Selecting the right therapy for advanced ER-positive metastatic breast cancer has become increasingly complex in the era of ESR1 mutations, PIK3CA-targeted therapies, and novel oral SERDs. At the Best of Hematology & Breast Cancer 2026 conference, Dr. Xiaowen Wang presented a case-based discussion illustrating how next-generation sequencing (NGS), circulating tumor DNA (ctDNA) monitoring, and evolving clinical trial data—including EMERALD, SOLAR-1, INAVO120, and emerging SERD combination studies—are reshaping treatment sequencing. Her insights highlight how personalized therapy selection can maximize progression-free survival while preserving quality of life for patients navigating multiple lines of endocrine-based therapy.

Dr. Xiaowen Wang is a board-certified medical oncologist who treats patients with all types of cancer at Providence. She has a particular interest in the management of hematologic malignancies, breast cancer, liver cancer, neuro-oncology, and ovarian cancer. At the Best of Hematology & Breast Cancer 2026 conference in Seattle, Dr. Wang presented a case-based discussion exploring the evolution of treatment options for ER-positive metastatic breast cancer over a seven-year period, highlighting key decision points in therapy sequencing and the growing complexity of treatment selection in the era of novel SERDs and targeted combinations.

The transcript report below has not been reviewed by the speaker and may contain errors.

Case Presentation: Initial Diagnosis and Early Treatment

The patient is a 56-year-old woman diagnosed with right breast early-stage breast cancer in 2009. The tumor was grade 3, T1N2, and she underwent lumpectomy with axillary lymph node dissection. Six nodes were positive. The tumor was ER and PR strongly positive, HER2 2+ by IHC but negative by FISH. She received adjuvant chemotherapy with dose-dense AC followed by Taxol in December 2009. She underwent prophylactic oophorectomy and was prescribed anastrozole for approximately five years, though there was some non-compliance, which she later disclosed.

Nine years later, in 2018, she presented with recurrence involving bone metastases only, confirmed by left sacral bone biopsy. The tumor remained ER strongly positive but was now PR negative and HER2 negative by FISH. She was started on first-line letrozole and palbociclib in September 2018.

Treatment Challenges and Disease Progression

The patient, who was in her late 40s at the time of metastatic diagnosis, experienced significant side effects from palbociclib and discontinued it in 2021. She subsequently developed bone progression and agreed to restart palbociclib at a lower dose, but tumor markers continued to rise. Although scans were relatively stable without showing evidence of progression, Guardant360 testing was performed in August 2023, revealing both ESR1 and PIK3CA mutations.

Clinical Decision Point: Timing of Next-Generation Sequencing

This case raises an important question regarding the optimal timing of next-generation sequencing. Should NGS be ordered at initial metastatic diagnosis, or should clinicians wait until second-line or third-line settings? For this patient, knowledge of the PIK3CA mutation at the beginning would have potentially changed management, though it certainly would have introduced different toxicity considerations.

Discussion among experts suggested that for patients with a long interval between initial treatment and metastatic recurrence who are slow progressors, triple therapy at the outset may not be necessary due to toxicity concerns and prior tolerance issues. Current practice patterns typically involve ordering NGS once patients develop metastatic disease and undergo a confirmatory biopsy. This approach is particularly important because PIK3CA mutations are often stable over time, whereas ESR1 mutations can fluctuate. Many clinicians obtain sequencing at the beginning and may repeat it after one to two lines of therapy, depending on the time interval.

The NATALEE study was mentioned as relevant for patients who are primarily resistant during adjuvant therapy, though this did not apply to the presented case.

Monitoring with Circulating Tumor DNA

The question arose whether serial ctDNA analysis during first-line treatment could be beneficial. This relates to the SERENA-6 study, which was updated at San Antonio last month with PFS2 data. The study showed statistically significant results, with PFS1 measuring from randomization to first progression and PFS2 extending to second progression. Overall survival data are not yet available. Importantly, the control arm was not allowed to receive SERDs or alpelisib plus fulvestrant, which limits interpretation regarding whether starting SERDs early or six weeks earlier provides benefit.

The consensus view for slow, smoldering disease is that there is no rush to deplete the arsenal of non-toxic agents before reaching the chemotherapy phase. The study also reported quality of life measures and delay to chemotherapy as clinically meaningful outcomes. More data are needed regarding how many control arm patients received SERDs. In current practice, ctDNA monitoring would not be routinely used unless patients are anxious and requesting CT scans every three months.

Treatment Selection After First-Line Progression

After progression on first-line therapy, the patient had excellent performance status, was asymptomatic, and had progression with both ESR1 and PIK3CA mutations present. Available options included switching the endocrine backbone or switching CDK4/6 inhibitors, though these approaches are more appropriate for patients without ESR1 mutations. The main decision came down to elacestrant alone versus alpelisib plus fulvestrant.

At the time of decision-making in August 2023, elacestrant approval as a single agent was based on the EMERALD study, showing 9.1 months progression-free survival for patients who had received CDK4/6 inhibitor for more than 12 months and were ESR1 positive. The SOLAR-1 study evaluating alpelisib plus fulvestrant was conducted mostly in post-menopausal women without prior CDK4/6 inhibitor exposure, showing impressive progression-free survival. However, the INAVO120 study, recently presented at San Antonio, included patients who all received CDK4/6 inhibitor, and progression-free survival was not as impressive. This finding was confirmed in the EPIK-B study. The toxicity profile of alpelisib compared to elacestrant was a significant consideration.

The patient, being young and wanting to maintain an active life without additional toxicities, chose to switch to elacestrant alone. She experienced a remarkable and durable response lasting more than two years with normal quality of life and no side effects, making her very satisfied with the decision.

Expanded Treatment Options in the Current Era

Today, patients progressing through first-line AI and CDK4/6 inhibitors have significantly more options. Imlunestrant was approved just a few months ago based on the EMBER-3 trial. Multiple combination trials reported at ASCO and San Antonio last year showed promising results combining novel SERDs with other targeted agents.

For patients with PIK3CA mutations, capivasertib was approved two years ago, though this option was not available when the patient initially progressed. The VIKTORIA-1 study, first reported at ESMO and then at San Antonio, demonstrated that the pan-AKT inhibitor capivasertib targeting the PI3K-AKT pathway showed very good progression-free survival in the mutant population. Results for the wild-type population are awaited.

Combination Therapy Trials with Novel SERDs

A summary of combination trials with novel SERDs and targeted agents reveals a clear message: progression-free survival is substantially better than single-agent SERD, not just in ESR1-positive patients but across all patients in intention-to-treat analyses, including those with PIK3CA mutations. Combinations of SERDs with either alpelisib or abemaciclib show progression-free survival exceeding 10 months. The ELARIO trial combining elacestrant with capivasertib is particularly exciting and awaited.

Subsequent Progression and Treatment Selection

After approximately two years of excellent response, the patient developed progression several months ago with rising tumor markers. She remained asymptomatic with excellent performance status and very active. The decision was made to switch to capivasertib with fulvestrant. Expert discussion validated this as a reasonable choice, noting the transition from one SERD to another SERD with an AI and capivasertib, though this specific combination lacks proven data. The alternative consideration was comparing side effects between alpelisib plus fulvestrant versus capivasertib, with capivasertib potentially being less toxic.

Evolution of Treatment Landscape Over Seven Years

This patient's seven-year journey provides a backdrop for examining the evolution of available options for patients progressing through first-line AI and CDK4/6 inhibitor therapy. The treatment landscape has expanded considerably, with SERENA-4 and PERSEVERE data on first-line SERD anticipated. If SERDs prove superior to SERD plus CDK4/6 inhibitor combinations, checking ESR1 mutation status may become less relevant if all patients benefit more from SERDs from the beginning.

Current Challenges and Future Directions

With expanded options come new questions and challenges. Key considerations include determining which patients can receive single-agent SERD with minimal toxicity versus those requiring combination therapy, which is expected to receive approval. Additional questions involve selecting combinations based on mutation profiles and optimal sequencing strategies. These represent the current complexities in the field.

However, there is substantial reason for optimism. The bar has been raised from progression-free survival of two to three months several years ago, to five to five-and-a-half months with single-agent SERDs in studies like EMERALD, to eleven months now being observed with combinations. This progress brings the field closer to the ultimate goal of prolonging patient lives while preserving good quality of life. Significant progress continues to be made in achieving this objective.