Introduction

Hormone receptor-positive, HER2-negative (HR+/HER2-) breast cancer is the most common subtype of breast cancer and its treatment landscape has never been more complex or more promising. The endocrine therapy toolkit has expanded substantially over the past decade, moving from tamoxifen and aromatase inhibitors to CDK4/6 inhibitors, selective estrogen receptor degraders (SERDs), PI3K/AKT/mTOR pathway inhibitors, and emerging agents including PROTACs. The challenge now is knowing which tool to use, for which patient, and when.

This review covers the most clinically relevant 2025–2026 data across the disease continuum: genomic testing to guide chemotherapy decisions in early-stage disease, CDK4/6 inhibitor maturation in the adjuvant setting, the emergence of next-generation SERDs including giredestrant and camizestrant, and new options for PIK3CA-mutant metastatic disease.

Guiding Chemotherapy Decisions with Genomics: FLEX and OPTIMA

A central question in early-stage HR+/HER2- breast cancer is which patients benefit from chemotherapy. Tumor biology, not just anatomic stage, is increasingly the answer.

The FLEX trial (O'Shaughnessy, SABCS 2024 and 2025) uses the MammaPrint 70-gene panel to stratify patients by molecular subtype and identify who benefits from specific chemotherapy backbones. Key insights: luminal A (low-risk) tumors show minimal pathologic complete response to neoadjuvant chemotherapy while high-risk luminal B tumors and basal-like tumors derive the greatest benefit. Critically, when comparing anthracycline-containing (AC-T) versus anthracycline-free (TC) regimens in the adjuvant setting, MammaPrint high-risk group 2 tumors (and those with oncotype DX score >30 and tumor >2 cm) benefit meaningfully from adriamycin-based chemotherapy, while high-risk group 1 tumors show equivalent outcomes with TC. Low and ultra-low risk tumors raise the question of whether chemotherapy provides any meaningful benefit at all. The ongoing OFSET trial (NCT05879926) is a phase III trial randomizing chemotherapy to ovarian function suppression and plus endocrine therapy in early HR positive HER2 negative breast cancer patients with oncotype <25 and pN0-1 tumors. The ongoing SWOG S2206 trial (NCT06058377) is testing the addition of durvalumab to dose-dense ACT in stage II and III MammaPrint high-risk group 2 patients.

The OPTIMA trial (Stein RC et al.) addressed a complementary question: can the Prosigna (PAM50) risk of recurrence (ROR) score guide chemotherapy decisions in patients with up to nine positive lymph nodes? In this phase 3 non-inferiority trial, patients with ROR >60 received chemotherapy plus endocrine therapy, while those with ROR ≤60 received endocrine therapy alone. The primary endpoint was invasive breast cancer-free survival (iBCFS).

Non-inferiority was demonstrated for both the complete per-protocol population (adjusted HR 1.03; 90% CI 0.85–1.25) and the low-score subgroup (ROR ≤60; adjusted HR 1.06; 90% CI 0.80–1.40), with observed 5-year differences of 1.5% and 1.2% favoring chemotherapy, respectively, both within the non-inferiority margins. Distant recurrence-free interval results were concordant. Subgroup analysis was reassuringly consistent, with hazard ratios clustering tightly around 1.0.

The implication is significant: for patients with low Prosigna ROR scores, including those with up to nine positive lymph nodes, chemotherapy may not add meaningful benefit beyond endocrine therapy. This is particularly relevant for patients with multiple positive nodes and low-grade tumors, a population where chemotherapy has historically been given reflexively despite uncertain benefit. OPTIMA is not yet practice-changing for most clinicians given its four-year median follow-up, and important questions remain about concordance with oncotype DX and MammaPrint. 

CDK4/6 Inhibitors Mature: Monarch E and NATALEE

Two adjuvant CDK4/6 inhibitor trials have now reported long-term data.

Monarch E (ESMO 2025; Teplinsky et al.) reported 10-year invasive disease-free survival and, importantly, overall survival benefit with abemaciclib added to endocrine therapy in high-risk, node-positive HR+/HER2- early breast cancer. The OS benefit, long awaited, confirms that the iDFS separation seen at earlier timepoints translates to a survival advantage.

NATALEE (Hortobagyi, Ann Oncol 2025) reported three-year data for ribociclib plus endocrine therapy in a broad early-stage HR+/HER2- population (including some stage II patients), continuing to show separation of the iDFS curves. Some patients enrolled in NATALEE have now completed their two-year ribociclib course, and follow-up data confirm durable benefit.

In practice, selecting between abemaciclib and ribociclib requires individualization. For high-risk patients who meet Monarch E eligibility criteria (node-positive, high-risk features), abemaciclib is the preferred choice; the diarrhea is manageable with loperamide. For lower-risk patients, younger patients, or those who do not meet Monarch E criteria, ribociclib is a reasonable and well-tolerated alternative. The two drugs are not interchangeable in eligibility terms, and the different trial populations mean direct comparison is not straightforward.

Next-Generation SERDs in the Adjuvant Setting: lidERA BC

The lidERA BC trial (NCT04961996; Schmid P et al.) is a global phase 3 trial randomizing 4,170 patients with stage I–III ER+/HER2- early breast cancer to giredestrant 30 mg orally once daily versus standard-of-care endocrine therapy (tamoxifen or aromatase inhibitor), with ovarian function suppression required for premenopausal women. Patients could have received prior chemotherapy and up to 12 weeks of endocrine therapy or CDK4/6 inhibitor before enrollment.

At data cutoff August 8, 2025, giredestrant demonstrated improved distant recurrence-free interval (DRFI) compared to standard endocrine therapy in both premenopausal patients (3-year DRFI 95.5% vs 92.6%, HR 0.58; 95% CI 0.38–0.90) and postmenopausal patients (3-year DRFI 93.6% vs 91.6%, HR 0.76; 95% CI 0.56–1.04), with a statistically significant benefit in premenopausal women. Exploratory analyses showed benefit versus both tamoxifen and aromatase inhibitors.

The tolerability profile was favorable: arthralgia and hot flushes were the most common adverse events, consistent with endocrine therapy class effects. Fewer patients switched to alternative endocrine therapy in the giredestrant arm (5.7% vs 10.1%), and fewer discontinued due to adverse events (5.3% vs 8.2%).

This is part of a growing body of evidence supporting next-generation SERDs in early-stage disease. Additional trials including ELEGANT (elacestrant) and CAMBRIA-2 (camizestrant, without any concomitant AI) are ongoing, and the field is moving toward oral SERDs as potential adjuvant standards.

SERDs in Metastatic Disease: persevERA and SERENA-6

persevERA: First-Line Giredestrant Plus Palbociclib

The persevERA BC trial (NCT04546009; Goetz MP et al.) was a phase 3, randomized, double-blind trial comparing giredestrant 30 mg orally once daily plus palbociclib versus letrozole plus palbociclib in 992 patients with first-line HR+/HER2- locally advanced or metastatic breast cancer.

The primary endpoint of investigator-assessed PFS was not met: median PFS was 28.2 months with giredestrant plus palbociclib versus 33.1 months with letrozole plus palbociclib (HR 0.89; 95% CI 0.76–1.05; p=0.1553). Overall survival was also not significantly different (HR 1.03; 95% CI 0.83–1.28). The PFS curves showed some late separation, and the question of whether giredestrant might benefit specific subpopulations (particularly those with ESR1 mutations at baseline or de novo metastatic disease) remains open. For now, this trial does not change first-line practice; letrozole or anastrozole plus CDK4/6 inhibitor remains the standard.

SERENA-6: Early ESR1 Mutation Detection Changes the Game

The more compelling metastatic SERD story comes from SERENA-6 (Goetz MP et al.), which took a strategically different approach: rather than replacing first-line therapy, it asked whether detecting ESR1 mutations early on serial ctDNA testing, before radiographic progression, could guide a timely switch to camizestrant.

Among 3,256 patients undergoing serial ESR1 mutation screening every two to three months, approximately 20% developed an ESR1 mutation within two years. Of those with a detected mutation but no radiographic progression, 315 were randomized to switch to camizestrant plus CDK4/6 inhibitor or continue AI plus CDK4/6 inhibitor. The results were striking: median PFS of 16.8 months with camizestrant versus 9.2 months with AI (HR 0.45; 95% CI 0.34–0.59; p<0.00001). PFS2 was also significantly improved (median 25.7 vs 19.1 months, HR 0.63; p=0.00373). Overall survival data remain immature at 30% (HR 0.87, trending favorably).

The clinical implication is that ESR1 mutation testing on serial liquid biopsy during first-line CDK4/6 inhibitor therapy can identify patients who are about to progress on AI-based therapy, and switching to a next-generation oral SERD at that point, before overt progression, yields substantially better outcomes than waiting. This represents a meaningful new strategy for sequencing endocrine therapy in the metastatic setting.

PIK3CA-Mutant Disease: VIKTORIA-1 and Gedatolisib

The VIKTORIA-1 trial (Hurvitz SA et al., J Clin Oncol 2026) evaluated gedatolisib, a pan-class I PI3K/mTOR inhibitor, in two parallel studies. Study 2 (PIK3CA-mutant) randomized 310 patients with HR+/HER2- advanced breast cancer who had progressed on CDK4/6 inhibitor plus non-steroidal aromatase inhibitor to gedatolisib 180 mg IV weekly plus palbociclib 125 mg daily plus fulvestrant versus alpelisib plus fulvestrant.

The primary endpoint was met convincingly: median PFS 11.1 months with gedatolisib triplet versus 5.6 months with alpelisib plus fulvestrant (HR 0.50; 95% CI 0.37–0.68; p<0.0001). The benefit was consistent across all prespecified subgroups. Interim OS favored gedatolisib (mOS NR vs 31.1 months, HR 0.76) but did not reach significance at 45.8% maturity (p=0.0908).

Compared to alpelisib, gedatolisib had a more manageable toxicity profile: the hyperglycemia and rash that limit alpelisib use were substantially reduced, though prophylactic steroid "swish and spit" and antihistamine therapy were protocol-mandated. VIKTORIA-2 is now enrolling gedatolisib in the first-line setting.

For patients with PIK3CA-mutant HR+/HER2- metastatic breast cancer progressing on CDK4/6 inhibitor therapy, gedatolisib plus palbociclib plus fulvestrant offers a meaningful improvement over alpelisib plus fulvestrant and adds to the growing menu of options alongside capivasertib (AKT inhibitor) and inavolisib (PI3Kα inhibitor). The imlunestrant plus abemaciclib combination and use of imlunestrant outside the ESR1-mutant setting are also emerging data points to watch.

Lobular Breast Cancer: A Distinct Biology Demanding a Distinct Approach

Invasive lobular carcinoma (ILC) represented a dedicated session at ASCO 2026, reflecting growing recognition that ILC is biologically and clinically distinct from invasive ductal carcinoma. Key takeaways: standard imaging including mammography and PET often underestimates ILC size or fails to detect it; breast MRI should be used when feasible. Breast-conserving surgery is generally safe but carries higher positive margin rates; shave margins and oncoplastic approaches are recommended. The question of whether sentinel node omission is safe in ILC remains unresolved, given the likelihood of occult nodal involvement.

From a systemic therapy standpoint, there are no ILC-specific treatment recommendations, and current practice mirrors that of HR+/HER2- ductal cancers. However, multiple retrospective studies suggest decreased response to chemotherapy in early-stage ILC, and molecular tools to predict chemotherapy benefit are lacking. The past decade has produced substantially greater biologic insight, and rationally designed clinical trials with correlative science are beginning to push ILC toward precision medicine.

For Patients

If you have been diagnosed with HR-positive, HER2-negative breast cancer, one of the most important conversations to have with your oncologist is whether genomic testing of your tumor tissue can help guide treatment decisions. Tests like MammaPrint (70-gene), Oncotype DX, and Prosigna (PAM50) can help identify whether chemotherapy is likely to add meaningful benefit beyond endocrine therapy, potentially allowing some patients to avoid chemotherapy and its side effects.

If you have been on CDK4/6 inhibitor therapy in the metastatic setting, ask about serial liquid biopsy testing for ESR1 mutations. Detecting an ESR1 mutation before you show progression on imaging may open the door to an earlier switch to a more effective endocrine therapy, improving outcomes.

The range of treatment options for HR+/HER2- breast cancer continues to grow. This means more individualized treatment is possible, but it also means that multidisciplinary expertise and access to clinical trials are increasingly important for optimizing care.

Key Takeaways

  • FLEX data establish that tumor genomic subtype (MammaPrint) can guide both the decision to use chemotherapy and the choice of backbone: high-risk group 2 tumors benefit from anthracycline-based regimens; high-risk group 1 tumors have equivalent outcomes with TC.

  • OPTIMA demonstrated non-inferiority of a Prosigna-guided, test-directed approach versus standard chemotherapy in patients with up to nine positive lymph nodes and low ROR scores; data are maturing and not yet practice-changing but support the principle that biology matters more than node count.

  • Monarch E (ESMO 2025) confirmed an OS benefit for adjuvant abemaciclib in high-risk node-positive HR+/HER2- early breast cancer at 10-year follow-up; NATALEE 3-year data show continued iDFS separation with ribociclib.

  • lidERA BC: giredestrant significantly improved DRFI versus standard endocrine therapy in premenopausal patients (HR 0.58) and showed a favorable trend in postmenopausal patients, with a better tolerability and discontinuation profile than standard endocrine therapy.

  • persevERA BC: giredestrant plus palbociclib did not improve PFS over letrozole plus palbociclib in the first-line metastatic setting; standard CDK4/6 inhibitor plus AI remains the first-line standard.

  • SERENA-6: early detection of ESR1 mutations on serial liquid biopsy and proactive switch to camizestrant plus CDK4/6 inhibitor (before radiographic progression) improved PFS from 9.2 to 16.8 months (HR 0.45) versus continuing AI.

  • VIKTORIA-1 (Study 2): gedatolisib plus palbociclib plus fulvestrant improved PFS from 5.6 to 11.1 months (HR 0.50) versus alpelisib plus fulvestrant in PIK3CA-mutant HR+/HER2- advanced breast cancer post-CDK4/6 inhibitor; OS data are immature but trending favorably.

  • ILC is biologically distinct from ductal carcinoma and may respond differently to chemotherapy; MRI is preferred for local staging; dedicated ILC clinical trials are underway.

References

  1. O'Shaughnessy J, et al. FLEX trial: MammaPrint to guide chemotherapy selection in HR+/HER2- breast cancer. SABCS 2024 and SABCS 2025.

  2. Stein RC, et al. OPTIMA: Prosigna-guided chemotherapy decisions in node-positive HR+/HER2- breast cancer. [full citation needed; presented ASCO 2026]

  3. Teplinsky E, et al. Monarch E: 10-year iDFS and OS with adjuvant abemaciclib. ESMO 2025.

  4. Hortobagyi GN, et al. NATALEE: 3-year ribociclib plus endocrine therapy in early HR+/HER2- breast cancer. Ann Oncol. 2025. [full citation needed]

  5. Schmid P, et al. lidERA BC: giredestrant versus standard endocrine therapy in early HR+/HER2- breast cancer. NCT04961996. Data cutoff August 8, 2025.

  6. Goetz MP, et al. persevERA BC: giredestrant plus palbociclib versus letrozole plus palbociclib in first-line HR+/HER2- metastatic breast cancer. NCT04546009.

  7. Goetz MP, et al. SERENA-6: camizestrant plus CDK4/6 inhibitor versus AI plus CDK4/6 inhibitor after ESR1 mutation detection without radiographic progression. Data cutoff January 2, 2026.

  8. Hurvitz SA, et al. VIKTORIA-1: gedatolisib plus palbociclib plus fulvestrant versus alpelisib plus fulvestrant in PIK3CA-mutant HR+/HER2- advanced breast cancer. J Clin Oncol. 2026. [full citation needed]

  9. Mukhtar R, et al. Clinical challenges in treating invasive lobular carcinoma. ASCO 2026.

  10. Jeselsohn R, et al. Systemic therapy considerations in invasive lobular carcinoma. ASCO 2026.