Tag: Breast Cancer

HER2CLIMB-05: Redefining First-Line Maintenance Therapy in HER2-Positive Metastatic Breast Cancer

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SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. It is estimated that in the US, approximately 316,950 new cases of female breast cancer will be diagnosed in 2025, and about 42,170 women will die of the disease, largely due to metastatic recurrence.

Approximately 15-20% of invasive breast cancers overexpress HER2/neu oncogene, which is a negative predictor of outcomes without systemic therapy. Patients with HER2-positive metastatic breast cancer are often treated with anti-HER2 targeted therapy along with chemotherapy, irrespective of hormone receptor status, and this has resulted in significantly improved treatment outcomes. With advances in systemic therapies for this patient population, the incidence of brain metastases as a sanctuary site has increased. Approximately 50% of patients with HER2-positive metastatic breast cancer develop brain metastases. However, systemic HER2-targeted agents, including Tyrosine Kinase Inhibitors, as well as chemotherapy have limited antitumor activity in the brain. Local therapeutic interventions for brain metastases include neurosurgical resection and Stereotactic or Whole-Brain Radiation Therapy. There is a high unmet need for systemic treatment options to treat established brain metastases and reduce the risk for progression in the Central Nervous System (CNS).

Expanding Options Beyond Standard Maintenance

Despite major advances in the management of Human Epidermal growth factor Receptor 2–positive (HER2+) metastatic breast cancer (MBC), disease progression during maintenance therapy remains a persistent challenge. The long-standing first-line (1L) standard of care, induction with Trastuzumab, Pertuzumab, and a Taxane followed by Trastuzumab plus Pertuzumab maintenance, has delivered durable benefit, yet most patients ultimately relapse within two years. This unmet need is particularly relevant in a modern population increasingly exposed to HER2-targeted therapy in the early-stage setting and enriched for de novo metastatic disease.

HER2CLIMB-05 was designed to test whether intensifying HER2 blockade during the maintenance phase, by adding the highly selective oral HER2 tyrosine kinase inhibitor (TKI) Tucatinib (TUKYSA®), could further delay disease progression while preserving tolerability and quality of life.

Study Design and Patient Population

HER2CLIMB-05 (NCT05132582) is a randomized, double-blind, placebo-controlled, International Phase 3 trial enrolling patients with centrally confirmed HER2+ unresectable locally advanced or metastatic breast cancer. Eligible patients had no evidence of disease progression following 4 to 8 cycles of standard 1L induction therapy with Trastuzumab, Pertuzumab, and a taxane, an ECOG performance status of 0 or 1, and no or asymptomatic brain metastases.

A total of 654 patients were randomized 1:1 to receive Tucatinib (300 mg PO twice daily) or placebo, in combination with Trastuzumab and Pertuzumab administered IV every 21 days. Randomization was stratified by de novo versus recurrent disease, Hormone Receptor (HR) status, and presence or history of brain metastases. Endocrine therapy was permitted for patients with HR-positive disease. The Primary endpoint was investigator-assessed Progression-Free Survival (PFS) per RECIST v1.1. Key Secondary endpoints included Overall Survival (OS), PFS by Blinded Independent Central Review (BICR), Central Nervous System (CNS) PFS, safety, and Patient-Reported Outcomes.

The enrolled population reflects current real-world patterns of HER2+ MBC. All patients were female, with a median age of 54 years. Nearly 70% presented with de novo metastatic disease, over half had HR-positive tumors, and 12.4% had a presence or history of brain metastases at baseline. Most patients had excellent performance status, with nearly two-thirds classified as ECOG 0.

Primary Endpoint Met: Significant and Clinically Meaningful PFS Improvement

At a median follow-up of approximately 23 months, HER2CLIMB-05 met its Primary endpoint. The addition of Tucatinib to Trastuzumab and Pertuzumab resulted in a statistically significant and clinically meaningful improvement in PFS compared with standard maintenance therapy alone. Median PFS was 24.9 months in the Tucatinib arm versus 16.3 months in the control arm, corresponding to a 36% reduction in the risk of disease progression or death (Hazard Ratio [HR], 0.64; P < 0.0001). Results from BICR were consistent, reinforcing the robustness of the primary analysis.

Importantly, the PFS benefit was observed across all prespecified subgroups, including patients with and without brain metastases and those with HR-positive or HR-negative disease. This consistency highlights the broad applicability of Tucatinib-based maintenance therapy in HER2+ MBC.

Early Signals in Overall Survival and CNS Outcomes

Overall Survival data remain immature, with approximately 20% of the required events observed at the time of this primary analysis. Median OS has not yet been reached in either arm, with no evidence of detriment associated with Tucatinib and a favorable trend observed.

While CNS-PFS was not reached in the overall population, patients with baseline brain metastases experienced a numerical improvement with Tucatinib, with median CNS-PFS nearly doubling compared with control (8.5 vs 4.3 months). Although preliminary, these findings align with prior HER2CLIMB data supporting Tucatinib’s activity in CNS disease.

Safety Profile: Consistent and Manageable

The safety profile of Tucatinib in combination with Trastuzumab and Pertuzumab was consistent with known toxicities of HER2-directed regimens. Diarrhea, nausea, and transaminase elevations were the most common treatment-emergent adverse events in the Tucatinib arm, the majority of which were low grade and manageable with supportive care and dose modifications.

Grade ≥3 adverse events were more frequent with Tucatinib, particularly elevated ALT and AST; however, hepatic events were generally asymptomatic, reversible, and occurred early in treatment. Discontinuation of Tucatinib due to adverse events occurred in 13.5% of patients, underscoring the importance of proactive monitoring and toxicity management in clinical practice. No new safety signals were identified.

Positioning HER2CLIMB-05 in an Evolving Treatment Landscape

HER2CLIMB-05 adds to a growing body of evidence supporting maintenance intensification strategies in HER2+ MBC. Alongside recent Phase 3 trials such as PATINA and DESTINY-Breast09, these data emphasize that meaningful improvements in disease control can be achieved beyond traditional chemotherapy-based induction regimens.

Unlike antibody–drug conjugate based approaches, Tucatinib-based maintenance offers a chemotherapy-free option that targets HER2 both extracellularly and intracellularly, with particular relevance for patients with brain metastases or those who may not be ideal candidates for prolonged cytotoxic therapy.

Clinical Implications

The HER2CLIMB-05 primary analysis demonstrates that adding Tucatinib to Trastuzumab and Pertuzumab as 1L maintenance therapy significantly prolongs PFS, extending disease control to more than two years in patients with HER2+ metastatic breast cancer. The benefit was consistent across key subgroups, including HR status and CNS involvement, and was achieved with a manageable and familiar safety profile.

As the HER2+ metastatic treatment paradigm continues to evolve, Tucatinib-based maintenance represents an important new option that may delay progression and postpone the need for subsequent cytotoxic therapy. Ongoing follow-up will clarify the impact on Overall Survival, CNS outcomes, and patient-reported Quality of Life, further informing individualized treatment decisions.

HER2CLIMB-05: A Phase 3 Study of Tucatinib Versus Placebo in Combination with Trastuzumab and Pertuzumab as First-line Maintenance Therapy for HER2+ Metastatic Breast Cancer. Dieras V, Curigliano G, Martin M, et al. on behalf of the HER2CLIMB-05 investigators. J Clin Oncol. DOI: 10.1200/JCO-25-02600

First Line Sacituzumab Govitecan in Advanced Triple-Negative Breast Cancer

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SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. It is estimated that in the US, approximately 316,950 new cases of female breast cancer will be diagnosed in 2025, and about 42,170 women will die of the disease, largely due to metastatic recurrence.

Clinical Context

TNBC accounts for roughly 10–15% of breast cancers and is characterized by its aggressive biology and lack of targetable receptors. Survival prospects in the metastatic setting are particularly poor and fewer than 20% of patients are alive at 5 years. Treatment options remain limited for patients with newly diagnosed, locally advanced unresectable or metastatic triple-negative breast cancer (TNBC) who are not candidates for PD-1/PD-L1 blockade, as approximately 60% of metastatic TNBCs are PD-L1–negative (CPS <10), excluding them from approved chemo-immunotherapy regimens. Aside from PARP inhibitors, which apply only to a minority with germline BRCA1/2 mutations, cytotoxic chemotherapy has remained the default first-line therapy despite short survival and limited durability. Compounding this unmet need, real-world data show that nearly half of patients never receive second-line therapy due to rapid progression or early mortality. Thus, optimizing first-line outcomes is essential, particularly for patients not eligible for immunotherapy.

TRODELVY® (Sacituzumab govitecan) is an Antibody-Drug Conjugate (ADC) in which SN-38, an active metabolite of Irinotecan, a Topoisomerase I inhibitor, is coupled to the humanized Anti-Trophoblast cell-surface antigen 2 (Trop-2) monoclonal antibody (hRS7 IgG1κ), through the cleavable CL2A linker. SN-38 cannot be given directly to patients because of its toxicity and poor solubility. Trop-2, a transmembrane calcium signal transducer, stimulates cancer-cell growth, and this cell surface receptor is overexpressed in several epithelial cancers including cancers of the breast, colon and lung, and has limited expression in normal human tissues. Trop-2 is expressed in more than 85% of breast tumors including Triple Negative Breast Cancer. Upon binding to Trop-2, the anti-TROP-2 monoclonal antibody is internalized and delivers SN-38 directly into the tumor cell, making it a suitable transporter for the delivery of cytotoxic drugs. Further, the cleavable linker enables SN-38 to be released both intracellularly into the tumor cells, as well as the tumor microenvironment, thereby allowing for the delivery of therapeutic concentrations of the active drug in bystander cells to which the conjugate has not bound. Thus, TRODELVY®-bound tumor cells are killed by intracellular uptake of SN-38, whereas the adjacent tumor cells are killed by the extracellular release of SN-38. The Phase 3 ASCENT-03 trial provides important new evidence supporting Sacituzumab govitecan as a frontline therapeutic foundation for this high-risk group.

ASCENT-03 Trial Overview

ASCENT-03 was an International, open-label, randomized Phase 3 trial evaluating Sacituzumab govitecan versus investigator’s choice of chemotherapy (Paclitaxel, nab-Paclitaxel, or Gemcitabine/Carboplatin) in patients with untreated advanced or metastatic TNBC who were not candidates for PD-1/PD-L1 inhibitors. Most participants (about 99% in each arm) had PD-L1–negative disease. Eligibility also included PD-L1–positive patients previously treated with checkpoint inhibitors or those with comorbidities precluding immunotherapy. A total of 558 patients were enrolled globally and randomized 1:1 to receive Sacituzumab govitecan (279 patients) or chemotherapy (279 patients – 56% were selected to receive a taxane and 44% to receive Gemcitabine plus Carboplatin). Treatment continued until disease progression, or unacceptable toxicity. Crossover to Sacituzumab govitecan was permitted for patients in the chemotherapy arm after progression. The Primary endpoint was Progression-Free Survival (PFS) assessed by Blinded Independent Central Review. Key Secondary endpoints included Overall Survival (OS), Objective Response Rate (ORR), Duration of Response (DOR), and Safety.

Efficacy: Meaningful Extension of Disease Control

Sacituzumab govitecan delivered a statistically robust and clinically meaningful improvement in PFS:

  • Median PFS:
    • 9.7 months with Sacituzumab govitecan
    • 6.9 months with chemotherapy
  • Risk reduction: 38% reduction in risk of progression or death (HR 0.62; 95% CI, 0.50–0.77; P<0.001)

Response rates were numerically similar between arms (48% vs. 46%), but Sacituzumab govitecan produced a notably longer median duration of response (12.2 vs. 7.2 months), underscoring the sustained disease control characteristic of Trop-2–targeted therapy.

Improved PFS with Sacituzumab govitecan was observed across most prespecified subgroups, including those with particularly poor prognostic indicators such as early recurrence after curative-intent therapy and the presence of liver metastases.

OS results were immature at the time of analysis and are confounded by crossover; however, the strong PFS signal aligns with survival benefits previously demonstrated in later-line settings (ASCENT) and in PD-L1–positive patients treated with Sacituzumab govitecan plus Pembrolizumab (ASCENT-04).

Safety and Tolerability

The toxicity profile of Sacituzumab govitecan was consistent with prior experience, without new safety signals. Grade ≥3 adverse events were 66% with Sacituzumab govitecan versus 62% with chemotherapy. Most common grade ≥3 events with Sacituzumab govitecan included neutropenia (43%), diarrhea (9%), leukopenia (7%). Despite comparable rates of high-grade events, Sacituzumab govitecan led to fewer dose reductions and considerably fewer discontinuations compared with chemotherapy (4% vs. 12%), suggesting improved treatment continuity. Neutropenia remains an important risk, and emerging regulatory guidance recommends considering primary G-CSF prophylaxis in patients with elevated risk for febrile neutropenia (e.g., age ≥65, prior neutropenia, poor performance status, comorbid organ dysfunction).

Positioning ASCENT-03 Within the Evolving TNBC Landscape

ASCENT-03 complements the ASCENT-04 findings, where Sacituzumab govitecan combined with Pembrolizumab demonstrated meaningful benefit in PD-L1–positive previously untreated metastatic TNBC. Together, these trials provide convergent evidence that Sacituzumab govitecan contributes substantially to disease control, regardless of PD-L1 status, and can serve as either a foundational monotherapy or as part of combination immunotherapy.

For the large subset of patients with PD-L1–negative disease, or those ineligible for checkpoint blockade, ASCENT-03 establishes Sacituzumab govitecan as a superior first-line option compared with standard chemotherapy.

Key Considerations and Limitations

  • The trial’s open-label design introduces potential bias, although PFS assessment was safeguarded by Blinded Independent Central Review.
  • Enrollment of PD-L1–positive patients and those previously treated with PD-1/PD-L1 inhibitors was limited, restricting generalizability to those subgroups.
  • Despite specific efforts to enhance racial diversity, representation of Black patients remained low, highlighting ongoing disparities in TNBC clinical trial participation.

Conclusion

Sacituzumab govitecan significantly prolonged Progression-Free Survival compared with standard chemotherapy in the first-line treatment of advanced or metastatic TNBC among patients who are not candidates for PD-1/PD-L1 inhibitors. With durable responses, a manageable safety profile, and fewer treatment discontinuations than chemotherapy, Sacituzumab govitecan offers a meaningful advance for a population in critical need of more effective therapies.

As experience accumulates from ASCENT-03, ASCENT-04, and ongoing studies in early-stage disease, Sacituzumab govitecan is poised to reshape the treatment paradigm across the TNBC continuum.

Sacituzumab Govitecan in Untreated, Advanced Triple-Negative Breast Cancer. Cortés J, Punie K, Barrios C, et al. N Engl J Med 2025;393:1912-1925

Updated ASCO–ASTRO–SSO Guideline Clarifies Indications and Best Practices for Postmastectomy Radiation Therapy in Breast Cancer

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SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. It is estimated that in the US, approximately 316,950 new cases of female breast cancer will be diagnosed in 2025, and about 42,170 women will die of the disease, largely due to metastatic recurrence.

Background

Postmastectomy radiation therapy (PMRT) remains a cornerstone of curative-intent treatment for many patients with invasive breast cancer, significantly reducing the risk of locoregional recurrence (LRR) and improving Disease-Specific Survival. However, with evolving systemic therapies, less extensive axillary surgery, and modern radiation techniques, the benefit of PMRT now varies widely across patient subgroups. Recognizing the need to update clinical decision-making in this context, the American Society for Radiation Oncology (ASTRO), American Society of Clinical Oncology (ASCO), and Society of Surgical Oncology (SSO) have released a comprehensive new guideline to replace the 2016 version.

The new recommendations jointly published in Journal of Clinical Oncology, Practical Radiation Oncology, and Annals of Surgical Oncology provide refined guidance on when and how PMRT should be applied in both upfront surgical and post-neoadjuvant settings.

Development and Scope

A multidisciplinary task force representing Radiation, Medical, and Surgical Oncology collaborated with experts from the European Society for Radiotherapy and Oncology. The group conducted a systematic review of evidence published between 2005 and 2024 and used structured consensus methods to determine recommendation strength and evidence quality.
The guideline addresses four primary clinical domains:

  1. Indications for PMRT after upfront mastectomy.
  2. Indications for PMRT following Neoadjuvant Systemic Therapy (NAST).
  3. Appropriate treatment volumes and dose-fractionation schedules.
  4. Optimal delivery techniques and normal tissue sparing strategies.

The recommendations are intended for adult patients with breast cancer undergoing mastectomy and are directed toward Radiation, Surgical, and Medical Oncologists, as well as other oncology professionals involved in multidisciplinary breast cancer management.

Key Recommendations

  1. PMRT After Upfront Mastectomy
  • Node-positive disease: PMRT is strongly recommended for most patients with pathologically positive axillary lymph nodes to reduce recurrence and breast cancer–specific mortality.
  • pT4 tumors: Strong recommendation for PMRT regardless of nodal status.
  • pT3N0 tumors: PMRT is conditionally recommended; omission or volume reduction may be appropriate when clinicopathologic features are favorable.
  • pT1–2N0 tumors: PMRT is generally not recommended but may be considered in the presence of multiple high-risk factors (e.g., triple-negative biology, LVI, young age, high grade, or central/medial tumor location).
  • Positive margins: In patients with positive surgical margins but no other PMRT indication, treatment limited to the chest wall or reconstructed breast alone is conditionally advised.
  1. PMRT After Neoadjuvant Systemic Therapy
  • Locally advanced disease (cT4 or cN2–3): PMRT is strongly recommended irrespective of pathologic response.
  • Residual nodal disease (ypN+): Strong recommendation for PMRT to the chest wall and regional nodes.
  • Pathologic complete response (ypN0) after cT1–3N1 or cT3N0 disease: PMRT is conditionally recommended for patients with high-risk features (young age, lymphovascular invasion, high residual cancer in breast); omission may be appropriate for select patients with favorable features.
  • cT1–2N0 disease with ypN0 response: PMRT is generally not indicated unless multiple high-risk factors are present such as young age, lymphovascular invasion, and high residual cancer in breast.
  • Positive post-neoadjuvant margins: PMRT is strongly recommended.
  1. Treatment Volumes and Dose-Fractionation
  • Target volumes: Irradiation should encompass the ipsilateral chest wall or reconstructed breast and regional lymphatics (axillary, supraclavicular, and internal mammary nodes). For selected pT3N0 cases, chest wall treatment alone or reconstructed breast alone may be reasonable.
  • Internal mammary coverage: Should be individualized based on tumor location, nodal burden, and risk features.
  • Fractionation: Moderate hypofractionation is preferred for most patients, including those with reconstruction, while conventional fractionation remains acceptable in select circumstances.
  • Boost therapy: A boost to the chest wall or scar may be considered for patients with T4 disease or close/positive margins. A nodal boost is recommended when residual nodal disease is suspected and surgical clearance is incomplete.
  1. Recommended Techniques for PMRT Delivery
  • Planning and delivery: CT-based volumetric planning using 3-dimensional conformal radiation therapy (3D-CRT) is the standard approach.
  • Advanced modalities: Intensity-Modulated Radiation Therapy (IMRT) or Volumetric Modulated Arc Therapy (VMAT) is advised when 3D-CRT cannot meet dosimetric goals; daily image guidance is recommended.
  • Cardiopulmonary sparing: Deep inspiration breath hold (DIBH) should be used whenever it reduces dose exposure to the heart and lungs, supported by real-time monitoring and image verification.
  • Bolus use: Routine use of tissue-equivalent bolus is not recommended. However, bolus may be selectively applied in cases with skin involvement, positive superficial margins, dermal lymphatic invasion, or extensive lymphovascular invasion.

Implementation Considerations

The guideline emphasizes individualized, multidisciplinary decision-making that weighs recurrence risk against treatment-related toxicities.

  • For patients with limited nodal disease (e.g., T1–2N1), omission of PMRT may be reasonable if the expected absolute benefit is low.
  • Patient preferences and quality-of-life considerations should inform discussions, especially regarding reconstructive implications and late toxicity risks.
  • The recommendations endorse shared decision-making across disciplines, highlighting the importance of coordinated care between surgeons, radiation oncologists, and medical oncologists.

Clinical Perspective

The expert panel acknowledged that radiation therapy after mastectomy can meaningfully reduce recurrence and improve survival, but the benefit must be balanced with the individual’s disease profile and values. The update also acknowledges persistent evidence gaps, particularly regarding patients who achieve nodal pathologic complete response after neoadjuvant therapy, underscoring the need for ongoing prospective research.

Postmastectomy Radiation Therapy: An ASTRO-ASCO-SSO Clinical Practice Guideline. Jimenez RB, Abdou Y, Anderson P, et al. J Clin Oncol, 2025;43:3292-3311

Endocrine Therapy Omission in ER-Low Early Stage Breast Cancer Linked to Worse Survival Outcomes

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SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. It is estimated that in the US, approximately 316,950 new cases of female breast cancer will be diagnosed in 2025, and about 42,170 women will die of the disease, largely due to metastatic recurrence.

Background
Approximately 70% of breast tumors express Estrogen Receptors and/or Progesterone Receptors. Adjuvant Endocrine Therapy (ET) is a cornerstone in managing Estrogen Receptor (ER)–positive early-stage breast cancer, contributing significantly to reduced recurrence and improved Overall Survival (OS). However, its role in patients with ER-low disease, defined as tumors with 1%-10% ER positivity by ImmunoHistoChemistry (IHC), remains unclear and controversial.

Study Objective
The present study was conducted to determine the association between ET omission and OS in high-risk, ER-low early-stage breast cancer patients who received chemotherapy, leveraging Real-World Data from the National Cancer Database (NCDB).

Methods
A retrospective cohort analysis was conducted using the 2021 NCDB Participant User File, focusing on female patients diagnosed with Stage I–III ER-positive breast cancer between 2018 and 2020. ER-low status was defined as 1%-10% ER expression per ASCO/CAP guidelines. Progesterone Receptor (PR)–positive disease was defined as 1% or more receptor expression. This study included patients who received neoadjuvant or adjuvant chemotherapy, reflecting a high-risk population with aggressive tumor features. The study excluded male patients, Stage IV disease, noninvasive cancers, and cases with incomplete treatment or outcome data. The final cohort comprised 7,018 ER-low patients who received chemotherapy.

Key Findings

  • Endocrine Therapy (ET) Usage Patterns:
    Among patients with ER-low breast cancer receiving chemotherapy, 42% did not initiate ET within 12 months post-surgery. ET omission was more prevalent in tumors that were:

    • Progesterone Receptor (PR)–negative
    • HER2–negative
    • High grade (2 or 3)
    • High proliferative index (Ki67 ≥20%)
    • Treated with NeoAdjuvant Chemotherapy (NAC)
  • Survival Impact:
    Over a median follow-up of 3 years, 586 deaths occurred. ET omission was associated with significantly poorer OS:

    • Overall HR: 1.23 (95% CI, 1.04–1.46; P =0.02)
    • ER 1%-5% subgroup: HR 1.15 (95% CI, 0.91–1.45; P =0.24)
    • ER 6%-10% subgroup: HR 1.42 (95% CI, 1.00–2.02; P =0.048)
  • Effect in Residual Disease (RD) After NAC:
    • For patients with RD, ET omission led to worse OS (HR, 1.26; 95% CI, 1.00–1.57; P =0.046)
    • No OS difference was observed in patients who achieved pathologic Complete Response (pCR) (HR, 1.06; P =0.84)
  • 3-Year OS Estimates:
    • With ET: 92.3% (95% CI, 91.3–93.3%)
    • Without ET: 89.1% (95% CI, 87.8–90.5%)

Clinical Implications
These findings suggest that omission of ET in ER-low breast cancer is associated with an increased risk of mortality, particularly in patients with:

  • Residual disease after neoadjuvant chemotherapy
  • Tumors with higher ER expression (6%-10%)

This supports the clinical value of ET even in ER-low disease subsets, which have historically been managed more like Triple-Negative Breast Cancer (TNBC) due to their aggressive features and ambiguous endocrine responsiveness.

Guideline and Research Context
The 2010 ASCO/CAP guidelines established 1% or more ER positivity as the threshold for ET eligibility. Yet, international variation remains. Swedish guidelines, for instance, never adopted the lower threshold, and recent European discourse suggests reverting to 10% or more. Compounding the uncertainty, clinical trials often exclude ER-low tumors or treat them as TNBC. Retrospective studies from Sweden and China have shown mixed results regarding ET’s benefit in ER-low disease, further emphasizing the need for prospective data.

Discussion
Despite the relatively small proportion of ER-low tumors (3% of ER-positive breast cancer), the findings could impact the care of tens of thousands of patients globally. The biologic heterogeneity of ER-low tumors, often resembling basal-like subtypes, complicates treatment decisions. Still, evidence from this large cohort supports offering ET, particularly in patients with residual disease post-neoadjuvant chemotherapy, or tumors on the higher end of the ER-low spectrum. Additionally, the data align with emerging strategies to escalate therapy in ER-low BC, including use of CDK4/6 inhibitors (e.g., Abemaciclib, Ribociclib), which have demonstrated benefit even in this subgroup.

Limitations

  • Lack of data on ET adherence, recurrence, or cause of death
  • Short follow-up (3 years)
  • Potential confounding due to observational design
  • Lack of molecular characterization to distinguish responders

Nevertheless, sensitivity analyses confirmed the robustness of findings.

Conclusion
Omission of endocrine therapy in ER-low, early-stage breast cancer, especially following chemotherapy, is linked to inferior Overall Survival. The strongest signal of benefit is in patients with residual disease post- neoadjuvant chemotherapy and those with ER expression closer to 10%. Until randomized trials clarify endocrine sensitivity in this population, clinicians should counsel patients on the potential survival benefit of ET, even in cases with limited ER expression.

Key Takeaway for Oncologists:
In the absence of prospective trial data, Real-World Evidence supports continued use of endocrine therapy in patients with ER-low early-stage breast cancer, particularly those with residual disease after neoadjuvant chemotherapy or higher ER expression within the 1%-10% range.

Endocrine Therapy Omission in Estrogen Receptor–Low (1%-10%) Early-Stage Breast Cancer. Choong GM, Hoskin TL, Boughey JC, et al. J Clin Oncol 2025;43:1875-1885.

Polygenic Risk Scores Predict Future Breast Cancer Events After In Situ Disease

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SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. It is estimated that in the US, approximately 316,950 new cases of female breast cancer will be diagnosed in 2025, and about 42,170 women will die of the disease, largely due to metastatic recurrence.

Preinvasive breast lesions such as Ductal Carcinoma In Situ (DCIS) and Lobular Carcinoma In Situ (LCIS) are well recognized precursors to invasive disease, yet clinicians currently lack precise tools to predict which patients will ultimately progress. Identifying individuals at highest risk is essential for guiding management, balancing the benefits of early intervention against the harms of overtreatment.

Epidemiologic data suggest that approximately 20–40% of untreated DCIS lesions eventually evolve into invasive breast cancer, while women diagnosed with LCIS have a 7–12-fold higher risk of developing invasive malignancy in either breast over time. Both entities also confer elevated risk for contralateral breast cancer. In this context, genomic risk stratification offers an opportunity to personalize surveillance and preventive strategies.

Understanding PRS313

The 313-SNP breast cancer Polygenic Risk Score (PRS313) quantifies an individual’s inherited susceptibility to breast cancer by integrating the effects of 313 Single Nucleotide Polymorphisms (SNPs) known to influence disease risk. Each variant contributes modestly on its own, but together they generate a composite score that captures the polygenic architecture of breast cancer predisposition.

Using DNA derived from blood or saliva, PRS313 calculates a weighted sum of risk alleles to estimate lifetime breast cancer risk. This score can stratify women into distinct risk quartiles, offering refined insight beyond traditional factors such as family history, breast density, and age. Importantly, PRS313 has been validated in population studies as a predictor of primary breast cancer risk. Recent research now explores its ability to forecast subsequent disease after an initial diagnosis of in situ carcinoma.

Study Overview

Investigators from the ICICLE (Investigate the genetiCs of In situ Carcinoma of the ductaL subtypE) and GLACIER (Genetics of LobulAr Carcinoma In situ in EuRope) studies conducted a retrospective analysis to evaluate whether PRS313 could predict subsequent breast cancer events following DCIS or LCIS.

The study included 2,169 women with DCIS and 185 with LCIS, each followed for a median of 11 years. Cox regression models assessed associations between PRS313 and several outcomes: any subsequent in situ or invasive breast cancer (including distant metastasis), ipsilateral breast disease, invasive ipsilateral disease, and contralateral breast cancer. For DCIS, results were analyzed by PRS313 quartiles; for LCIS, risk was modeled as a continuous variable.

Key Findings

Analysis revealed a significant association between increasing PRS313 and contralateral breast cancer after DCIS (hazard ratio [HR], 1.30; 95% CI, 1.08–1.56). Women in the highest PRS313 quartile were roughly twice as likely to develop contralateral disease compared with those in the lowest quartile. However, PRS313 was not significantly associated with ipsilateral recurrence in DCIS.

In contrast, among women with LCIS, higher PRS313 correlated strongly with ipsilateral breast cancer risk (HR, 2.16; 95% CI, 1.22–3.81). The association was even more pronounced among participants with a family history of breast cancer, where PRS313 increases translated to more than a threefold elevation in ipsilateral disease risk, rising to nearly fourfold when women who had undergone mastectomy or radiotherapy were excluded.

Lead investigator comments emphasized that while LCIS is often managed conservatively, these findings suggest that patients with a strong family history and high PRS313 may derive benefit from additional risk-reducing interventions, such as endocrine therapy or intensified surveillance.

Clinical Implications

This study provides compelling evidence that polygenic risk assessment can refine prognostication in women with in situ breast cancer, distinguishing those most likely to develop future disease. The results support integrating PRS313 into post-diagnosis risk discussions to help patients make informed decisions regarding surgery, chemoprevention, and long-term follow-up intensity.

“By combining genomic data with clinicopathologic features,” the authors noted, “clinicians can deliver more individualized care, moving beyond histologic appearance, to a truly personalized estimate of recurrence risk.”

Study Limitations

The researchers acknowledged several limitations. PRS313 was originally designed to predict invasive breast cancer risk rather than in situ disease specifically, and relevant genetic variants unique to DCIS or LCIS may remain undiscovered. Additionally, the relatively small LCIS cohort limited statistical power and generalizability across ancestries. Ongoing validation in larger and more diverse populations will be necessary before broad clinical implementation.

Conclusion

The ICICLE and GLACIER analyses underscore the potential of PRS313 as a predictive biomarker for future breast cancer events, particularly contralateral disease after DCIS and ipsilateral disease after LCIS. Incorporating polygenic risk profiling into the management of in situ breast lesions could help identify patients who warrant closer monitoring or preventive therapy, while sparing others from unnecessary intervention.

As genomic medicine advances, tools like PRS313 may become integral to personalized breast cancer prevention and survivorship care, aligning treatment intensity with each woman’s unique genetic risk landscape.

Breast Cancer Polygenic Risk Score Associated with Outcomes after In Situ Breast Disease. Timbres J, Kohut K, Mavaddat N, et al. Cancer Epidemiol Biomarkers Prev OF1–OF10. https://doi.org/10.1158/1055-9965.EPI-25-0529. Published: 01 October 2025.

 

FDA Approval of INLURIYO® for ESR1-Mutated ER-positive, HER2-negative Metastatic Breast Cancer: Insights from EMBER-3

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SUMMARY: The FDA on September 25, 2025, approved Imlunestrant (INLURIYO®), an Estrogen Receptor antagonist, for adults with Estrogen Receptor (ER)-positive, Human Epidermal growth factor Receptor 2 (HER2)-negative, ESR1-mutated advanced or metastatic breast cancer with disease progression following at least one line of endocrine therapy. FDA also approved the Guardant360 CDx assay as a companion diagnostic device to identify patients with breast cancer with ESR1 mutations for treatment with Imlunestrant.

Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. It is estimated that in the US, approximately 316,950 new cases of female breast cancer will be diagnosed in 2025, and about 42,170 women will die of the disease, largely due to metastatic recurrence.

Approximately 70% of breast tumors express Estrogen Receptors and/or Progesterone Receptors. The most common subtype of metastatic breast cancer is Hormone Receptor-positive (HR-positive), HER2-negative breast cancer (65% of all metastatic breast tumors), and these patients are often treated with anti-estrogen therapy as first line treatment. However, resistance to hormonal therapy occurs in a majority of the patients, with a median Overall Survival (OS) of 36 months. With the development of Cyclin Dependent Kinases (CDK) 4/6 inhibitors, endocrine therapy plus a CDK4/6 inhibitor is the mainstay, for the management of ER+/HER2-negative metastatic breast cancer, as first line therapy. Even with this therapeutic combination, most patients will eventually experience disease progression, with up to 50% of patients acquiring ESR1 (Estrogen Receptor gene alpha) mutations after exposure to prior endocrine therapy in combination with CDK4/6 inhibitors. These mutations enable constitutive activation of the estrogen receptor, rendering tumors less responsive to traditional endocrine agents. Although Selective Estrogen Receptor Degraders (SERDs) such as Fulvestrant are often used in this setting, their clinical activity is modest and limited by pharmacokinetic and mechanistic constraints, especially in heavily pretreated, endocrine-resistant disease.

Imlunestrant: A Next-Generation ER Antagonist
Imlunestrant is an oral selective estrogen receptor antagonist and degrader designed to provide continuous ER inhibition, including in ESR1-mutated cancers. By binding, blocking, and promoting degradation of the receptor, Imlunestrant aims to suppress ER-driven tumor growth beyond the limits of standard endocrine therapy. Further, Imlunestrant crosses the blood-brain barrier.

The EMBER-3 Trial: Pivotal Data Supporting Approval
The efficacy and safety of Imlunestrant were evaluated in the Phase 3 EMBER-3 trial (NCT04975308), an open-label randomized study that enrolled 874 patients with ER-positive, HER2-negative locally advanced or metastatic breast cancer. All participants had received prior treatment with an aromatase inhibitor, either as monotherapy or in combination with a CDK4/6 inhibitor, but were ineligible for PARP inhibitor therapy.

Patients were randomized (1:1:1) to one of three arms:

  • Arm A: Imlunestrant monotherapy 400 mg orally once daily (N=331)
  • Arm B: Investigators choice of Fulvestrant or Exemestane (N=330)
  • Arm C: Imlunestrant plus Abemaciclib (N=213, investigational)

Randomization was stratified by prior CDK4/6 inhibitor exposure, visceral disease status, and geographic region. ESR1 mutation status was determined via ctDNA analysis using the Guardant360 CDx assay, restricted to defined ligand-binding domain mutations.

The FDA approval was specifically based on results in the ESR1-mutated cohort (N=256). In this subgroup, 21% received therapy as first-line treatment for metastatic breast cancer (following recurrence on adjuvant Aromatase Inhibitor-AI) and 79% as second-line treatment (post-progression on AI, with or without prior CDK4/6 inhibitor).

Efficacy Outcomes

  • Primary endpoint (PFS): Median Progression-Free Survival was 5.5 months with Imlunestrant vs. 3.8 months with standard endocrine therapy (HR 0.62; 95% CI: 0.46–0.82; P=0.0008).
  • Objective Response Rate (ORR): 14.3% with Imlunestrant vs. 7.7% with investigator’s choice.
  • Overall Survival (OS): Data remain immature, with 31% of deaths reported at the time of analysis.

These findings demonstrate a statistically and clinically meaningful improvement in PFS for patients with ESR1-mutant disease, a group with limited therapeutic options following resistance to aromatase inhibitors.

Safety Profile
The safety profile of Imlunestrant was consistent with ER-targeting strategies. Common adverse events (≥10%) included hematologic abnormalities (decreased hemoglobin, neutrophils, platelets), musculoskeletal pain, fatigue, gastrointestinal effects (diarrhea, nausea, constipation, abdominal pain), and laboratory changes such as elevated liver enzymes, triglycerides, or cholesterol.

Looking Ahead: Ongoing EMBER Program
Beyond metastatic disease, Imlunestrant is being studied in earlier disease settings. The EMBER-4 trial is enrolling about 8,000 patients worldwide to evaluate Imlunestrant in the adjuvant treatment of ER-positive, HER2-negative early breast cancer, at elevated risk of recurrence. Combination strategies, including Imlunestrant plus Abemaciclib, are also under active investigation to further enhance ER pathway blockade.

Clinical Perspective
The approval of Imlunestran marks an important advance in precision endocrine therapy, particularly for patients with ESR1-mutated metastatic breast cancer, a population historically limited to suboptimal options after progression on aromatase inhibitors. By offering a targeted, oral agent with meaningful PFS benefit, Imlunestran provides oncologists with a new tool to extend disease control in a challenging clinical context.

Imlunestrant with or without Abemaciclib in Advanced Breast Cancer. Jhaveri KL, Neven P, Casalnuovo ML, et al. for the EMBER-3 Study Group. N Engl J Med 2025;392:1189-1202 

Hormonal Contraception and Breast Cancer Risk in BRCA1/2 Mutation Carriers

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SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. It is estimated that in the US, approximately 316,950 new cases of female breast cancer will be diagnosed in 2025, and about 42,170 women will die of the disease, largely due to metastatic recurrence.

The tumor suppressor genes such as BRCA1 and BRCA2 help repair damaged DNA and thus play an important role in maintaining cellular genetic integrity, failing which these genetic aberrations can result in malignancies. Mutations in BRCA1 and BRCA2 account for about 20 to 25 percent of hereditary breast cancers and about 5 to 10 percent of all breast cancers. These mutations can be inherited from either of the parents and a child has a 50 percent chance of inheriting this mutation, and the deleterious effects of the mutations are seen even when a second copy of the gene in an individual is normal. Women with germline BRCA1 or BRCA2 mutations face markedly elevated lifetime risks of breast cancer, estimated at up to 70%. More than half of these cancers occur before the age of 50, underscoring the importance of informed counseling regarding risk-modifying exposures. One such factor is hormonal contraception, widely used for birth control and non-contraceptive health benefits, but also a potential contributor to breast cancer risk. The present study was conducted to assess the association between use of any hormonal contraception and breast cancer risk for BRCA1 and BRCA2 mutation carriers using individual participant data from four prospective cohorts.

Study Design
A large observational analysis pooled data from four prospective cohorts across Australia, New Zealand, Europe, Canada, and the United States (kConFab FUP, BCFR, RFS, and the UPenn Registry). The study included 3,882 women with BRCA1 mutations and 1,509 with BRCA2 mutations who were followed for a median of approximately six years. Associations between hormonal contraception use and breast cancer incidence were assessed using Cox regression modeling.

Key Findings

  • Hormonal Contraception use prevalence: 53% of BRCA1 carriers and 71% of BRCA2 carriers reported 1 year or more of use (median duration, 4.8 and 5.7 years, respectively). Hormonal contraceptives included birth control pills, patches, implants, injections, vaginal rings, and IUDs containing any hormones.
  • Cancer incidence: During follow-up, 488 BRCA1 and 191 BRCA2 carriers developed breast cancer during median follow-up of 5.9 and 5.6 years, respectively.
  • BRCA1 mutation carriers:
    • Ever use of hormonal contraception was associated with a 29% increased relative risk of breast cancer (HR, 1.29; 95% CI, 1.04–1.60).
    • Longer cumulative use conferred higher risk, with an estimated 3% increase in risk per additional year of use.
    • Current use and recent use were not independently significant, but a dose–response relationship emerged with duration.
  • BRCA2 mutation carriers: No significant association was observed between hormonal contraception use and breast cancer risk (HR for ever use, 1.07; 95% CI, 0.73–1.57). However, the relatively small number of events limits certainty.

Absolute Risk Implications

For BRCA1 carriers, small relative increases translate into substantial absolute risk shifts due to their high baseline susceptibility. For example, modeling suggested that an 18-year-old BRCA1 carrier with a family history of breast cancer would at age 58 face:

  • 51.3% lifetime risk without hormonal contraception use,
  • 56.6% with 5 years of use,
  • 62.0% with 10 years of use,
  • 67.3% with 15 years of use.

Shorter-term use was associated with minimal increases in absolute risk, whereas prolonged exposure yielded more clinically meaningful elevations.

Context and Clinical Considerations

  • Findings align with evidence in the general population showing modest increases in breast cancer risk with hormonal contraception use, though the higher baseline risk in BRCA1 carriers amplifies the absolute impact.
  • The lack of association for BRCA2 carriers should be interpreted cautiously due to limited statistical power.
  • Importantly, while oral contraceptives reduce tubo-ovarian cancer risk, this benefit may be less relevant for BRCA1/2 carriers who undergo guideline-recommended risk-reducing salpingo-oophorectomy by ages 35–45.
  • Study strengths include large BRCA1 cohort size, prospective data collection, and consistent findings across international cohorts. Limitations include observational design, potential misclassification of hormonal contraception type, and limited data beyond 15 years of use.

Take-Home Message for Oncologists
Hormonal contraceptives appear to increase breast cancer risk for BRCA1 mutation carriers, particularly with longer cumulative use, while evidence for BRCA2 remains inconclusive. When counseling patients, absolute risk estimates and individual values should guide decisions. Shorter-term use may be acceptable for some women, but prolonged use could confer risk increases that outweigh potential benefits.

Hormonal Contraception and Breast Cancer Risk for Carriers of Germline Mutations in BRCA1 and BRCA2. Phillips K-A, Kotsopoulos J,  Domchek SM, et al. J Clin Oncol. 2025;43:422-431

Elinzanetant Reduces Vasomotor Symptoms in Women Receiving Endocrine Therapy for HR-Positive Breast Cancer

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SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. It is estimated that in the US, approximately 316,950 new cases of female breast cancer will be diagnosed in 2025, and about 42,170 women will die of the disease, largely due to metastatic recurrence.

Approximately 70% are Hormone Receptor (HR)–positive, and long-term endocrine therapy, typically 5 to 10 years of Tamoxifen or an Aromatase Inhibitor, with or without a GnRH analogue, substantially lowers recurrence and mortality. However, treatment-related Vasomotor Symptoms (VMS), such as hot flashes, are frequent and often more severe than those seen in natural menopause, particularly in younger women receiving GnRH suppression. These adverse effects diminish quality of life and contribute to nonadherence.

Because postmenopausal hormone therapy is contraindicated in this setting, current management options rely on lifestyle measures, behavioral strategies, or off-label medications (e.g., SSRIs, Gabapentin, Clonidine, Oxybutynin), each with limited evidence and tolerability concerns. Thus, effective nonhormonal therapies are a critical unmet need.

Elinzanetant and Mechanism of Action

Elinzanetant is a dual Neurokinin-1 (NK-1) and Neurokinin-3 (NK-3) receptor antagonist. It acts on hypothalamic KNDy (Kisspeptin–Neurokinin–Dynorphin) neurons, which regulate thermoregulation and are hyperactivated by estrogen withdrawal from natural menopause or endocrine therapy. This results in elevated expression of Neurokinin B and Substance P which are responsible for vasomotor symptoms. By modulating Neurokinin B and Substance P signaling, Elinzanetant reduces VMS and may improve sleep disturbances. Unlike other agents in this class, trials to date have not demonstrated hepatotoxicity.

Trial Design

The OASIS-4 trial is a Phase 3, randomized, double-blind, placebo-controlled study conducted at 90 sites across Europe, Canada, Israel, and Kazakhstan. This study included 474 women (aged 18–70) with HR-positive breast cancer or at high risk, receiving Tamoxifen or an Aromatase Inhibitor with or without GnRH analogue, and reporting 35 or more moderate-to-severe VMS episodes per week. Patients were randomized in a 2:1 to receive Elinzanetant 120 mg daily for 52 weeks (N=316) or Placebo once daily for 12 weeks followed by Elinzanetant 120 mg daily for 40 weeks (N=158). The Primary end points were the change in the mean daily frequency of moderate-to-severe vasomotor symptoms from baseline to week 4 and to week 12. While a general guideline is lacking for a “clinically meaningful” reduction in vasomotor symptoms (VMS) caused by endocrine therapy, the reduction of at least 50% from baseline is considered a significant individual benefit for women in natural menopause.

Results:

Elinzanetant significantly reduced moderate-to-severe vasomotor symptoms, improved sleep, and enhanced menopause-related quality of life compared to a placebo

  • Baseline mean daily VMS frequency: About 11 episodes/day in both arms
  • Week 4: Mean reduction of 6.5 daily episodes of moderate-to-severe VMS with Elinzanetant vs. reduction of 3.0 daily episodes with placebo (P <0.001)
  • Week 12: Mean reduction of 7.8 episodes of moderate-to-severe VMS with Elinzanetant vs. reduction of 4.2 daily episodes with placebo (P <0.001)
  • 50% or more reduction in VMS frequency at 12 weeks was achieved by >70% of Elinzanetant-treated participants
  • Benefits extended to improvements in sleep and menopause-related quality of life
  • Safety: most common adverse events were headache, fatigue, and somnolence; serious adverse events occurred in 2.5% vs. 0.6% with placebo
  • No hepatotoxicity signal was detected through 52 weeks
  • Treatment satisfaction: 91.6% of participants completing 52 weeks opted into a 2-year extension

Clinical Implications

Vasomotor symptoms and sleep disruption are among the most burdensome adverse effects of endocrine therapy and are key contributors to poor adherence, which directly impacts long-term breast cancer outcomes. Currently, management options are limited and inconsistently effective, particularly in this population where hormone therapy for menopausal symptoms is contraindicated.

Elinzanetant represents a novel, well-tolerated, nonhormonal strategy that demonstrated reproducible reductions in VMS across both naturally menopausal and endocrine therapy–induced settings. While OASIS-4 was not powered to evaluate breast cancer recurrence or survival, reducing symptom burden may indirectly enhance adherence to endocrine therapy and improve outcomes.

Limitations and Next Steps

The trial population was predominantly White, limiting generalizability. Long-term breast cancer outcomes were not assessed and Real-world tolerability and adherence remain to be defined. Ongoing extension studies and future trials will clarify durability of benefit, potential endocrine effects, and impact on long-term treatment adherence and survival.

Conclusion

In women receiving endocrine therapy for HR-positive breast cancer, Elinzanetant significantly reduced vasomotor symptoms (VMS), improved sleep, and enhanced quality of life with a favorable safety profile. These findings highlight its potential role as a much-needed nonhormonal therapeutic option to support adherence and improve patient-centered outcomes in breast cancer care.

Elinzanetant for Vasomotor Symptoms from Endocrine Therapy for Breast Cancer. Cardoso F, Parke S, Brennan DJ, et al. N Engl J Med 2025;393:753-763

Endocrine Therapy Omission in ER-Low Early Stage Breast Cancer Linked to Worse Survival Outcomes

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SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. It is estimated that in the US, approximately 316,950 new cases of female breast cancer will be diagnosed in 2025, and about 42,170 women will die of the disease, largely due to metastatic recurrence.

Background
Approximately 70% of breast tumors express Estrogen Receptors and/or Progesterone Receptors. Adjuvant Endocrine Therapy (ET) is a cornerstone in managing Estrogen Receptor (ER)–positive early-stage breast cancer, contributing significantly to reduced recurrence and improved Overall Survival (OS). However, its role in patients with ER-low disease, defined as tumors with 1%-10% ER positivity by ImmunoHistoChemistry (IHC), remains unclear and controversial.

Study Objective
The present study was conducted to determine the association between ET omission and OS in high-risk, ER-low early-stage breast cancer patients who received chemotherapy, leveraging Real-World Data from the National Cancer Database (NCDB).

Methods
A retrospective cohort analysis was conducted using the 2021 NCDB Participant User File, focusing on female patients diagnosed with Stage I–III ER-positive breast cancer between 2018 and 2020. ER-low status was defined as 1%-10% ER expression per ASCO/CAP guidelines. Progesterone Receptor (PR)–positive disease was defined as 1% or more receptor expression. This study included patients who received neoadjuvant or adjuvant chemotherapy, reflecting a high-risk population with aggressive tumor features. The study excluded male patients, Stage IV disease, noninvasive cancers, and cases with incomplete treatment or outcome data. The final cohort comprised 7,018 ER-low patients who received chemotherapy.

Key Findings

  • Endocrine Therapy (ET) Usage Patterns:
    Among patients with ER-low breast cancer receiving chemotherapy, 42% did not initiate ET within 12 months post-surgery. ET omission was more prevalent in tumors that were:

    • Progesterone Receptor (PR)–negative
    • HER2–negative
    • High grade (2 or 3)
    • High proliferative index (Ki67 ≥20%)
    • Treated with NeoAdjuvant Chemotherapy (NAC)
  • Survival Impact:
    Over a median follow-up of 3 years, 586 deaths occurred. ET omission was associated with significantly poorer OS:

    • Overall HR: 1.23 (95% CI, 1.04–1.46; P =0.02)
    • ER 1%-5% subgroup: HR 1.15 (95% CI, 0.91–1.45; P =0.24)
    • ER 6%-10% subgroup: HR 1.42 (95% CI, 1.00–2.02; P =0.048)
  • Effect in Residual Disease (RD) After NAC:
    • For patients with RD, ET omission led to worse OS (HR, 1.26; 95% CI, 1.00–1.57; P =0.046)
    • No OS difference was observed in patients who achieved pathologic Complete Response (pCR) (HR, 1.06; P =0.84)
  • 3-Year OS Estimates:
    • With ET: 92.3% (95% CI, 91.3–93.3%)
    • Without ET: 89.1% (95% CI, 87.8–90.5%)

Clinical Implications
These findings suggest that omission of ET in ER-low breast cancer is associated with an increased risk of mortality, particularly in patients with:

  • Residual disease after neoadjuvant chemotherapy
  • Tumors with higher ER expression (6%-10%)

This supports the clinical value of ET even in ER-low disease subsets, which have historically been managed more like Triple-Negative Breast Cancer (TNBC) due to their aggressive features and ambiguous endocrine responsiveness.

Guideline and Research Context
The 2010 ASCO/CAP guidelines established 1% or more ER positivity as the threshold for ET eligibility. Yet, international variation remains. Swedish guidelines, for instance, never adopted the lower threshold, and recent European discourse suggests reverting to 10% or more. Compounding the uncertainty, clinical trials often exclude ER-low tumors or treat them as TNBC. Retrospective studies from Sweden and China have shown mixed results regarding ET’s benefit in ER-low disease, further emphasizing the need for prospective data.

Discussion
Despite the relatively small proportion of ER-low tumors (3% of ER-positive breast cancer), the findings could impact the care of tens of thousands of patients globally. The biologic heterogeneity of ER-low tumors, often resembling basal-like subtypes, complicates treatment decisions. Still, evidence from this large cohort supports offering ET, particularly in patients with residual disease post-neoadjuvant chemotherapy, or tumors on the higher end of the ER-low spectrum. Additionally, the data align with emerging strategies to escalate therapy in ER-low BC, including use of CDK4/6 inhibitors (e.g., Abemaciclib, Ribociclib), which have demonstrated benefit even in this subgroup.

Limitations

  • Lack of data on ET adherence, recurrence, or cause of death
  • Short follow-up (3 years)
  • Potential confounding due to observational design
  • Lack of molecular characterization to distinguish responders

Nevertheless, sensitivity analyses confirmed the robustness of findings.

Conclusion
Omission of endocrine therapy in ER-low, early-stage breast cancer, especially following chemotherapy, is linked to inferior Overall Survival. The strongest signal of benefit is in patients with residual disease post- neoadjuvant chemotherapy and those with ER expression closer to 10%. Until randomized trials clarify endocrine sensitivity in this population, clinicians should counsel patients on the potential survival benefit of ET, even in cases with limited ER expression.

Key Takeaway for Oncologists:
In the absence of prospective trial data, Real-World Evidence supports continued use of endocrine therapy in patients with ER-low early-stage breast cancer, particularly those with residual disease after neoadjuvant chemotherapy or higher ER expression within the 1%-10% range.

Endocrine Therapy Omission in Estrogen Receptor–Low (1%-10%) Early-Stage Breast Cancer. Choong GM, Hoskin TL, Boughey JC, et al. J Clin Oncol 2025;43:1875-1885.

Late Breaking Abstract – ASCO 2025: Targeting ESR1 Mutations in Advanced Breast Cancer: Phase 3 VERITAC-2 Validates Vepdegestrant as a Promising Next-Generation Endocrine Therapy

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SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. It is estimated that in the US, approximately 316,950 new cases of female breast cancer will be diagnosed in 2025, and about 42,170 women will die of the disease, largely due to metastatic recurrence.

Background and Clinical Unmet Need
Approximately 70% of breast tumors express Estrogen Receptors and/or Progesterone Receptors. The most common subtype of metastatic breast cancer is Hormone Receptor-positive (HR-positive), HER2-negative breast cancer (65% of all metastatic breast tumors), and these patients are often treated with anti-estrogen therapy as first line treatment. However, resistance to hormonal therapy occurs in a majority of the patients, with a median Overall Survival (OS) of 36 months. With the development of Cyclin Dependent Kinases (CDK) 4/6 inhibitors, endocrine therapy plus a CDK4/6 inhibitor is the mainstay, for the management of ER+/HER2-negative metastatic breast cancer, as first line therapy. Even with this therapeutic combination, most patients will eventually experience disease progression, with up to 50% of patients acquiring ESR1 (Estrogen Receptor gene alpha) mutations after exposure to prior endocrine therapy in combination with CDK4/6 inhibitors. These mutations enable constitutive activation of the estrogen receptor, rendering tumors less responsive to traditional endocrine agents. Although Selective Estrogen Receptor Degraders (SERDs) such as Fulvestrant and Elacestrant are often used in this setting, their clinical activity is modest and limited by pharmacokinetic and mechanistic constraints, especially in heavily pretreated, endocrine-resistant disease.

A Novel Approach: Vepdegestrant and the PROTAC Platform
Vepdegestrant represents a first-in-class, oral PROteolysis TArgeting Chimera (PROTAC) designed to degrade the ER through direct engagement of the ubiquitin-proteasome system. Unlike traditional SERDs, which bind to and inactivate the ER before relying on indirect degradation pathways, Vepdegestrant forms a ternary complex between the ER and an E3 ubiquitin ligase. This results in efficient and targeted ubiquitination and subsequent degradation of the ER protein. Early-phase trials demonstrated that Vepdegestrant was well tolerated and exhibited promising antitumor activity in patients with heavily pretreated ER+/HER2-negative advanced breast cancer. This laid the foundation for VERITAC-2, the first Phase 3 study evaluating a PROTAC agent in oncology.

VERITAC-2: Study Design and Patient Population
Study Overview:
VERITAC-2 is a global, randomized Phase 3 trial comparing oral Vepdegestrant 200 mg once-daily continuously with Fulvestrant 500 mg intramuscularly days 1 and 15 of cycle 1 and day 1 of subsequent cycles, in postmenopausal women and men with ER+/HER2-negative advanced breast cancer, previously treated with a CDK4/6 inhibitor plus endocrine therapy. An additional line of endocrine therapy was permitted. However, patients previously exposed to SERDs or chemotherapy in the metastatic setting were excluded. A total of 624 patients (median age 60 years; 43% with ESR1mutation tumors) were randomized 1:1 to receive Vepdegestrant (N=313) or Fulvestrant (N=311). Approximately 80% were postmenopausal, and 20% had received two prior lines of therapy in the advanced setting. Patients were stratified by ESR1 mutation status and presence of visceral disease. The Primary endpoint was Progression-Free Survival (PFS) as assessed by Blinded Independent Central Review (BICR), first in the ESR1mutations subgroup and then in the overall population contingent on statistical assumptions. Secondary endpoints included Overall Survival (OS), Objective Response Rate (ORR), Clinical Benefit Rate (CBR), and Safety.

Key Efficacy Findings

In the ESR1-Mutant Population:

  • Median PFS: 5.0 months with Vepdegestrant vs 2.1 months with Fulvestrant
  • Hazard Ratio: 0.57 (95% CI, 0.42–0.77); P=0.0001
  • 6-Month PFS Rate: 45.2% with Vepdegestrant vs 22.7% with Fulvestrant
  • Objective Response Rate: 18.6% vs 4.0% (P=0.001)
  • Clinical Benefit Rate: 42.1% vs 20.2% (P<0.001)

There was a 43% relative reduction in the risk of disease progression or death with Vepdegestrant compared with Fulvestrant. These results represent a statistically significant and clinically meaningful improvement in PFS and response outcomes among ESR1mutated patients, reinforcing the hypothesis that targeted ER degradation via PROTAC technology can overcome a key mechanism of endocrine resistance.

In the Overall Population:

  • Median PFS: 3.7 months (Vepdegestrant) vs 3.6 months (Fulvestrant)
  • HR: 0.83 (95% CI, 0.68–1.02); P=0.07

Although trends favored Vepdegestrant, the PFS difference in the unselected population did not reach statistical significance, underscoring the critical role of ESR1 mutation status as a biomarker of response to this agent.

Safety and Tolerability
Vepdegestrant was generally well tolerated, with most Adverse Events (AEs) being Grade 1 or 2. Grade 3 or more Treatment-Emergent AEs occurred in 23.4% receiving Vepdegestrant versus 17.6% with Fulvestrant. The most toxicities with Vepdegestrant were fatigue, elevated ALT/AST, nausea, vomiting and diarrhea. Discontinuation due to AEs occurred in only 2.9% of patients receiving Vepdegestrant. Importantly, gastrointestinal side effects, often limiting with oral SERDs, were infrequent and generally low-grade, reflecting the favorable tolerability of this novel agent.

Clinical Implications and Future Directions
The VERITAC-2 trial offers a landmark clinical validation for PROTACs in oncology. For patients with ER+/HER2-negative advanced breast cancer harboring ESR1 mutations, Vepdegestrant offers a statistically significant and clinically relevant advantage in Progression-Free Survival over Fulvestrant. The favorable safety profile, oral dosing convenience, and mechanistic novelty support its development as a next-generation standard of care in this biomarker-defined subgroup.

Although benefit was not observed in the all-comer population, the compelling results in ESR1mutated disease position Vepdegestrant as a precision endocrine therapy option that could reshape the treatment landscape. Ongoing investigations will clarify its role in earlier lines of therapy and in combination strategies, including with targeted or immunotherapeutic agents.

Conclusion
Vepdegestrant has emerged as a promising, targeted therapy for patients with ESR1-mutated ER+/HER2-negative advanced breast cancer who have progressed on prior CDK4/6 inhibitor plus endocrine therapy. As the first PROTAC to reach Phase 3, its success in VERITAC-2 signals the clinical viability of targeted protein degradation platforms in hormone receptor–driven malignancies.

Vepdegestrant, a PROTAC estrogen receptor (ER) degrader, vs fulvestrant in ER-positive/human epidermal growth factor receptor 2 (HER2)–negative advanced breast cancer: Results of the global, randomized, phase 3 VERITAC-2 study. Hamilton H, De Laurentiis M, Jhaveri K, et al. J Clin Oncol 43, 2025 (suppl 17; abstr LBA1000)