Sequencing ESR1/AKT/PIK3CA targeted therapies in patients with breast cancer

By Naveed Saleh, MD, MS | Medically reviewed by Jeffrey A. Bubis, DO, FACOI, FACP
Published March 5, 2024

Key Takeaways

  • Many patients with advanced breast cancer exhibit resistance to endocrine therapy.

  • The latest research has focused on treating breast cancer that exhibits ESR1 and PIK3CA mutations, which are major drivers of endocrine resistance in hormone receptor-positive breast cancer.

  • Researchers have been exploring strategies such as PI3K/AKT/PTEN pathway targeting while emphasizing recent studies with drugs like alpelisib and capivasertib, highlighting potential breakthroughs in addressing endocrine resistance.

Hormone receptor-positive (HR+), HER2-negative (HER2−) represents about 70% of all metastatic breast cancer cases, and patients with this type of breast cancer often exhibit resistance to endocrine therapy. 

Researchers have been hard at work developing strategies to overcome such resistance by means of precision interventions. Let’s take a closer look.

Resistance pathways

Endocrine resistance can evolve from post-translational modifications, genetic dysregulation, and altered cell signaling promoting ligand-independent activation of the estrogen receptor and decreased sensitivity to anti-estrogens.

Often noted following treatment with aromatase inhibitors, according to Harvard researchers publishing in Clinical Cancer Research, a major mechanism of resistance is mutation of the ERα gene or ESR1.[] The majority of somatic ESR1 mutations occur at the level of the ESR1 ligand-binding domain within D538 or Y537. Whether fulvestrant is effective against such mutations remains to be elucidated. 

PI3K pathway dysregulation in metastatic breast cancer progression and endocrine resistance also plays a major role in endocrine resistance present in breast cancer progression.

In nearly 40% of HR+, HER2− advanced breast cancers, mutations are present in PIK3CA, which encodes the phosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit α, thus leading to a gain-of-function phenotype and increased downstream signaling and oncogenesis.

“Most mutations occur at E542K or E545K of exon 9 (helical domain of p110α), and H1047R/L of exon 20 (activation loop in the kinase domain), representing ‘hotspot’ mutations,” write the Clinical Cancer Research authors. “Prior clinical studies have demonstrated HR+ breast cancers with mutations in either exon 9 or exon 20 exhibited decreased response to ET. To address this clinically, several targeted therapies have been developed to inhibit the PI3K pathway. Efficacy of the PI3Kα inhibitor alpelisib in an endocrine-resistant population with HR+, HER2− ABC [advanced breast cancer] was demonstrated in the phase III SOLAR-1 study, demonstrating improved median PFS in combination with fulvestrant in patients with PIK3CA-mutant tumors, although no statistical benefit in OS was observed.”

Targeting PI3K/AKT/PTEN

PIK3CA mutations occur in about 40% of patients with HR+, HER2− breast cancer. According to the results of a phase 3 study (n=572) published in the NEJM, investigators compared alpelisib plus fulvestrant with placebo plus fulvestrant in patients with HR+, HER2− advanced breast cancer who had received prior endocrine therapy.[] The PFS was 11.0 months for the alpelisib-fulvestrant group vs 5.7 months in the placebo-fulvestrant group.

“These results show improvements in patients’ outcomes with the addition of an α-specific PI3K inhibitor to standard treatment for PIK3CA-mutated, HR-positive, HER2-negative advanced breast cancer, findings that validate PIK3CA as an important treatment target in this population,” the investigators wrote. “Patients with PIK3CA-mutated, HR-positive, HER2-negative advanced breast cancer that had progressed during or after the receipt of endocrine therapy had significantly longer progression-free survival when they received alpelisib-fulvestrant than when they received placebo-fulvestrant,” they continued, noting an estimated 35% lower risk of progression or death.

The investigators did not note a benefit treating with alpelisib-fulvestrant in the cohort without PIK3CA-mutated cancer. However, in the cohort with PIK3CA-mutated cancer, alpelisib-fulvestrant was associated with better treatment response vs the placebo cohort.

“Progression-free survival was similar in the placebo groups in the two cohorts defined according to PIK3CA mutation status,” they concluded.

As detailed in another study published by NEJM, CAPItello-291 (n=708) is a phase 3, randomized, double-blind study that assessed the AKT inhibitor capivasertib in combination with fulvestrant vs placebo and fulvestrant in patients who had hormone receptor-positive metastatic breast cancer pretreated with an aromatase inhibitor followed by disease progression.[] The median PFS was 7.2 months in the capivasertib–fulvestrant group vs 3.6 months in the placebo-fulvestrant group. 

“Capivasertib–fulvestrant therapy resulted in significantly longer progression-free survival than treatment with fulvestrant alone among patients with hormone receptor-positive advanced breast cancer whose disease had progressed during or after previous aromatase inhibitor therapy with or without a CDK4/6 inhibitor,” the authors concluded.

Capivasertib (Truqap) is a potent inhibitor of all 3 AKT isoforms (AKT1, AKT2, AKT3), which is an effector of the PI3K/AKT/PTEN pathway that is downstream of PI3K and PTEN.[]

In November 2023, the FDA approved capivasertib for adult patients with HR+, HER2− locally advanced or metastatic breast cancer with one or more PIK3CA/AKT1/PTEN-alterations, as detected by an FDA-approved test (FoundationOne CDx assay), following progression on at least one endocrine-based regimen in the metastatic setting or recurrence on or within 12 months of completing adjuvant endocrine therapy.[]


ESR1 mutations are linked to increased mortality. Dutch researchers assessed the effects of ESR1 mutations detected by circulating tumor DNA (ctDNA) for impact on outcome to taxane-based chemotherapy using paclitaxel/bevacizumab in advanced breast cancer patients, publishing their findings in Breast Cancer Research and Treatment.[]

PFS at 6 months was 86% in patients with an ESR1 mutation detected and 85% in wildtype ESR1 patients, while median PFS was 8.2 months for ESR1 mutant patients compared with 8.7 months for ESR1 wildtype patients (p = 0.47). The median OS was 20.7 months for ESR1 mutant patients compared with 28.1 months for ESR1 wildtype patients (p = 0.27). Patients with ≥ 2 ESR1 mutations exhibited a significantly worse OS vs patients who did not (p = 0.003), although PFS was unaffected.

“Presence of ESR1 mutations in baseline ctDNA might not be associated with inferior PFS and OS in advanced breast cancer patients treated with paclitaxel/bevacizumab,” the researchers concluded.


In the EMERALD trial, examined in an article from the Journal of the National Comprehensive Cancer Network (JNCCN), investigators compared the use of elacestrant vs endocrine therapy of physician choice (fulvestrant or aromatase inhibitor) in patients (n=477) who were previously administered 1 or 2 lines of endocrine therapy, including 1 line containing a CDK4/6 inhibitor and up to 1 line of chemotherapy in the metastatic setting.[] ESR1 mutational status was assessed via cell-free circulating tumor DNA (ctDNA).

At 1 year, all patients administered elacestrant exhibited an improved PFS vs the control group (22.3% vs 9.5%), with significantly higher PFS improvements at 1 year among the subgroup that received elacestrant and had ESR1 mutations (26.8% vs 8.2%).

The NCCN’s formal recommendation reads, “In the recently updated guidelines, the panel has included elacestrant as a new treatment option for postmenopausal females or adult males with ER-positive, HER2-negative, ESR1-mutated tumors after disease progression on 1 or 2 prior lines of endocrine therapy, including 1 line containing a CDK4/6 inhibitor. The panel recommends evaluating ESR1 mutational status using next-generation sequencing or by assessing the ctDNA in the blood using PCR. Because ESR1 mutations are acquired during treatment, primary archived breast cancer should not be used as a source of tumor tissue for ESR1 mutation testing.”

Abemaciclib plus fulvestrant

The Harvard researchers performed an exploratory analysis to determine the efficacy of abemaciclib plus fulvestrant in patients with or without PIK3CA or ESR1 mutations in MONARCH 2.

Abemaciclib plus fulvestrant lengthened PFS compared with placebo plus fulvestrant in both PIK3CA-wildtype (median 16.9 months vs 12.3 months) and PIK3CA-mutant subgroups (median 17.1 months vs 5.7 months). The same was seen in ESR1-wildtype (median 15.3 months vs 11.2 months) and ESR1-mutant subgroups (median 20.7 months vs 13.1 months). Regardless of PIK3CA or ESR1 mutation status, OS and other outcomes also improved following treatment with abemaciclib plus fulvestrant.

“In this exploratory analysis,” they wrote, “we show in HR+, HER2− ABC, abemaciclib plus fulvestrant improved both PFS and OS, regardless of PIK3CA or ESR1 mutation status. In addition, abemaciclib plus fulvestrant improved other endpoints, including TTC, CFS, and PFS2, regardless of PIK3CA or ESR1 mutation status." The authors noted, however, that their analysis was limited by sample size.

They continued: “While acknowledging the limitations of cross study comparisons, the similarity of outcomes for the single-agent fulvestrant control arms in PIK3CA-mutant cancers between MONARCH 2 and SOLAR-1 and the magnitude of improvement in PFS and OS demonstrated in MONARCH 2 also highlights a potential therapeutic strategy for treatment of HR+, PIK3CA-mutant metastatic breast cancer and support further evaluation in prospective, and suitably powered, clinical trials.”

What this means for you

HR-positive, HER2-negative breast cancer represents about 70% of all metastatic breast cancer, with resistance to endocrine therapy common. Mutations in ESR1 and PIK3CA commonly underlie endocrine resistance, and recent research has focused on finding effective regimens to overcome such resistance.

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