Nowhere is the de-escalation philosophy more visible than in the surgical management of the axilla, the lymph node basin under the arm whose removal has historically caused lymphoedema, numbness, and chronic morbidity. Building on the legacy of the ACOSOG Z0011 trial, the SENOMAC study delivered definitive high-level evidence that patients with small primary tumors and one or two sentinel-node macrometastases can safely skip full axillary lymph node dissection. In this large cohort, omitting the dissection offered no additional benefit in recurrence-free or overall survival, firmly establishing sentinel node biopsy alone as the standard for this common scenario. Yet the commentary adds an important caveat: nearly 90 percent of patients in the sentinel-biopsy-only arm received postoperative radiotherapy, meaning the safety of the approach is contingent on access to appropriate radiation. In resource-limited settings where comprehensive radiotherapy is restricted, the direct application of the SENOMAC protocol demands caution, a point with profound implications for global health equity.

Two further trials pushed the surgical frontier even further by asking whether sentinel node biopsy itself could be abandoned in select low-risk patients. The SOUND trial showed that in women with small, clinically node-negative tumors, omitting sentinel biopsy produced non-inferior five-year distant disease-free survival compared with performing the procedure, with rates of 98.0 percent versus 97.7 percent. The larger INSEMA trial confirmed the finding in a similar population undergoing breast-conserving surgery, demonstrating no difference in five-year invasive disease-free survival. For a well-defined group of early-stage patients, axillary surgery may now be safely omitted entirely. However, the commentary notes that INSEMA left key questions unresolved: enrollment of patients with slightly larger T2 tumors was low, the precise criteria for safely skipping axillary surgery remain unclear, and the resulting uncertainty in nodal staging can complicate subsequent treatment decisions. The path forward is promising but not yet fully mapped.

In hormone receptor-positive disease, the story of the past two years has been the consolidation of CDK4/6 inhibitors in the curative setting and the urgent search for what comes after they fail. Updated results from the monarchE trial, which tested two years of adjuvant abemaciclib, confirmed a sustained and significant reduction in recurrence risk, with the absolute benefit in invasive disease-free survival reaching 7.6 percent at five years, 83.6 percent versus 76.0 percent. The NATALEE trial, testing three years of adjuvant ribociclib, expanded eligibility to a broader intermediate-to-high-risk population and demonstrated a 4.9 percent absolute improvement in four-year invasive disease-free survival, alongside a 28.5 percent reduction in the risk of distant recurrence. Notably, a subgroup analysis of node-negative patients with high-risk features, a population excluded from monarchE, showed a substantial 5.1 percent absolute benefit, effectively covering a larger proportion of Stage II patients and addressing a critical unmet need.

With CDK4/6 inhibitors now ubiquitous in first-line metastatic treatment, defining the optimal strategy after progression has become a paramount research priority, and 2024 delivered several distinct answers. The postMONARCH trial was the first to prospectively validate simply continuing a CDK4/6 inhibitor: patients who progressed on prior CDK4/6 inhibition plus endocrine therapy gained a statistically significant but modest improvement in median progression-free survival when abemaciclib was added to fulvestrant, 6.0 versus 5.3 months. The benefit appeared concentrated in patients with longer prior CDK4/6 exposure and no visceral metastases, and the small absolute gain raises questions about universal utility, but the trial provides proof of concept that continued CDK pathway inhibition can help select patients. In parallel, the EMBER-3 trial showcased the oral selective estrogen receptor degrader imlunestrant, which significantly improved progression-free survival in tumors carrying ESR1 mutations, the classic driver of aromatase inhibitor resistance. More strikingly, combining imlunestrant with abemaciclib produced clear synergistic activity, extending median progression-free survival to 9.4 versus 5.5 months overall and 9.1 versus 3.7 months in the post-CDK4/6i subgroup, positioning oral SERDs as a powerful future backbone of therapy.

Perhaps the most practice-changing development was the expansion of the antibody-drug conjugate trastuzumab deruxtecan into tumors with barely detectable HER2 expression, including the newly defined HER2-ultralow category. The DESTINY-Breast06 trial enrolled patients with hormone receptor-positive, HER2-low or HER2-ultralow metastatic disease who had progressed on endocrine therapy and compared the drug with physician’s choice of chemotherapy. Trastuzumab deruxtecan delivered a median progression-free survival of 13.2 months versus 8.1 months, with results consistent across both expression groups and an objective response rate approaching 60 percent. The trial effectively redefines a large proportion of historically HER2-negative tumors as targetable, creating a highly effective, chemotherapy-sparing option for patients whose real-world outcomes on subsequent therapy have often been less than five months. Complementing this, the PAM signaling pathway, a key resistance mechanism, became druggable in routine practice: the AKT inhibitor capivasertib doubled progression-free survival when added to fulvestrant in CAPItello-291, with even greater benefit in tumors carrying AKT pathway alterations, while the PI3Kα inhibitor inavolisib, combined with palbociclib and fulvestrant in PIK3CA-mutated disease, delivered a remarkable median overall survival of 34.0 versus 27.0 months in the INAVO120 study. Given that PAM pathway alterations occur in roughly 60 percent of Chinese patient populations, these agents represent a major step toward genuinely personalized sequencing after CDK4/6 inhibitor failure.

In HER2-positive disease, the revolution runs in both directions: less treatment for early-stage patients, more potent treatment for the metastatic setting. The WSG-TP-II trial asked whether chemotherapy could be safely omitted for so-called triple-positive tumors sensitive to both endocrine therapy and HER2 blockade. Although the chemotherapy arm achieved a significantly higher pathological complete response rate, 56.0 percent versus 23.7 percent, five-year overall survival was remarkably similar and excellent in both groups, at 97.9 percent versus 100 percent. For selected patients, a chemotherapy-free neoadjuvant regimen of endocrine therapy plus dual HER2 blockade may therefore be a viable de-escalation strategy that spares significant toxicity without compromising survival. In the metastatic setting, the PHILA trial showed that the tyrosine kinase inhibitor pyrotinib, added to trastuzumab and docetaxel, doubled median progression-free survival to 22.1 versus 10.5 months, while DESTINY-Breast09 demonstrated that first-line trastuzumab deruxtecan plus pertuzumab extended median progression-free survival to an unprecedented 40.7 versus 26.9 months, providing direct evidence for moving the antibody-drug conjugate from second line to first line. Updated DESTINY-Breast03 data cemented the drug’s second-line dominance, with median progression-free survival of 29.0 versus 7.2 months against trastuzumab emtansine and median overall survival of 52.6 months, a figure approaching first-line results from the CLEOPATRA era.

Triple-negative breast cancer, long the most feared subtype for its aggressive biology and lack of targets, finally saw both immunotherapy and precision medicine mature. Final overall survival results from KEYNOTE-522 confirmed that adding pembrolizumab to neoadjuvant chemotherapy, followed by adjuvant pembrolizumab, produced a significant five-year overall survival benefit of 86.6 percent versus 81.7 percent, regardless of PD-L1 status, cementing the regimen as the global standard of care. In China, the CamRelief trial showed that the PD-1 inhibitor camrelizumab significantly increased pathological complete response rates when added to neoadjuvant chemotherapy, 56.8 percent versus 44.7 percent, while the antibody-drug conjugate Dato-DXd showed promise in the neoadjuvant I-SPY2.2 platform. In the metastatic setting, TORCHLIGHT established toripalimab plus nab-paclitaxel as a new standard for PD-L1-positive patients in China, with progression-free survival of 8.4 versus 5.6 months.

The most revolutionary TNBC result, however, came from the FUTURE-SUPER trial, which applied the molecular Fudan Subtypes model to guide first-line therapy for metastatic disease. Patients were stratified into biologically defined groups, including luminal androgen receptor tumors with HER2 or PI3K/AKT mutations, immunomodulatory tumors, and basal-like or mesenchymal-like subgroups, and each received subtype-specific treatment rather than uniform chemotherapy. The precision arm nearly doubled median progression-free survival, 11.3 versus 5.8 months, breaking a long-standing impasse in targeted therapy for this subtype. Later-line options also expanded dramatically: the TROP2-directed antibody-drug conjugate sacituzumab tirumotecan improved progression-free survival to 5.7 versus 2.3 months over chemotherapy in OptiTROP-Breast01, and ASCENT-04/KEYNOTE-D19 showed that sacituzumab govitecan combined with pembrolizumab extended first-line progression-free survival to 11.2 versus 7.8 months in previously untreated, PD-L1-positive advanced disease, offering a novel chemotherapy-sparing option.

The commentary’s authors close with a sober assessment of what remains. The challenge ahead lies in optimally sequencing these powerful new agents, identifying predictive biomarkers to guide their use, and ensuring that transformative therapies reach all patients who stand to benefit. Global disparities in regulatory approval and the burden of financial toxicity remain critical hurdles, and the cautionary notes embedded in the surgical trials, particularly the dependence of de-escalation on radiotherapy access, underscore that scientific evidence alone cannot guarantee equitable care. Still, the trajectory is unmistakable: breast cancer treatment in 2025 is increasingly personalized, potent, and patient-centered, defined as much by what clinicians can now safely withhold as by what they can newly offer.

Subject of Research: Precision-guided de-escalation and targeted therapy advances in breast cancer treatment

Article Title: Breast cancer in 2025: navigating new horizons of precision-guided de-escalation

Article References: Wang, Z., Yang, B., & Wu, J. (2026). Breast cancer in 2025: navigating new horizons of precision-guided de-escalation. Holistic Integrative Oncology, 5(1), Article 41. https://doi.org/10.1007/s44178-026-00258-9

Image Credits: AI Generated

DOI: 10.1007/s44178-026-00258-9

Keywords: breast cancer, de-escalation, CDK4/6 inhibitors, antibody-drug conjugates, trastuzumab deruxtecan, triple-negative breast cancer, immunotherapy, HER2-low, axillary surgery, precision medicine, SERDs, PI3K/AKT pathway