancer

Numerous other trials are ongoing evaluating other pan-PI3K and isoform-specific PI3K inhibitors in ER+ breast cancer (Table 2), including a neoadjuvant phase II trial of letrozole with or without buparlisib or BYL719 (an α-specific PI3K inhibitor; Novartis), for patients with operable ER+ breast cancer (NCT01923168). Results of this trial would not only address potential efficacy differences between the PI3K inhibitors, but also potential differences of treatment effect in ER+ PIK3CA mutant and wild-type tumors.HER2+ Breast Cancer and PI3K Pathway

The PI3K pathway is involved in tumor cell progression and survival in HER2-amplified breast cancers; HER2/HER3 dimers activate PI3K, which leads to tumor survival and growth.³¹ Resistance to HER2-targeted therapies, such as trastuzumab, resulting in poor outcome and overall survival, has been associated with somatic alterations that further dysregulate the PI3K signaling pathway,³² such as PTEN-inactivating mutations³³ or PTEN loss³⁴ and “hot-spot” PIK3CA mutations.³⁵ Pre-clinically, PI3K pathway inhibitors can overcome trastuzumab resistance in tumors with PIK3CA mutation or PTEN loss.^35,36 In addition, HER2-amplified tumors that also harbor PIK3CA mutations are less responsive to combinations of HER2-targeted treatments (trastuzumab/lapatinib and trastuzumab/pertuzumab).^{4,23,33,37-40} In contrast to ER+ breast cancer, the presence of alterations in the PI3K pathway in HER2-amplified breast cancers has been consistently associated with resistance to HER2-targeted therapies in vivo. Large neoadjuvant clinical trials with trastuzumab, lapatinib, or the combination of these drugs for patients with stage II and III HER2-amplified breast cancers revealed that about 20% of patients had a PIK3CA mutation in their tumor.⁴¹ In line with similar analyses of the Neo-ALTTO[⁴²],Neosphere⁴³ and the TBCRC006⁴⁴ phase II clinical trials, the observed rate of pathologic complete response seen in the patients with PIK3CA-mutated tumors was significantly lower than that of the patients with wild-type PIK3CA.

PI3K inhibitors and HER2+ Breast Cancer

Evidence emerging from the clinic confirms that targeting the PI3K axis in addition to HER2 may be a strategy to overcome resistance. BOLERO-3, a phase III randomized trial of trastuzumab and vinorelbine with or without everolimus in women with HER2-amplified metastatic breast cancers refractory to prior HER2 therapies, showed a modest but statistically significant increase in progression-free survival.⁴⁵ Interestingly, patients with ER+/HER2+ tumors did not seem to benefit as much as patients with ER-/HER2+ tumors, but tumors with low PTEN expression and high pS6 were associated with benefit to everolimus addition, suggesting that PI3K/AKT/mTOR pathway activation may be a marker of sensitivity to PI3K pathway inhibitors in HER2+ breast cancer. Researchers conducting a phase I/Ib dose-escalation study of BEZ235 (Novartis), a dual PI3K/mTOR inhibitor, with trastuzumab, aimed to enrich for patients with PI3K pathway alterations by limiting the study to patients with mutations in PIK3CA or PTEN or loss of PTEN by IHC in tumor samples.⁴⁶

Table 2. Select Clinical Trials of PI3K Inhibitors by Breast Cancer Type

Conclusion

Despite clinical activity, the combination was ultimately found to be too toxic, and the study was discontinued. Several other phase I, II, and III trials with various PI3K inhibitors are ongoing (Table 2). Notably, NeoPHOEBE (NCT01816594) is a phase II randomized trial of neoadjuvant paclitaxel and trastuzumab with or without the pan-PI3K inhibitor buparlisib (BKM120) for treatment of stage II and III HER2+ breast cancers, and will evaluate response in PIK3CA mutant vs wild-type tumors.The PI3K pathway is the most frequently altered pathway in cancer, and its activation has been shown to confer resistance to endocrine and HER2-targeted therapies preclinically. Conflicting data have been published regarding the prognostic significance, hormone receptor association, and treatment implications of PIK3CA mutations, and the clinical superiority of PI3K inhibitors, particularly isoform-specific inhibitors, in breast cancers with or without PIK3CA mutations remains to be seen. Nevertheless, emerging clinical data in ER+ and HER2-amplified breast cancers suggest preliminary clinical activity from PI3K inhibitors in combination with endocrine therapy and HER2-targeted therapy, respectively. Several novel and rational clinical trials involving different/complementary pathway inhibitors (phase I, II, and III studies combining PI3K inhibitors with FGFR inhibitors, HER3 inhibitors, CDK4/6 inhibitors, in addition to endocrine therapies, HER2-targeted therapies and chemotherapies) are under way, in an effort to circumvent multiple pathway redundancies and pathway crosstalk.

ABOUT THE AUTHOR

Affiliation: Department of Medicine; Breast Cancer Research Program, Vanderbilt-Ingram Cancer Center; Vanderbilt University School of Medicine, Nashville, TN.

Disclosure: Dr. Mayer has received research funding from Novartis.

Address correspondence to: Ingrid A. Mayer, MD, MSCI, Associate Professor of Medicine, Div. Hematology/Oncology/Department of Medicine, Vanderbilt University School of Medicine, 2220 Pierce Avenue, 777 PRB, Nashville, TN 37232-6307; tel: 615 936 3524; fax: 615 343-7602; email: ingrid.mayer@vanderbilt.edu.

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