Key Ideas

The treatment landscape for hormone receptor-positive, HER2-negative breast cancer is expanding well beyond aromatase inhibitors, with next-generation oral degraders, PROTAC inhibitors, and PI3K/AKT pathway-targeted agents all offering new chemotherapy-free options. Circulating tumor DNA (ctDNA) is moving from a purely prognostic tool toward a genuinely interventional one, with a landmark trial now showing that switching therapy based on an emerging resistance mutation, before clinical progression, meaningfully extends how long a first-line regimen keeps working.

A Rapidly Expanding Amount of Oral Options

Care for hormone receptor-positive, HER2-negative advanced breast cancer is broadening well past the traditional aromatase inhibitor backbone. Newer oral selective estrogen receptor degraders (SERDs), PROTAC-based ER degraders, and PI3K pathway-targeted agents are opening more chemotherapy-free treatment sequences for patients, and ctDNA testing is shifting from a tool that mostly tells us prognosis to one that can genuinely guide a treatment decision before a scan shows progression.

Switching Therapy Before Progression: The SERENA-6 Approach

ESR1 mutations are rare at diagnosis, present in fewer than 5% of tumors, but they emerge through aromatase inhibitor exposure and are detectable in roughly 40% of patients at the time of disease progression, since these hotspot mutations cause constitutive activation of the estrogen receptor regardless of estrogen levels. Camizestrant is a next-generation oral SERD and complete ER antagonist designed to degrade both mutant and wild-type estrogen receptor.

The phase 3 SERENA-6 trial enrolled 315 patients with HR-positive, HER2-negative advanced breast cancer who had received at least six months of first-line aromatase inhibitor plus a CDK4/6 inhibitor (palbociclib, ribociclib, or abemaciclib). Patients underwent ESR1 mutation testing via a ctDNA-based test roughly every two to three months, considerably more frequently than most practices currently test in the real world. Upon detection of an ESR1 mutation without evidence of clinical progression, patients were randomized to switch to camizestrant while continuing the same CDK4/6 inhibitor, or to continue the aromatase inhibitor plus CDK4/6 inhibitor. Randomization also accounted for visceral versus non-visceral disease, time since treatment initiation, and which CDK4/6 inhibitor the patient was on.

Median progression-free survival was 16 months with the camizestrant switch versus 9.2 months with continued aromatase inhibitor therapy, a substantial difference. The strategy suggests that when an ESR1 mutation emerges, switching just the endocrine backbone to camizestrant while keeping the same CDK4/6 inhibitor extends the benefit of that first-line combination considerably, offering a meaningful chemotherapy-free option for longer. Camizestrant received FDA approval based on this data.

Post-CDK4/6 Options: EMBER-3 and VERITAC-2

For patients whose disease progresses after CDK4/6 inhibitor therapy, treatment is increasingly biologically targeted rather than defaulting straight to chemotherapy. EMBER-3, approved in 2025, compared imlunestrant against standard-of-care endocrine therapy, and separately against imlunestrant plus abemaciclib, in pretreated patients with advanced breast cancer. The combination of imlunestrant and abemaciclib extended progression-free survival to 10.9 months across all patients; overall survival data remain immature, though median overall survival in ESR1-mutated patients was 34.5 months with imlunestrant alone versus standard of care, regardless of ESR1 mutation status, and had not yet been reached in the imlunestrant-abemaciclib group at the time of presentation, compared with 34.4 months in the comparator arm.

VERITAC-2 tested a different mechanism entirely: vepdegestrant is a first-in-class PROTAC (proteolysis-targeting chimera) inhibitor that uses the proteasome degradation pathway and selectively degrades both wild-type and mutant estrogen receptor. This randomized phase 3 trial compared vepdegestrant against fulvestrant in patients with radiological progression on prior treatment; prior CDK4/6 inhibitor therapy was required, and prior chemotherapy was allowed, though prior fulvestrant was not. In the ESR1-mutated subgroup, progression-free survival was meaningfully longer with vepdegestrant, 5 months versus 2.1 months with fulvestrant; across all patients regardless of ESR1 mutation status, the difference was smaller, 3.7 months versus 3.6 months. Clinical benefit rate nearly doubled with vepdegestrant, and objective response rates were also better, though the absolute numbers are modest and worth discussing honestly with patients, since a longer progression-free survival is still measured in a small number of months. Vepdegestrant received FDA approval in May of this year for ESR1-mutated advanced or metastatic breast cancer, using a companion ctDNA diagnostic to confirm ESR1 mutation status.

Comparing the Current Field of Estrogen Receptor Degraders

Several ER-degrading agents are now approved in this space, each studied against a slightly different comparator: fulvestrant, based on the FALCON trial, showed 16.6 months versus 13.8 months compared with an aromatase inhibitor; elacestrant, based on the EMERALD trial, showed 3.8 months versus 1.9 months; imlunestrant showed 5.5 months versus 3.8 months; and vepdegestrant showed 5 months versus 2 months. Toxicities across these newer oral agents tend to include fatigue and musculoskeletal pain, and clinicians should monitor for QTc prolongation and mild nausea; bradycardia is also worth watching for with any of these agents.

A newer oral SERD combined with a CDK4/6 inhibitor after prior CDK4/6 inhibitor progression has shown a substantial reduction in risk of disease progression in early data, with a larger benefit in ESR1-mutated patients than in the intention-to-treat population overall; this combination remains under FDA review, with a decision anticipated later this year, and appears generally well tolerated, though overall survival data remain immature.

The PI3K Pathway: Two Options Now Available

For PIK3CA-mutated, hormone receptor-positive, HER2-negative disease, INAVO120 supported a new frontline approval combining a PI3K inhibitor with palbociclib for patients developing metastatic disease after prior adjuvant endocrine therapy. Patients with PIK3CA mutations tend to have worse outcomes on endocrine therapy alone, which is part of the rationale for treating with this triplet upfront rather than waiting. Median progression-free survival was 15 months with the triplet compared with 7.3 months with palbociclib-based therapy alone, and objective response rate was 58% versus 25%; overall survival did not reach statistical significance, though there was an overall trend toward benefit. This combination is generally well tolerated, though which CDK4/6 inhibitor partner is truly optimal in this setting remains an open, evidence-free question.

CAPItello-291 addressed a related but distinct population: PI3K-wild-type, hormone receptor-positive advanced breast cancer, using capivasertib, which targets the PI3K-AKT-mTOR pathway more broadly, in combination with fulvestrant versus fulvestrant alone, in patients who had progressed during or after a CDK4/6 inhibitor. Median progression-free survival was 9.3 months with the combination versus 2 months with fulvestrant alone; common toxicities included neutropenia, stomatitis, rash, hyperglycemia, and diarrhea, similar to what is generally seen with PI3K-AKT pathway-targeted agents. This regimen is given intravenously on days 1, 8, and 15 of each 28-day cycle in combination with fulvestrant, making it a non-chemotherapy option even though it requires infusion visits, and received FDA approval earlier this year. A related follow-up analysis of overall survival in this setting did not reach statistical significance, likely reflecting that the study was underpowered for that endpoint rather than a true absence of benefit, and capivasertib-based combinations are also being explored in earlier-stage disease.

Rethinking Genomic Testing and Chemotherapy Decisions in Early-Stage Disease

The OPTIMA trial addressed a very practical question in early-stage, node-positive, hormone receptor-positive breast cancer: using the Prosigna (PAM50) recurrence score, an assay not commonly used in the United States, to guide chemotherapy decisions. In this trial, patients received adjuvant chemotherapy at investigator discretion in the control arm, while the test-directed arm randomized patients with a high recurrence score to chemotherapy plus endocrine therapy and those with a low score, using a cutoff of 60, to endocrine therapy alone. Among patients with a recurrence score below that cutoff, there was no meaningful difference in outcomes between the two approaches, even in a population that included patients with zero to nine involved lymph nodes. That finding is genuinely difficult to fully absorb, since it suggests chemotherapy may be safely omitted even in some node-positive patients when genomic risk is low, though the field is still working out exactly how, and in whom, to apply this in practice, and there remains no good decision-making tool yet for very young patients specifically.

The lidERA trial examined a related but distinct question in the curative-intent, adjuvant setting: comparing adjuvant chemotherapy with standard endocrine therapy against giredestrant, a newer oral SERD, in stage I to III disease, using a somewhat higher-risk selection than typical stage I populations. Three-year invasive disease-free survival was 94% with giredestrant versus 91.5% with standard endocrine therapy in premenopausal women, and 91.3% versus 88.3% in postmenopausal women. Toxicity was generally driven by musculoskeletal pain related to giredestrant, without other significant added toxicity, and discontinuation rates were actually somewhat lower with giredestrant, making this a potential future option worth watching.

Separately, a large meta-analysis of roughly 15,000 premenopausal women with hormone receptor-positive breast cancer receiving endocrine therapy found that ovarian function suppression substantially reduced 15-year recurrence and death, with the benefit more pronounced in women under 45, particularly those confirmed to be premenopausal after completing chemotherapy. This is a conversation worth having proactively and more assertively with younger patients, since the benefit appears meaningful.

For Patients: What This Means for Your Treatment Options

If you have hormone receptor-positive breast cancer and your cancer has progressed on treatment, ask your oncologist whether ctDNA blood testing for resistance mutations, such as ESR1, might be relevant to your care, since a positive result can open up newer oral treatment options that avoid chemotherapy. If you are premenopausal and under 45, ask specifically about ovarian function suppression as part of your endocrine therapy, since data show this can meaningfully reduce the risk of recurrence over the long term. And if your treatment team recommends genomic testing on your tumor before deciding on chemotherapy, understand that this reflects a genuine and evolving effort to spare patients from chemotherapy they may not need, though the science here is still developing, especially for younger patients.

Key Takeaways

  • The SERENA-6 trial showed that switching to camizestrant while continuing the same CDK4/6 inhibitor, guided by ctDNA detection of an ESR1 mutation before clinical progression, extends progression-free survival to 16 months versus 9.2 months with continued aromatase inhibitor therapy.

  • Vepdegestrant (VERITAC-2), a first-in-class PROTAC ER degrader, and imlunestrant (EMBER-3) both offer new oral options after CDK4/6 inhibitor progression, particularly in ESR1-mutated disease, though absolute gains in progression-free survival remain modest and worth discussing honestly with patients.

  • For PIK3CA-mutated disease, INAVO120 supports a frontline triplet combination; for PI3K-pathway-wild-type disease progressing after CDK4/6 inhibitor therapy, capivasertib plus fulvestrant (CAPItello-291) offers another option.

  • The OPTIMA trial suggests that genomically low-risk, node-positive, hormone receptor-positive breast cancer may not benefit from added chemotherapy, though how to apply this finding in routine practice is still being worked out.

  • Ovarian function suppression substantially reduces long-term recurrence and death in premenopausal women under 45 with hormone receptor-positive breast cancer and should be discussed proactively with these patients.

References

  1. Bidard FC, Kalinsky K, Cristofanilli M, et al. Camizestrant plus CDK4/6 inhibitor for emergent ESR1 mutations in advanced breast cancer (SERENA-6). Presented at ASCO 2025.

  2. Jhaveri KL, Neven P, Casalnuovo ML, et al. Imlunestrant with or without abemaciclib in ESR1-mutated advanced breast cancer (EMBER-3). Presented at San Antonio Breast Cancer Symposium 2024.

  3. Hurvitz SA, Bardia A, Quiroga V, et al. Vepdegestrant versus fulvestrant in ESR1-mutated advanced breast cancer (VERITAC-2). Presented at ASCO 2025.

  4. Turner NC, Im SA, Saura C, et al. Inavolisib, palbociclib, and fulvestrant in PIK3CA-mutated, hormone receptor-positive advanced breast cancer (INAVO120). N Engl J Med. 2024.

  5. Turner NC, Oliveira M, Howell SJ, et al. Capivasertib in hormone receptor-positive advanced breast cancer (CAPItello-291). N Engl J Med. 2023;388:2058-2070.

  6. Bartlett J, Stein RC, Bliss J, et al. Prosigna (PAM50)-directed chemotherapy decisions in node-positive hormone receptor-positive breast cancer (OPTIMA).