Tag: Breast Cancer

Late Breaking Abstract – ASCO 2025: Redefining the First-Line Standard: DESTINY-Breast09 Highlights T-DXd Plus Pertuzumab as a Potential New Benchmark in HER2+ 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.

The HER or erbB family of receptors consist of HER1, HER2, HER3 and HER4. Approximately 15%-20% of invasive breast cancers overexpress HER2/neu oncogene, which is a negative predictor of outcomes without systemic therapy. Trastuzumab (HERCEPTIN®) is a humanized monoclonal antibody targeting HER2. Trastuzumab binds to subdomain IV of the HER2 extracellular domain and blocks the downstream cell signaling pathways (PI3K-AKT pathway) and induces Antibody Dependent Cellular Cytotoxicity (ADCC). Pertuzumab (PERJETA®) is a recombinant humanized monoclonal antibody that binds to the HER2 at a different epitope of the HER2 extracellular domain (subdomain II) compared to Trastuzumab, and prevents the dimerization of HER2 with HER3 receptor. Pertuzumab stimulates ADCC similar to Trastuzumab. By combining Trastuzumab and Pertuzumab, a more comprehensive blockade of HER2 signaling can be accomplished, as these two agents bind to different HER2 epitopes and may complement each other and improve efficacy.

Trastuzumab deruxtecan (T-DXd) (ENHERTU®) is a next-generation Antibody-Drug Conjugate (ADC) composed of a humanized monoclonal antibody specifically targeting HER2, with the amino acid sequence similar to Trastuzumab, a cleavable tetrapeptide-based linker, and a potent cytotoxic Topoisomerase I inhibitor as the cytotoxic drug (payload). T-DXd has a favorable pharmacokinetic profile and the tetrapeptide-based linker is stable in the plasma and is selectively cleaved by cathepsins that are up-regulated in tumor cells. Unlike  ado-Trastuzumab emtansine, another ADC targeting HER2, T-DXd has a higher drug-to-antibody ratio (8 versus 4), released payload easily crosses the cell membrane with resulting potent cytotoxic effect on neighboring tumor cells regardless of target expression, and the released cytotoxic agent (payload) has a short half-life, thus minimizing systemic exposure.

Background and Clinical Rationale
Trastuzumab deruxtecan (T-DXd) has demonstrated potent antitumor activity in HER2-positive breast cancer across multiple treatment lines. However, prior to the DESTINY-Breast09 study, all approved indications for T-DXd required patients to have received prior systemic therapy in either the metastatic or adjuvant setting. With the longstanding CLEOPATRA regimen, Docetaxel, Trastuzumab, and Pertuzumab (THP) established over a decade ago as the first-line standard of care, the oncology community has been eager to evaluate whether T-DXd could improve frontline outcomes.

Study Design and Patient Population
DESTINY-Breast09 (NCT04784715) is a randomized, global Phase 3 study designed to evaluate the efficacy and safety of first-line T-DXd with or without Pertuzumab, versus Taxane plusTrastuzumab plus Pertuzumab (THP), in patients with HER2-positive advanced/metastatic breast cancer. A total of 1,157 patients were enrolled across 283 sites worldwide. Eligible patients had centrally confirmed HER2-positive disease (IHC 3+ or ISH+), no prior chemotherapy or HER2-targeted therapy in the metastatic setting, and ≤1 prior line of endocrine therapy. Patients were stratified by Hormone Receptor (HR) status, PIK3CA mutation status, and de novo vs recurrent disease, and randomized 1:1:1 to:

  • T-DXd + placebo – N=387
  • T-DXd + pertuzumab (T-DXd + P) – N=383
  • THP (control arm) – N=387

The interim analysis presented at ASCO 2025 focused on the comparison between T-DXd + P and THP. The T-DXd monotherapy arm remains blinded until the final PFS analysis.

The Primary endpoint was Progression-Free Survival (PFS) by Blinded Independent Central Review (BICR) in the intent-to-treat population. Secondary endpoints included Overall Survival (OS), PFS by investigator (INV), Objective Response Rate (ORR), Duration of Response (DOR), and Safety

Efficacy Outcomes: Progression-Free Survival and Response
At a median follow-up of 29 months, T-DXd + P demonstrated a statistically significant and clinically meaningful improvement in PFS compared to THP:

  • Median PFS by BICR:
    • T-DXd + P: 40.7 months
    • THP: 26.9 months
    • HR: 0.56; P <0.00001
  • PFS by Investigator Assessment:
    • Median: 40.7 months vs 20.7 months
    • HR: 0.49 (95% CI: 0.39–0.61)
  • Overall Response Rate (ORR):
    • T-DXd + P: 85.1%
    • THP: 78.6%
  • Complete Response Rate:
    • T-DXd + P: 15.1%
    • THP: 8.5%
  • Median Duration of Response:
    • T-DXd + P: 39.2 months
    • THP: 26.4 months

The PFS benefit was consistent across all patient subgroups, including HR status and PIK3CA mutation.

Safety Profile and Adverse Events
The safety profile of T-DXd + P in the frontline setting was consistent with known toxicities of T-DXd, with no new safety signals. Adjudicated drug-related Interstitial Lung Disease/pneumonitis occurred in 12.1% of patients receiving T-DXd + P (mostly grade 1 and 2) in contrast to only 1.0% among patients receiving THP. Other treatment-related toxicities such as nausea, vomiting, and constipation were more common with T-DXd + P, possibly due to longer median treatment exposure (~3.5 years).

Clinical Implications and Emerging Questions
The marked 13.8-month PFS improvement positions T-DXd + P as a strong candidate to replace THP as the first-line standard for HER2-positive advanced metastatic breast cancer. These results mirror the transformative impact of T-DXd seen in the second-line DESTINY-Breast03 trial comparing T-DXd with ado-Trastuzumab emtansine, where it yielded a median PFS of 28.8 months.

However, while efficacy is unquestionable, questions remain around treatment sequencing, duration, and long-term quality of life:

  • Could T-DXd be reserved for second-line therapy in select patients with less aggressive disease?
  • Might a strategy of T-DXd + P induction followed by de-escalation to maintenance Trastuzumab/Pertuzumab reduce toxicity?
  • Can biomarker-driven personalization refine who should receive first-line T-DXd?

The researchers of this study emphasized that these results represent a paradigm shift in first-line treatment of advanced HER2-positive breast cancer.

Conclusion
DESTINY-Breast09 demonstrates that T-DXd + Pertuzumab significantly improves PFS compared to THP, with durable responses and manageable toxicity. The findings suggest a potential new first-line standard for HER2-positive metastatic breast cancer. While overall survival and long-term safety data are still maturing, the study sets a new benchmark in the frontline treatment landscape and invites critical dialogue on optimizing sequencing, duration, and patient-centered outcomes.

Trastuzumab deruxtecan (T-DXd) + pertuzumab (P) vs taxane + trastuzumab + pertuzumab (THP) for first-line (1L) treatment of patients (pts) with human epidermal growth factor receptor 2–positive (HER2+) advanced/metastatic breast cancer (a/mBC): Interim results from DESTINY-Breast09. Tolaney S, Jiang Z, Zhang Q, et al. J Clin Oncol 43, 2025 (suppl 17; abstr LBA1008)

Late Breaking Abstract – ASCO 2025: SERENA-6: A ctDNA-Guided Switch to Camizestrant Improves PFS in HR-Positive/HER2-Negative Advanced 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% 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, including the development of ESR1 (Estrogen Receptor gene alpha) mutations.

Background
The SERENA-6 trial is the first global registrational Phase 3 study to evaluate a ctDNA-guided approach for the early detection and treatment of ESR1 mutations in HR+, HER2-negative advanced breast cancer. ESR1 mutations, which promote ligand independent Estrogen Receptor activation, are a common mechanism of acquired resistance to estrogen deprivation therapies such as Aromatase Inhibitors (AIs) plus CDK4/6 inhibitors (CDK4/6i). ESR1 mutations Y537S and D538G mutations detected in baseline plasma samples from ER+/HER- advanced breast cancer patients, has been associated with shorter Overall Survival. ESR1 mutations are typically absent at diagnosis but emerge during AI therapy. Detecting ESR1 mutations through circulating tumor DNA (ctDNA) provides a non-invasive method to identify molecular progression prior to radiographic evidence.

Camizestrant is an oral, next-generation Selective Estrogen Receptor Degrader (SERD) with antagonist activity against both wild-type and mutant estrogen receptors. SERENA-6 evaluated whether switching to Camizestrant plus continued CDK4/6i upon ctDNA detection of ESR1 mutations, but before radiographic progression, can improve outcomes, compared to continuing the standard AI-based regimen.

Study Design and Results
SERENA-6 is a randomized, double-blind, Phase 3 trial in which 3,256 patients with HR+/HER2-negative advanced breast cancer who had received 6 or more  months of first-line AI + CDK4/6 inhibitor (Palbociclib, Ribociclib, or Abemaciclib) were surveilled for ESR1 mutations using ctDNA performed every 2-3 months alongside routine imaging. Upon ESR1 mutations detection without clinical progression, 315 eligible patients (N=315) who were found to have an ESR1 mutation during ctDNA surveillance were randomized were randomized 1:1 to Switch to Camizestrant (75 mg daily) + continued CDK4/6i + placebo for AI (N=157) or continue AI + CDK4/6i + placebo for Camizestrant (N=158). Both treatment groups were well balanced. Stratification included visceral disease status, timing of ESR1 mutation detection, prior duration of therapy, and CDK4/6 inhibitor type. The Primary endpoint was Investigator-assessed Progression-Free Survival (PFS).

At the prespecified interim analysis, about 50% had ESR1mutations detected on the first ctDNA test. The median PFS was significantly longer with Camizestrant – 16.0 vs 9.2 months; HR=0.44, P<0.00001. This PFS benefit was consistent across all subgroups. The 12-month PFS rates were 60.7% in the Camizestrant group vs 33.4% in the control group. The 24-month PFS rates: 29.7% vs 5.4%. Overall survival (OS) data remains immature. Patients in the Camizestrant arm had a quality of life that was maintained longer than the AI group.

Treatment discontinuation due to adverse events were low at 1.3% for the Camizestrant, and 1.9% for the Aromatase Inhibitor group.

Clinical Implications
SERENA-6 demonstrated that early, ctDNA-guided switching from AI to Camizestrant in patients with emergent ESR1 mutations significantly prolonged PFS without added toxicity. This trial is the first to validate a molecular response–guided treatment strategy in HR+/HER2-negative advanced breast cancer, potentially redefining first-line management.

However, questions remain regarding long-term Overall Survival benefits and the cost-effectiveness and logistical feasibility of serial ctDNA monitoring. Additional follow-up and Real-World Data will be crucial to determine the broader clinical utility of this approach.

Conclusion
Camizestrant in combination with CDK4/6 inhibition, guided by ctDNA detected ESR1 mutations emergence, offers a promising new treatment paradigm for HR+/HER2-negative advanced breast cancer. SERENA-6 paves the way for incorporating precision molecular monitoring into routine first-line management.

Camizestrant + CDK4/6 inhibitor (CDK4/6i) for the treatment of emergent ESR1 mutations during first-line (1L) endocrine-based therapy (ET) and ahead of disease progression in patients (pts) with HR+/HER2– advanced breast cancer (ABC): Phase 3, double-blind ctDNA-guided SERENA-6 trial. Turner N, Mayer E, Park YH, et al. J Clin Oncol 43, 2025 (suppl 17; abstr LBA4).

DATROWAY® (Datopotamab deruxtecan-dlnk)

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The FDA on January 17, 2025, approved DATROWAY®, a Trop-2-directed antibody and topoisomerase inhibitor conjugate, for adult patients with unresectable or metastatic, Hormone Receptor (HR)-positive, Human Epidermal growth factor Receptor 2 (HER2)-negative (IHC 0, IHC1+ or IHC2+/ISH-) breast cancer who have received prior endocrine-based therapy and chemotherapy for unresectable or metastatic disease. DATROWAY® is a product of  Daiichi Sankyo, Inc.

Metabolic Syndrome and Breast Cancer Prognosis: A Comprehensive Meta-Analysis Highlights Urgent Need for Integrated Survivorship Strategies

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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 Rationale: As oncologists continue to shift from a purely disease-focused model to one that embraces survivorship, a growing body of evidence suggests that metabolic syndrome may play a crucial, underappreciated role in determining long-term outcomes for women diagnosed with breast cancer.
Metabolic syndrome—characterized by the presence of at least three of the following risk factors: hypertension, hyperglycemia, central obesity, hypertriglyceridemia, and low HDL cholesterol—is known to elevate the risk for cardiovascular and chronic metabolic diseases. More recently, it has also been implicated in breast cancer incidence and prognosis, potentially through inflammatory, hormonal, and metabolic pathways.

Study Objective: A recent systematic review and meta-analysis sought to quantify the impact of metabolic syndrome on breast cancer-specific outcomes, including recurrence, mortality, and disease-free survival (DFS). The goal: to assess whether metabolic syndrome at the time of breast cancer diagnosis correlates with a poorer prognosis, independent of other risk factors.

Methodology, Study Population and Demographics: The investigators performed systematic literature searches in PubMed and Embase, using combinations of search terms like breast neoplasms, metabolic syndrome, and survival and From an initial pool of 1,019 studies, 17 high-quality studies were selected for meta-analysis and data were drawn from 42,135 breast cancer survivors. Seven studies, which included 9029 women, provided data on breast cancer recurrence, another 7 studies involving 31,008 women reported on breast cancer mortality, and 8 studies with 17,235 women provided data on Overall Survival (OS). These studies were conducted across North America, Europe, and Asia, the average age was 53.2 years and average follow-up time was 94.8 months. Metabolic syndrome was defined consistently across studies based on AHA criteria: presence of ≥3 of the following—waist circumference >35 inches (women), elevated triglycerides, reduced HDL-C, high fasting glucose, and elevated blood pressure.

Results: The analysis revealed statistically significant associations between metabolic syndrome and adverse breast cancer outcomes. Patients with metabolic syndrome had a 69% increased risk of recurrence, 83% increased risk of breast cancer-related death (Breast Cancer Specific Mortality) and 57% higher likelihood of experiencing an adverse event (recurrence, new malignancy, or death) impacting Disease-Free Survival. Subgroup analyses showed geographically consistent associations across North America, Europe, and Asia, reinforcing the global applicability of the findings.

Limitations:

  • Lack of consistent reporting on ER status, preventing stratified analysis by tumor subtype
  • Inability to isolate effects of individual metabolic components
  • Missing data on pharmacological treatments (e.g., statins, antidiabetics)
  • Residual confounding factors (e.g., socioeconomic status, lifestyle, genetics)
  • Predominantly observational designs, limiting causal inference

Clinical Implications: This study sheds light on an often-overlooked factor in breast cancer prognosis: metabolic health at diagnosis. With over 40,000 survivors included, the findings make a compelling case for integrating metabolic screening and intervention into breast cancer care pathways. Cardiovascular disease is the second leading cause of death among breast cancer survivors. Managing metabolic syndrome could address both cancer and cardiovascular risk.

Opportunities for Oncologists:

  • Early metabolic screening for BC patients at diagnosis and during follow-up
  • Interdisciplinary care involving endocrinologists, dietitians, and cardiologists
  • Lifestyle counseling as a standard element of survivorship care
  • Pharmacologic management using statins, antihypertensives, and antidiabetic agents with potential antitumor effects

Conclusion: Metabolic syndrome is more than a cardiovascular risk factor—it’s a cancer prognostic marker. This meta-analysis, the most comprehensive to date, makes it clear: women diagnosed with both breast cancer and metabolic syndrome face significantly worse outcomes. Clinical guidelines should evolve to include routine metabolic screening and targeted interventions for breast cancer survivors. Addressing metabolic health may be one of the most cost-effective ways to improve survival and quality of life in this growing population.

Metabolic syndrome is associated with breast cancer mortality: A systematic review and meta-analysis. Harborg S, Larsen HB, Elsgaard S, et al. J Intern Med. 2025;297:262-275.

 

 

Exploring the emerging HER2-Low and HER2-Ultralow subtypes in breast cancer therapy advancements

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Written by: Denise Yardley, MD
Sponsored by: Daiichi-Sankyo

The landscape of breast cancer treatment is advancing with innovative discoveries challenging the traditional HER2 classification. The identification of HER2-low and HER2-ultralow subtypes offers a more nuanced understanding of tumor biology, paving the way for personalized therapies that promise better outcomes for a wider range of patients. This fresh perspective reshapes clinical practice, indicating a new era in the fight against breast cancer where precision medicine leads the charge.

Breast cancer remains an extremely heterogeneous disease, with a number of subtypes characterized by distinct molecular and clinical features. One key classifying marker is the human epidermal growth factor receptor 2 (HER2). The expression of HER2 or lack thereof traditionally serves to categorize tumors as either HER2 positive or HER2 negative, based on the detected level of HER2 protein expression. The emergence of new antibody conjugate drugs challenged the reliance of conventional HER2 targeted therapies on 3+ HER2 expression by immunohistochemistry (IHC) or gene amplification, thereby establishing HER2 low as a novel breast cancer entity that stands to benefit from HER2 targeted therapies. As a result of DESTINY-Breast 04 in 2022, ASCO CAP guidelines for HER2 testing, affirming the importance of accurately identifying with HER2 low to ensure optimal patient selection for HER2 targeted therapies, were revised in 2023 to include advancements in diagnostic techniques that have led to the identification of two additional subtypes: HER2-low and HER2-ultralow breast cancer. Identifying these novel HER2 subtypes have significant implications for treatment and prognosis.

The identification of the HER2 prototype oncogene served as a ripe therapeutic target in breast cancer as well as other cancers. The focus of these therapeutic interventions were on the small 15-20% group of tumors demonstrating HER2 protein overexpression as a function of HER2 gene amplification. The development and subsequent efficacy of the targeted monoclonal anti-HER2 antibody trastuzumab led to its approval for metastatic breast cancer in 1998 followed by the approval of pertuzumab in 2012. Trastuzumab worked by binding the HER2 protein receptor, inhibiting HER2 homodimerization thus preventing HER2-mediated signalling while pertuzumab inhibited HER2 heterodimerization with HER3, a related growth factor receptor. However, a low or moderate expression of the HER2 target without gene amplification failed to benefit from conventional anti-HER2 agents (NSABP B-47).

Extensive pathology training efforts and quality assurance programs followed to reliably achieve high concordance for identifying and characterizing tumors denoted as HER2+ with the intent of identifying tumors most likely to benefit from classical HER2 targeted agents. The HER2 testing algorithm resulted in a binary categorization of tumors that were either HER2 negative or HER2 positive, on the basis on an IHC score of 3+ or IHC 2+ with in situ hybridization (ISH) positive. HER2 negative was a catchall that included tumors that were completely devoid of the HER2 protein (IHC 0) as well as those that had low to moderate expression labelled as IHC 1+ and IHC 2+ but ISH negative. This distinction however was not clinically meaningful, and the two groups were combined and were not eligible for HER2 therapies. It was not at all clear if there was a distinct tumor biology associated with lower level HER2 expression. The monoclonal anti-HER2 antibodies were ineffective in HER2 low tumors because their activity relies mainly on the blockade of aberrant HER2 signaling via dimerization inhibition, HER2 internalization, and/or antibody dependent cellular cytotoxicity (ADCC). Since these therapies bind the extracellular domain of the HER2 receptor, effective efficacy hinged on HER2 receptor overexpression which facilitates ADCC.

Despite the impact of the success of these agents in improving outcomes in HER2+ overexpressing tumors, a subgroup of patients failed to respond or experience disease recurrence, creating a robust pathway for the development of more effective and well tolerated second line therapies. Antibody drug conjugates (ADC), already a mainstay in hematologic malignancies, functioned as tumoral antibody specific antibodies connected via a linker to a potent cytotoxic payload. Trastuzumab emtansine (T-DM1) soon emerged, incorporating the antitumor properties of trastuzumab joined via a noncleavable linker with the cytotoxic activity of the microtubule inhibitory agent DM1. Use of this ADC allowed for targeted receptor binding and transport of cytotoxic chemotherapy, specifically into cancer cells, with subsequent disruption of the intracellular signaling pathways. The results of the EMILIA trial moved trastuzumab emtansine as a new standard in the second line setting of HER2+ MBC, following the demonstration of improved PFS and OS coupled with a more favorable toxicity profile than lapatinib and capecitabine.

Given these advances, refractoriness in classical HER2+ breast cancers developed to trastuzumab emtansine fostering the development of the third generation ADC trastuzumab deruxtecan, with a monoclonal anti-HER2 antibody linked to a topoisomerase payload through a tetrapeptide cleavable linker. This ADC had a higher drug to antibody ratio of 8 and was effective in trastuzumab emtansine insensitive HER2+ breast tumors. A series of trials referred to as DESTINY trials, evaluated this third generation ADC with DESTINY Breast 01, 02, and 03 in HER2+ breast cancer while DESTINY Breast 04 and 06 looked at HER2 low breast cancer, embracing the 80% of breast cancers assessed as HER2 negative and historically not candidates for anti-HER2 therapy. The DAISY trial was deigned to evaluate trastuzumab deruxtecan according to HER2 expression levels showing the greatest response in the HER2 overexpressing tumors defined by IHC 3+ or ISH positive followed by cohort 2 consisting of HER2 low tumors defined as IHC2+/ISH negative or HER2 nonexpressing tumors or IHC 0. This suggested that very low levels of HER2 expression could allow for receptor binding of trastuzumab deruxtecan and furthermore, that the definition of HER2 low needed to be expanded to include HER2 ultralow, cases that show faintly perceptible HER2 staining that is greater than 0% and < 10% (currently considered IHC 0). What emerged was that HER2 expression is now increasingly perceived as a continuum that defies the former classical dichotomous distinction of HER2 positive and HER2 negative cancers that traditionally guided treatment decision making. While monoclonal antibodies were ineffective in HER2 low tumors because their activity relies mainly on binding of the extracellular domain of the HER2 receptor and is more effective if the receptor is overexpressed facilitating ADCC. This is in stark contrast to the ADC trastuzumab deruxtecan, which can overcome some of these monoclonal antibody limitations by also being able to release a cytotoxic payload that can be internalized by surrounding cells that do not express HER2 (bystander effect). With the introduction of the third generation ADC therapies in what was previously collectively classified as HER2 negative tumors, a paradigm shift in the treatment of tumors without conventionally defined HER2 overexpression or HER2 gene amplification has occurred.

The identification of HER2-low and HER2-ultralow breast cancer represents a significant advancement in the field of breast cancer research and treatment. HER2 IHC scoring, nomenclature, testing modalities and current treatment protocols are evolving and the reproducibility of pathologists truly being able to separate IHC HER2 0 and HER2 1+ persists. Alternative assays and/or testing modalities to better discriminate low levels of HER2 protein expression may lead to future algorithms but at present, ongoing research and clinical trials are essential to further understand the biological behavior and clinical significance of HER2-low and HER2-ultralow breast cancer. As an example, the majority of HER2-low and HER2-ultralow breast cancers are hormone receptor-positive (HR+) which has important implications for treatment with the combinations of hormone therapy with HER2-targeted therapy and the potential to further improve outcomes for patients with HR+/HER2-low and HR+/HER2-ultralow breast cancer. Of overriding importance, is the need for additional studies to also evaluate the long-term outcomes of patients with these HER2 subtypes and to identify additional HER2-targeted therapies that may be effective. The DESTINY Breast 04 and 06 trials highlight the need for refining the diagnostic techniques, and to develop standardized testing protocols, to ensure accurate classification of HER2 status. By embracing personalized treatment approaches, clinicians can improve outcomes for patients with HER2-low and HER2-ultralow breast cancer and provide more effective and targeted care. The traditional dichotomy of HER2 status has now been supplanted by the expanding spectrum of HER2 positivity in breast cancer. Comprehensive characterization of the evolving spectrum of HER2 tumors, to further define their clinical and molecular features, is of paramount importance.

KADCYLA® Improves Overall Survival in Residual HER2-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.

The HER or erbB family of receptors consist of HER1, HER2, HER3 and HER4. Approximately 15-20% of invasive breast cancers overexpress HER2/neu oncogene, which is a negative predictor of outcomes without systemic therapy. HERCEPTIN® (Trastuzumab) is a humanized monoclonal antibody targeting HER2, and adjuvant and neoadjuvant chemotherapy given along with HERCEPTIN® reduces the risk of disease recurrence and death, among patients with HER2-positive early stage, as well as advanced metastatic breast cancer. Since the approval of HERCEPTIN®, several other HER2-targeted therapies have become available. The duration of adjuvant HERCEPTIN® therapy has been 12 months and this length of treatment was empirically adopted from the pivotal registration trials.

KADCYLA® (Ado-Trastuzumab Emtansine, T-DM1) is an Antibody-Drug Conjugate (ADC) comprised of the antibody HERCEPTIN® and the chemotherapy agent Emtansine, linked together. Upon binding to the HER2 receptor, it not only inhibits the HER2 signaling pathways but also delivers a chemotherapy agent Emtansine, a microtubule inhibitor, directly inside the tumor cells. This agent is internalized by lysosomes and destroys the HER2-positive tumor cells upon intracellular release. In the EMILIA trial, KADCYLA® was associated with significant increase in Overall Survival (OS), when compared with TYKERB® (Lapatinib) plus XELODA® (Capecitabine), in HER2-positive metastatic breast cancer patients, who had previously received HERCEPTIN® and a Taxane.

It is well established that patients with HER2-positive early breast cancer, following HERCEPTIN® based neoadjuvant therapies, have a pathological Complete Response rate of 40-60%. Those without a pathological Complete Response tend to have significantly less favorable outcomes. These patients irrespective of pathological response status complete their standard adjuvant therapy which includes 12 months of HER2-targeted therapy.

KATHERINE trial was conducted to evaluate the benefit of switching from standard HER2-directed therapy to single-agent KADCYLA®, after neoadjuvant chemotherapy along with either single or dual HER2 targeted therapy, in patients with residual invasive cancer at surgery. This study was conducted to address the unmet need of patients who have residual invasive breast cancer after receiving neoadjuvant chemotherapy plus HER2-targeted therapy.

The KATHERINE trial is an open-label, Phase III global study, which compared KADCYLA® with HERCEPTIN®, as an adjuvant treatment for patients with HER2-positive early breast cancer, who had residual invasive disease following neoadjuvant chemotherapy and HERCEPTIN®. This study included 1,486 patients with HER2-positive early stage breast cancer, who were found to have residual invasive disease in the breast or axillary lymph nodes at surgery, following at least six cycles (16 weeks) of neoadjuvant chemotherapy with a Taxane (with or without Anthracycline) and HERCEPTIN®. Within 12 weeks of surgery, patients (N=1486) were randomly assigned in a 1:1 ratio to KADCYLA® 3.6 mg/kg IV every 3 weeks or HERCEPTIN® 6 mg/kg IV every 3 weeks, for 14 cycles (743 patients in each group). Patients also received standard-of-care radiation and endocrine therapy as per institutional guidelines. Both treatment groups were well balanced and Hormone Receptor positive disease was present in 72% of the patients. The majority of the patients (77%) had received an Anthracycline-containing neoadjuvant chemotherapy regimen, and in 19% of the patients, another HER2-targeted agent in addition to HERCEPTIN® (dual HER2 blockade) had been administered as a component of neoadjuvant therapy. The Primary end point was invasive Disease Free Survival-iDFS (defined as freedom from ipsilateral invasive breast tumor recurrence, ipsilateral locoregional invasive breast cancer recurrence, contralateral invasive breast cancer, distant recurrence, or death from any cause). The Primary analysis showed that 3-year invasive DFS was significantly higher in the KADCYLA® group than in the HERCEPTIN® group (88.3% vs. 77.0%; HR=0.50; P<0.001), suggesting that KADCYLA® reduced the risk of developing an invasive breast cancer recurrence or death by 50%.

The researchers in this publication reported the prespecified final analysis of invasive DFS, and the second interim analysis of Overall Survival. With a median follow-up of 8.4 years, KADCYLA® sustained its superiority over HERCEPTIN® in improving invasive DFS and OS. The 7-year invasive DFS rate was 80.8% with KADCYLA® vs. 67.1% with HERCEPTIN® (unstratified HR=0.54, confirming a 46% reduction in risk. The 7-year OS was 89.1% with KADCYLA® vs. 84.4% with HERCEPTIN® (unstratified HR=0.66; P=0.003), demonstrating a 34% reduction in mortality risk.

Further analyses revealed consistent benefits across key subgroups which included patients with low tumor burden minimal residual disease (1 cm or less, node-negative), HER2-negative residual disease on retesting, both ER-positive and ER-negative patients, as well as HER2 expression level, with patients with IHC 3+ HER2 expression experiencing the most significant benefit (HR=0.47), whereas those with IHC 2+ ISH-amplified tumors had a smaller, though still positive, effect (HR=0.84).

The incidence of adverse events of Grade 3 or higher was noted in 26.1% of patients receiving KADCYLA® compared to 15.7% in the HERCEPTIN® group. The frequency of CNS metastases was comparable between the two cohorts, suggesting that while KADCYLA® enhances control of extracranial disease, it does not necessarily reduce CNS metastases.

In conclusion, the KATHERINE trial has established KADCYLA® as the new standard of care for patients with HER2-positive early breast cancer with residual invasive disease following neoadjuvant therapy. Long-term follow-up confirms sustained benefits in invasive DFS and OS, with an acceptable safety profile. While KADCYLA® significantly reduces recurrence and improves survival, certain high-risk subgroups may require additional therapeutic strategies, prompting the need for ongoing research. Future advancements in HER2-targeted therapies, including Tyrosine Kinase Inhibitors, Antibody Drug Conjugates, and immunotherapy combinations, will further refine treatment strategies and improve outcomes for this high-risk patient population.

Survival with Trastuzumab Emtansine in Residual HER2-Positive Breast Cancer. Geyer CE, Untch M, Huang C-S, et al. for the KATHERINE Study Group. N Engl J Med 2025;392:249-257

Anthracycline Plus Taxane Based Adjuvant Therapy for High risk Early Stage 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 50% of all breast cancers are Estrogen Receptor (ER) positive, HER2-negative, axillary node-negative tumors. In the treatment of early-stage breast cancer, particularly in Hormone Receptor-positive (HR-positive) and HER2-negative cases, the standard approach to adjuvant chemotherapy has evolved, with the goal of optimizing patient outcomes while minimizing unnecessary toxicity. Historically, anthracyclines, a class of chemotherapy drugs, were combined with taxanes as part of chemotherapy regimens. However, recent studies have questioned the benefit of adding anthracyclines to treatment, for patients with HR-positive/HER2-negative breast cancer, particularly in those with lower recurrence risk. The addition of anthracyclines has not definitively demonstrated improvements in outcomes like invasive Disease-Free Survival (DFS) for patients with HR-positive/HER2-negative breast cancer who receive taxane-based chemotherapy. Anthracycline-free regimens are typically preferred for lower risk patients, as efficacy is not compromised and there is no heightened risk of long-term side effects, such as leukemia. Yet, a gap exists in the literature regarding the benefit of anthracycline therapy in patients with high-risk profiles, as identified by OncotypeDX assay.

The Oncotype DX breast cancer assay, is a multigene genomic test that analyzes the activity of a group of 21 genes and is able to predict the risk of breast cancer recurrence and likelihood of benefit from systemic chemotherapy following surgery, in women with early-stage breast cancer. Oncotype Dx assay categorizes patients based on Recurrence Scores (RS) into Low risk (0-10), Intermediate risk (11-25), and High risk (26-100) helping clinicians tailor treatment decisions. Despite the widespread clinical use of OncotypeDX, the potential benefits of anthracyclines for patients with high RS scores have not been comprehensively studied.

The Anthracyclines in Early Breast Cancer (ABC) trials demonstrated that the addition of anthracyclines to a taxane-based chemotherapy regimen did not significantly improve invasive DFS for patients with HR-positive breast cancer. As a result, HR-positive/HER2-negative patients with a lower RS or smaller tumors have generally been managed with anthracycline-free regimens.

TAILORx ((Trial Assigning Individualized Options for Treatment) is a Phase III, randomized, prospective, non-inferiority trial in which 10,273 women, 18-75 years of age, with HR-positive, HER2-negative, T1b-T2N0 early-stage axillary node-negative breast cancer were enrolled. Patients had tumors 1.1-5.0 cm in size (or 0.6-1.0 cm and intermediate/high grade). Patients were divided into three groups based on their Recurrence Score (RS). Women with a Low RS of 0-10 received endocrine therapy alone and those with a High RS of 26-100 received endocrine therapy in combination with standard adjuvant chemotherapy which included T-AC (Taxane usually Docetaxel along with anthracycline usually Doxorubicin plus Cyclophosphamide, or TC (Taxane plus Cyclophosphamide, but without an anthracycline). Patient with Intermediate RS of 11-25 (N=6711) were randomly assigned to receive endocrine therapy alone (N=3399) or endocrine therapy and adjuvant chemotherapy (N=3312).TAILORx study concluded that among patients with a Recurrence Score of 11-25, endocrine therapy alone was non-inferior to chemotherapy plus endocrine therapy.

A subset of 2,591 patients, who had a recurrence score between 11 and 100, formed the basis for this analysis. Among them, 437 patients received T-AC, while 2,091 received TC regimen. Outcomes were compared between patients who received T-AC and those who received TC, adjusting for key variables such as age, RS, tumor size, grade, and Estrogen/Progesterone Receptor status. Outcomes were stratified by RS > 31 and < 31.The study population had a median age of 55 years, and median follow up was 7.3 years. The Primary end point of this study was to evaluate Distant Recurrence-Free Interval (DRFI). Other outcomes included Recurrence-Free Survival (RFS) and Overall Survival (OS).

Impact of Recurrence Score
This analysis revealed that the addition of anthracyclines to chemotherapy provided distinct benefits for patients with a high RS, specifically those with an RS of 31 or higher. Among this high risk group, the 5-year Distant Recurrence-Free Interval (DRFI) was significantly improved with T-AC compared to TC (adjusted DRFI rate was 97.5% for T-AC versus 89.4% for TC (adjusted HR=0.27, P=0.01). Similarly, Distant Recurrence-Free Survival (DRFS) was 96.5% for T-AC versus 88.3% for TC (adjusted HR=0.45, P= 0.03), and Recurrence-Free Survival (RFS) was also superior with T-AC. There was a trend towards improved OS at 5 years. For patients with an RS of less than 31, no significant benefit was observed from the addition of anthracyclines. This was particularly true for patients with an RS between 26 and 30, where no clear advantage of T-AC over TC was seen. In these lower-risk patients, both the DRFI and DRFS were similar between the two regimens.
The benefit of T-AC over TC increased further for higher RS values indicating that patients with higher recurrence scores saw more significant benefits from the addition of anthracyclines (HR=0.60 for RS 40 and HR=0.45 for RS 50).

Effect of Tumor Size
The benefit of T-AC in high-risk patients was particularly pronounced in tumors larger than 2 cm. While the primary endpoint of DRFI showed improvement with T-AC when the recurrence score was higher than 31regardless of tumor size, secondary endpoints, including DRFS, were notably enhanced in patients with tumors above the 2 cm size threshold. In contrast, smaller tumors (2 cm or less) did not demonstrate a benefit from the addition of anthracyclines.

Effect in Premenopausal and Postmenopausal Patients
Both premenopausal and postmenopausal patients with high RS showed a benefit from the addition of anthracyclines to chemotherapy. The DRFI advantage was seen in both groups, with statistical significance for premenopausal patients (P=0.032) and a trend toward significance for postmenopausal patients (P=0.028).

Risk of Non-Breast Cancer Deaths
An important consideration when making treatment decisions are the potential risks associated with anthracycline use, especially long-term risks such as leukemia or other non-breast cancer deaths.

In conclusion, the TAILORx analysis suggests that for patients with early stage, HR-positive/HER2-negative breast cancer, OncotypeDX Recurrence Score appears to be a reliable predictor of which patients might benefit from anthracyclines. Patients with a high recurrence score (RS 31 or more) derived significant benefit from the addition of anthracyclines to chemotherapy, especially those with tumors larger than 2 cm. The study was a post-hoc analysis of the TAILORx trial, which was not specifically designed to evaluate the benefit of anthracyclines and must be interpreted with caution pending further validation in prospective trials.

Impact of Anthracyclines in High Genomic Risk Node-Negative HR+/HER2- Breast Cancer. Chen N, et al. Abstract GS3-03. Presented at: San Antonio Breast Cancer Symposium; Dec. 10-13, 2024; San Antonio, TX. Abstract GS3-03

FDA Approves DATROWAY® for Advanced Metastatic HR-Positive, HER-Negative Breast Cancer

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SUMMARY: The FDA on January 17, 2025, approved Datopotamab deruxtecan-dlnk (DATROWAY®, Dato-DXd)), a Trop-2-directed antibody and topoisomerase inhibitor conjugate, for adult patients with unresectable or metastatic, Hormone Receptor (HR)-positive, Human Epidermal growth factor Receptor 2 (HER2)-negative (IHC 0, IHC1+ or IHC2+/ISH-) breast cancer who have received prior endocrine-based therapy and chemotherapy for unresectable or metastatic disease.

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 in patients with metastatic disease are Estrogen Receptor (ER) and/or Progesterone Receptor (PR) positive and HER2-negative. These patients are often treated with single agent endocrine therapy, endocrine therapy in combination with CDK4/6 inhibitor, or chemotherapy. Resistance to hormonal therapy occurs in a majority of the patients and there is therefore an unmet need for agents with novel mechanisms of action.

Datopotamab-deruxtecan (Dato-DXd) is an ADC composed of a TROP2-directed monoclonal antibody conjugated to a potent topoisomerase I inhibitor via a stable tetrapeptide-based cleavable linker. Trop-2 is a transmembrane calcium signal transducer that stimulates cancer cell growth. TROP-2 is overexpressed in several epithelial cancers including cancers of the breast, colon and lung, and has limited expression in normal human tissues. It has been associated with poor Overall and Disease-Free Survival in several types of solid tumors. 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 the payload directly into the tumor cell, making it a suitable transporter for the delivery of cytotoxic drugs. Further, the cleavable linker enables the payload 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. Dato-DXd showed encouraging antitumor activity in the TROPION-PanTumor01 trial, an ongoing multicenter, open-label study, evaluating Dato-DXd in different dose levels in solid tumors.

The present FDA approval was based on TROPION-Breast01, which is an open-label, global, Phase III study in which 732 patients (N=732) with HR-positive, HER2-negative previously treated metastatic breast cancer were randomly assigned in a 1:1 ratio to receive either Dato-DXd (N=365) or investigators choice of chemotherapy (N=367). Dato-DXd was given at a dose of 6 mg/kg IV on day 1 every 3 weeks. Investigator choice of chemotherapy consisted of Eribulin mesylate, Vinorelbine, or Gemcitabine, all given IV on days 1 and 8 every 3 weeks, as well as Capecitabine given orally on days 1-14 every 3 weeks. Treatment continued until disease progression or unacceptable toxicities. The median age was 55 yrs, and enrolled patients had received 1 or 2 prior lines of chemotherapy in the inoperable or metastatic setting. Eligible patients had progressed on or were deemed unsuitable for endocrine therapy. Patients were stratified by the number of lines of chemotherapy received in the unresectable/metastatic setting, and treatment with a previous CDK4/6 inhibitor. The Co-Primary end points were Progression Free Survival (PFS) by Blinded Independent Central Review (BICR) and Overall Survival (OS). Secondary end points included Overall Response Rate (ORR), Safety, Patient Reported Outcomes (PRO), and Time to First Subsequent Therapy (TFST).

The Median PFS by BICR in the Dato-DXd arm was 6.9 months versus 4.9 months in the chemotherapy arm (HR=0.63; P < 0.0001). The PFS benefit with Dato-DXd over chemotherapy was noted irrespective of brain metastases and prior duration of treatment with CDK4/6 inhibitors. Although OS data were immature, a trend favoring Dato-DXd was observed. The confirmed ORR was 36.4% and 22.9% and median Duration of Response was 6.7 months and 5.7 months in the Dato-DXd and chemotherapy groups, respectively. The median Time to First Subsequent Therapy was 8.2 months with Dato-DXd and 5.0 months with chemotherapy. Dato-DXd also demonstrated a delay in time to deterioration in global health status/quality of life, compared to chemotherapy. Grade 3 or more treatment-related adverse events with Dato-DXd was lower than with chemotherapy (20.8% versus 44.7%) and the most common toxicities were nausea and stomatitis with Dato-DXd and neutropenia in the chemotherapy arm.

In conclusion, patients receiving Dato-DXd showed statistically significant and clinically meaningful improvement in Progression Free Survival compared to chemotherapy, with a favorable and manageable safety profile. The improved outcomes were observed across subgroups, supporting the benefit of this novel treatment option, for previously treated patients with inoperable/metastatic HR-positive, HER2-negative breast cancer.

Datopotamab Deruxtecan Versus Chemotherapy in Previously Treated Inoperable/Metastatic Hormone Receptor-Positive Human Epidermal Growth Factor Receptor 2-Negative Breast Cancer: Primary Results From TROPION-Breast01. Bardia A, Jhaveri K, Im S-A, et al. for the TROPION-Breast01 Investigators. J Clin Oncol. 2025;43:285-296.

Prolonged Survival Benefit with LYNPARZA® in BRCA Mutated Early Stage 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. Approximately 319,750 new cases of breast cancer will be diagnosed in 2025 and about 42,680 individuals will die of the disease, largely due to metastatic recurrence.

DNA can be damaged due to errors during its replication or as a result of environmental exposure to UV radiation from the sun or other toxins. The tumor suppressor genes such as BRCA1 (Breast Cancer 1) 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. The BRCA1 gene is located on the long (q) arm of chromosome 17 whereas BRCA2 is located on the long arm of chromosome 13. 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. Patients with BRCA mutations can present with aggressive, high-risk disease and are at a high risk of recurrence following completion of multimodality therapy including surgery, radiation, and chemotherapy. This is an area of unmet need, warranting identification of additional novel and effective therapies.

BRCA1 and BRCA2 are tumor suppressor genes and they recognize and repair double strand DNA breaks via Homologous Recombination (HR) pathway. Homologous Recombination is a DNA repair pathway utilized by cells to accurately repair DNA double-stranded breaks during the S and G2 phases of the cell cycle, and thereby maintain genomic integrity. The PARP (Poly ADP Ribose Polymerase) family of enzymes include PARP1 and PARP2, and is a related enzymatic pathway that repairs single strand breaks in DNA. In a BRCA mutant, the cancer cell relies solely on PARP pathway for DNA repair to survive.

Olaparib (LYNPARZA®) is a PARP inhibitor, that traps PARP onto DNA at sites of single-strand breaks, thereby preventing their repair and generate double-strand breaks. These breaks cannot be repaired accurately in tumors harboring defects in Homologous Recombination Repair pathway genes, such as BRCA1 or BRCA2 mutations, and this leads to cumulative DNA damage and tumor cell death.

OlympiA is a multicenter, randomized, placebo-controlled, double-blind, Phase III trial of adjuvant Olaparib after neoadjuvant/adjuvant chemotherapy, in patients with germline BRCA1/2 mutations, and high risk HER2-negative early breast cancer. This trial enrolled 1836 patients, including triple-negative and Hormone Receptor positive (HR-positive) breast cancer. All enrolled patients had already received standard adjuvant or neoadjuvant chemotherapy, surgery and if needed, radiation therapy, for early stage breast cancer (Stage II-III). Inclusion criteria required that patients have a high risk of disease recurrence. Patients with triple-negative breast cancer who received adjuvant chemotherapy were required to have axillary node–positive disease or an invasive primary tumor measuring at least 2 cm. Patients who were treated with neoadjuvant chemotherapy were required to have residual invasive breast cancer in the breast or resected lymph nodes (no pathological Complete Response from neoadjuvant therapy). Patients who were treated with adjuvant chemotherapy for HR-positive, HER2-negative breast cancer were required to have 4 or more pathologically confirmed positive lymph nodes. Patients were randomized 1:1 to receive Olaparib 300 mg PO BID continuously for 1 year (N=921) or placebo (N=915). Endocrine therapy and bisphosphonates were allowed. Treatment groups were well balanced. The median age was 42 years, germline mutations were present in BRCA1 in 72% of the patients, in BRCA2 in 27% of the patients, 82% of the patients had triple-negative breast cancer, 18% had HR-positive and HER2 negative disease, 62% were premenopausal and 38% were postmenopausal, 50% of the patients had received adjuvant chemotherapy and 50% had received neoadjuvant chemotherapy. The Primary endpoint was Invasive Disease Free Survival (IDFS) and Secondary endpoints included Distant DFS (DDFS), Overall Survival (OS) and Safety. At the pre-specified interim analysis (2.5 years), the estimated 3-year Invasive DFS was 85.9% for patients who received Olaparib compared with 77.1% for those who received placebo (HR=0.58; P<0.001), representing a 42% reduction in the risk of Invasive DFS with Olaparib compared to placebo. The 3-year Distant DFS was 87.5% versus 80.4% respectively (HR=0.57; P<0.001). The researchers in this updated analysis reported the results of the third pre-specified interim analysis with median follow-up of 6.1 years (maximum follow-up of 9.6 years).

The treatment benefit with Olaparib was maintained with longer follow up, and was similar to previously reported results. The Invasive DFS at 6 years was 79.6% in the Olaparib-treated group versus 70.3% in the placebo group, with an absolute difference of 9.3%, favoring the addition of Olaparib (HR=0.65). The Distant DFS at 6 years was 83.5% versus 75.7%, respectively, with an absolute difference of 7.8% (HR=0.65). The 6-year Overall Survival rate was 87.5% in the Olaparib group versus 83.2% in the placebo group, with a 28% reduction in the risk of death (HR=0.72). The benefit with adjuvant Olaparib was consistent across all key subgroups, including for patients with high risk and HR-positive disease.

Fewer cases of BRCA-associated cancers such as contralateral invasive and non-invasive breast cancers, new primary ovarian cancer and new primary fallopian tube cancer were reported, with adjuvant Olaparib versus placebo. Further, there was no increase in the risk of developing secondary myelodysplastic syndrome or acute myeloid leukemia.

It was concluded that at 6.1 years median follow-up, one year of adjuvant treatment with Olaparib after neoadjuvant or adjuvant chemotherapy continues to demonstrate meaningful improvements in Invasive DFS, Distant DFS and OS in patients with germline BRCA pathogenic variants and high risk, HER2-negative breast cancer, including those with HR-positive tumors. This study highlights the importance of BRCA testing in early stage breast cancer. Perhaps considering one year of adjuvant Olaparib followed by a CDK4/6 inhibitor in HR-positive, BRCA-positive, high risk HER2-negative early stage breast cancer patients, may be a reasonable approach.

Garber J: OlympiA-Phase 3, multicenter, randomized placebo-controlled trial of adjuvant olaparib after (neo)adjuvant chemotherapy in patients with germline BRCA1/BRCA2 pathogenic variants and high-risk HER2-negative primary breast cancer: Longer-term follow-up. 2024 San Antonio Breast Cancer Symposium. Abstract GS1-09. Presented December 11, 2024.