ESR1, PIK3CA, and Beyond: Precision Therapy Advances in HR+ Breast Cancer

Hormone receptor-positive (HR+) breast cancer (BC) is the most common subtype of all BC diagnoses, accounting for nearly 70% of all cases. Initial treatment for patients with HR+ BC typically includes CDK4/6 inhibitors, which have led to improved outcomes for patients. However, approximately 50% of patients progress after 18 months of initial treatment. These patients have limited options, underscoring the need for more targeted therapeutic approaches.¹

3D visualization of breast cancer on transparent body | Image Credit: © Crystal light - stock.adobe.com

In a session at the 2025 ASCO Annual Meeting, experts discussed Strategies and clinical approaches to the treatment of patients with HR+ BC following CDK4/6 inhibitor-combination therapy, highlighting the use of targeted and endocrine therapies, the growing landscape of cytotoxic therapies, and emerging agents for later lines of treatment.

Resistance to CDK4/6 inhibitors, Endocrine Therapy

Mutations are key drivers of resistance, poor treatment responses, and more severe disease. In HR+ BC, there are multiple mutations that drive worse disease, but they also act as predictive biomarkers and targets for evolving agents.¹

Cyclin E1 amplification has been identified as a key mechanism of resistance to CDK4/6 inhibitors in HR+ BC. It is linked to CDK2-dependent tumor cell proliferation, which allows cancer cells to bypass the CDK4/6 blockade. Cyclin E1 amplification may be used as a predictive biomarker to identify patients who require alternative therapeutic approaches that target downstream or parallel pathways.¹

Similarly, alterations in the p53 pathway are associated with a lack of long-term response to CDK4/6 inhibitors. These are found in approximately 27% to 30% of patients with hormone receptor–positive disease. Given their impact on treatment resistance, p53 pathway alterations also underscore the importance of exploring alternative strategies beyond CDK4/6 inhibition.¹

Endocrine therapy is another hallmark of therapy for patients with HR+ BC; however, resistance to endocrine therapy is a common obstacle. Resistance to endocrine therapy is also driven by mutations, namely ESR1 and PIK3CA, which occur in approximately 40% of all diagnoses.¹

ESR1 mutations typically develop during endocrine therapy—acting as adaptive mechanisms during treatment. Notably, ESR1 mutations are not all alike and different variants (D530G, Y537S, Y537N, and D538G) can have varying levels of sensitivity to treatment, with some more challenging to target than others.¹

"We would pose this question: how do these next-generation oral anti-estrogens fare against specific ESR1 variants?” Posed Seth Andrew Wander, MD, PhD, from the Massachusetts General Hospital Cancer Center, Harvard Medical School. “And can dynamic changes in ESR1 mutational burden inform our understanding of prognosis?"¹

Alongside ESR1, another frequently observed mutation in hormone receptor–positive breast cancer is PIK3CA. This gene encodes the catalytic subunit of the PI3K enzyme, which plays a critical role in regulating key cellular functions such as growth, proliferation, and survival. Mutations in PIK3CA lead to hyperactivation of the PI3K/AKT/mTOR signaling pathway, driving increased tumor growth and contributing to therapeutic resistance. Their presence has important treatment implications, as they are associated with reduced responsiveness to endocrine therapy.¹

Targeting Mutations

Selective estrogen receptor degraders (SERDs) are designed to overcome endocrine therapy resistance by specifically targeting ESR1 and have the potential to overcome resistance mechanisms. Elacestrant is the first FDA-approved SERD for patients with ESR1-mutant HR+ metastatic BC who are refractory to endocrine therapy. Its approval was based on data from the EMERALD trial (NCT03778931), where elacestrant led to an increase in progression-free survival (PFS) from 3.8 to as long as 9 months. The agent shows superior benefit in patients with longer CDK4/6 inhibitor therapy.^1,2

Another available SERD that shows promising potential for this patient population is camizestrant (AZD9833; AstraZeneca), which is under investigation for the treatment of HR+ BC. In the SERENA-2 trial (NCT04214288), camizestrant was evaluated against fulvestrant in the second-line metastatic setting. The drug demonstrated promising monotherapy activity, particularly in molecular subgroups with ESR1 mutations. Phase 3 trials are assessing a daily dose of 70 to 75 mg. One of the camizestrant’s distinguishing features is its favorable safety profile with generally low-grade adverse events (AEs). The most common AEs reported were mild bradycardia and photopsia (a visual light sensitivity). Notably, the drug has not been associated with high-grade toxicities.^1,3

Alpelisib is the first approved PIK3CA inhibitor, representing a significant advancement in the treatment of HR+ BC. The FDA’s decision was based on data from the randomized SOLAR-1 trial (NCT02437318) assessing fulvestrant monotherapy compared with fulvestrant plus alpelisib in endocrine refractory patients with HR+ BC harboring PIK3CA mutations. The data showed that adding apelisib to fulvestrant yielded improvements in PFS from approximately 6 to 11 months, supporting its use in precision medicine approaches. Additionally, apelisib has a favorable and manageable safety profile, with the most common AEs being hyperglycemia, diarrhea, and rash.^1,4

Beyond oral SERDs and targeted inhibitors, antibody drug conjugates (ADCs) have demonstrated potential for treatment of patients who progress beyond CDK4/6 or endocrine therapies, such as datopotamab deruxtecan (Dato-DXd, Datroway; AstraZeneca, Daiichi Sankyo), trastuzumab deruxtecan (T-DXd; Enhertu; Daiichi Sankyo and AstraZeneca), and sacituzumab govitecan-hziy (SG, Trodelvy; Gilead Sciences).¹

“We now have 3 FDA-approved ADCs: [T-DXd], [SG], and [Dato-DXd],” explained Rena Desai Callahan, MD, from UCLA Health Jonsson Comprehensive Cancer Center. “They do have side effects that can be similar to cytotoxic chemotherapy, and how to sequence them remains in question."¹

Across clinical trials, these agents show notable improvements in PFS and overall survival (OS). In the DESTINY-Breast04 trial (NCT03734029), T-DXd significantly increased PFS from 5 to 10 months and OS from 18 to 24 months. Trop-2–directed ADCs are also under investigation as promising treatment options. In the TROPiCS-02 trial (NCT03901339), SG improved PFS from 4 to 5.5 months and OS from 11 to 14 months in heavily pretreated patients with HR+ BC. Another Trop-2–targeted ADC is Dato-DXd. In the TROPION-Breast01 trial (NCT05104866), Dato-DXd improved PFS from 5 to 7 months.^{1, 5-7}

Optimizing targeted therapies through the identification and targeting of molecular markers is critical to overcome resistances to CDK4/6 inhibitors and endocrine therapy—and what to do next when those resistances occur. In his presentation, Wander shared what this really means for patients.

“It means delivering upon the promise of personalized medicine and precision oncology,” he said. “Finding the right drug, for the right patient, at the right time.”

REFERENCES

1. Jhaveri K, Wander S, Callahan R, et al. After a CDK4/6 inhibitor: State of the art in hormone receptor-positive metastatic breast cancer. 2025 ASCO Annual Meeting. May 30, 2025, to June 3, 2025. Chicago, IL.

2. Phase 3 trial of elacestrant vs. standard of care for the treatment of patients with ER+/​HER2- advanced breast cancer (EMERALD). Updated October 30, 2024. Accessed May 31, 2025. https://clinicaltrials.gov/study/NCT03778931

3. A study to investigate efficacy and safety with oral AZD9833 compared with intramuscular fulvestrant in post-menopausal women at least 18 years of age with advanced ER-positive HER2 negative breast cancer (SERENA-2). Updated April 11, 2025. Accessed May 31, 2025. https://clinicaltrials.gov/study/NCT04214288

4. Study assessing the efficacy and safety of alpelisib plus fulvestrant in men and postmenopausal women with advanced breast cancer which progressed on or after aromatase inhibitor treatment. (SOLAR-1). Updated February 13, 2025. Accessed May 31, 2025. https://clinicaltrials.gov/study/NCT02437318

5. Trastuzumab deruxtecan (DS-8201a) versus investigator's choice for HER2-low Breast cancer that has spread or cannot be surgically removed [DESTINY-Breast04]. Updated April 11, 2024. Accessed May 31, 2025. https://clinicaltrials.gov/study/NCT03734029

6. Study of sacituzumab govitecan-hziy versus treatment of physician's choice in participants with HR+/​HER2- metastatic breast cancer (TROPiCS-02). Updated October 21, 2024. Accessed May 31, 2025. https://clinicaltrials.gov/study/NCT03901339

7. A phase-3, open-label, randomized study of Dato-DXd versus investigator's choice of chemotherapy (ICC) in participants with inoperable or metastatic HR-Positive, HER2-negative breast cancer who have been treated with one or two prior lines of systemic chemotherapy (TROPION-Breast01). Updated April 14, 2025. Accessed May 31, 2025. https://clinicaltrials.gov/study/NCT05104866