Metastatic Breast Cancer Advances: T-DXd Data, ESMO Guideline, TMB Biomarker, Care Disparities

Several developments across 2025 and 2026 are reshaping the treatment of metastatic breast cancer, including updated trial data for trastuzumab deruxtecan, a revised ESMO guideline, and new analyses of immunotherapy biomarkers and racial disparities in care.

In HER2-positive advanced/metastatic breast cancer, a series of plenary and poster presentations at ASCO, ESMO, and the San Antonio Breast Cancer Symposium held across 2025 and 2026 outlined the evolving role of the antibody–drug conjugate trastuzumab deruxtecan (T-DXd). Latest interim data from DESTINY-Breast09 evaluated T-DXd plus pertuzumab in the first-line metastatic setting against docetaxel, trastuzumab, and pertuzumab (THP). T-DXd plus pertuzumab delivered durable disease control, with a median progression-free survival exceeding 40 months, and clinically meaningful PFS benefit was observed versus THP consistently across clinically relevant subgroups, including prior treatment history, hormone receptor status, and PIK3CA mutational status. Patient-reported outcomes showed similarly tolerable side effects between the arms, with no new safety signals reported overall.

The final analysis of DESTINY-Breast03 evaluated T-DXd monotherapy as second-line therapy versus trastuzumab emtansine (T-DM1) in patients whose disease had progressed after prior treatment with trastuzumab and a taxane. Five-year follow-up data confirmed the advantages of T-DXd in conferring sustained long-term survival. In an exploratory analysis, complete response was 13.0% and deep partial response was 16.5% in the T-DXd arm, totaling 29.5%. An exploratory analysis of DESTINY-Breast09 demonstrated that over half of patients treated with T-DXd plus pertuzumab achieved complete response or deep partial response. Earlier trials established T-DXd as third-line or later care, and DESTINY-Breast03 established T-DXd as second-line therapy with a median PFS of 28.8 months versus 6.8 months for T-DM1.

The European Society for Medical Oncology has released an updated Clinical Practice Guideline for metastatic breast cancer, published in Annals of Oncology, superseding the 2021 version. The guideline recommends that at first diagnosis of metastatic breast cancer, biopsy should be performed when feasible to confirm histology and reassess tumor biology, including estrogen receptor, progesterone receptor, and HER2 status. It recommends PD-L1 testing in metastatic triple-negative breast cancer and germline BRCA1/2 and PALB2 testing in HER2-negative metastatic disease when specific treatments are available. For ER-positive, HER2-negative disease, evaluation of PIK3CA mutations is recommended if PI3K inhibitors are available, and ESR1 mutation testing using circulating tumor DNA or tumor tissue is recommended after progression on an aromatase inhibitor with or without a CDK4/6 inhibitor. Reassessment of HER2 status as HER2-low, HER2-ultralow, or HER2-0 is recommended in patients who are not candidates for endocrine therapy, because HER2 expression level can influence antibody–drug conjugate selection. For first-line ER-positive, HER2-negative disease, ESMO recommends an aromatase inhibitor plus a CDK4/6 inhibitor for de novo disease or recurrence more than 12 months after adjuvant endocrine therapy, listing AI–ribociclib first by preference, followed by AI–abemaciclib and AI–palbociclib. In PIK3CA-mutated disease recurring on or within 12 months of adjuvant endocrine therapy, fulvestrant–palbociclib–inavolisib is recommended.

A real-world study examined whether a small group of patients with ultra-high tumor mutational burden (TMB), defined as at least 20 mutations per megabase, may represent a clinically meaningful subgroup. Among a genomic cohort of 2,049 patients with clinically advanced breast cancer who underwent comprehensive genomic profiling, 8.1% had TMB of at least 10 mutations/Mb and 2.2% had ultra-high TMB of at least 20 mutations/Mb. The median TMB in the ultra-high group was 26.3 mutations/Mb versus 2.5 mutations/Mb in tumors with TMB below 20 mutations/Mb. Ultra-high TMB tumors were more likely to be estrogen receptor-positive (86.6% versus 68.2%), invasive lobular carcinoma (40.0% versus 14.5%), PIK3CA-mutated (81.8% versus 37.9%), and CDH1-altered (45.5% versus 12.3%). Among patients with hormone receptor-positive/HER2-negative advanced breast cancer who received single-agent immunotherapy, most commonly pembrolizumab and often in later lines, those with ultra-high TMB had longer median time to next treatment (4.9 versus 2.6 months), progression-free survival (3.5 versus 1.7 months), and real-world overall survival (14.1 versus 3.2 months) than patients with lower TMB. The real-world overall survival hazard ratio was 0.37 for ultra-high TMB compared with TMB below 10 mutations/Mb. Pembrolizumab already has a tumor-agnostic indication for unresectable or metastatic solid tumors with TMB of at least 10 mutations per megabase when there are no satisfactory alternative treatment options. The results are retrospective and based on a small immunotherapy-treated cohort, and the median progression-free survival remained modest, indicating this is not a universally effective strategy.

A retrospective cross-sectional analysis of 117,743 female patients diagnosed with de novo metastatic breast cancer between 2010 and 2022 using the National Cancer Database, published in JAMA Network Open, found that Black and Hispanic patients experienced significant delays in treatment initiation across all subtypes compared with White patients. Among patients with HR-positive, ERBB2-negative disease, Black patients experienced significantly longer times to endocrine therapy initiation (6.6 days), chemotherapy (3.6 days), and radiotherapy (11.3 days) than White patients in fully adjusted models. For ERBB2-positive disease, Black patients had delays in ERBB2-directed therapy initiation (5.7 days) and chemotherapy (5.1 days), while Hispanic patients experienced a 7.3-day delay in ERBB2-directed therapy and a 15.6-day delay in chemotherapy. In triple-negative breast cancer, Black and Hispanic patients experienced longer times to immunotherapy initiation in age-adjusted models, but these differences were no longer significant after socioeconomic covariate adjustment. Across all subtypes, Medicaid enrollment, Medicare enrollment, and lack of insurance were associated with delayed treatment initiation, with living in areas with lower income and education levels also linked to delays across treatment modalities.

HER2-positive breast cancer is characterized by an overproduction of the HER2 protein due to amplification of the HER2 gene, and high levels of HER2 can be found in approximately 15–30% of all breast cancers. The disease is aggressive, historically marked by poor patient prognosis and a high risk of recurrence. In the landmark CLEOPATRA trial, docetaxel, trastuzumab, and pertuzumab demonstrated a median overall survival of 57.1 months versus 40.8 months in the placebo group, establishing dual HER2 blockade as the benchmark for first-line therapy. T-DM1, an earlier-generation antibody–drug conjugate, was evaluated in the MARIANNE trial but did not demonstrate superiority over trastuzumab plus taxane in efficacy and tolerability.