Estrogen receptor-positive (ER+) is the most common subtype of breast cancer. Endocrine therapy is the fundamental treatment against this entity, by directly or indirectly modifying estrogen production. Recent advances in novel compounds, such as cyclin-dependent kinase 4/6 inhibitors (CDK4/6i), or phosphoinositide 3-kinase (PI3K) inhibitors have improved progression-free survival and overall survival in these patients. However, some patients still develop endocrine resistance after or during endocrine treatment. Different underlying mechanisms have been identified as responsible for endocrine treatment resistance, where ESR1 gene mutations are one of the most studied, outstanding from others such as somatic alterations, microenvironment involvement and epigenetic changes. In this scenario, selective estrogen receptor degraders/downregulators (SERD) are one of the weapons currently in research and development against aromatase inhibitor- or tamoxifen-resistance. The first SERD to be developed and approved for ER+ breast cancer was fulvestrant, demonstrating also interesting activity in ESR1 mutated patients in the second line treatment setting. Recent investigational advances have allowed the development of new oral bioavailable SERDs. This review describes the evolution and ongoing studies in SERDs and new molecules against ER, with the hope that these novel drugs may improve our patients’ future landscape.

HER2-positive breast cancer accounts for 15–20% of all breast cancer cases. This subtype is characterized by an aggressive behavior and poor prognosis. Anti-HER2 therapies have considerably improved the natural course of the disease. Despite this, relapse still occurs in around 20% of patients due to primary or acquired treatment resistance, and metastasis remains an incurable disease. This article reviews the main mechanisms underlying resistance to anti-HER2 treatments, focusing on newer HER2-targeted therapies. The progress in anti-HER2 drugs includes the development of novel antibody–drug conjugates with improvements in the conjugation process and novel linkers and payloads. Moreover, trastuzumab deruxtecan has enhanced the efficacy of trastuzumab emtansine, and the new drug trastuzumab duocarmazine is currently undergoing clinical trials to assess its effect. The combination of anti-HER2 agents with other drugs is also being evaluated. The addition of immunotherapy checkpoint inhibitors shows some benefit in a subset of patients, indicating the need for useful biomarkers to properly stratify patients. Besides, CDK4/6 and tyrosine kinase inhibitors are also included in the design of new treatment strategies. Lapitinib, neratinib and tucatinib have been approved for HER2-positive metastasis patients, however clinical trials are currently ongoing to optimize combined strategies, to reduce toxicity, and to better define the useful setting. Clinical research should be strengthened along with the discovery and validation of new biomarkers, as well as a deeper understanding of drug resistance and action mechanisms.

Understanding the biological aspects of immune response in HER2+ breast cancer is crucial to implementing new treatment strategies in these patients. It is well known that anti-HER2 therapy has improved survival in this population, yet a substantial percentage may relapse, creating a need within the scientific community to uncover resistance mechanisms and determine how to overcome them. This systematic review indicates the immunological mechanisms through which trastuzumab and other agents target cancer cells, also outlining the main trials studying immune checkpoint blockade. Finally, we report on anti-HER2 vaccines and include a figure exemplifying their mechanisms of action.

Treatment for the HER2+ breast cancer subtype is still unsatisfactory, despite breakthroughs in research. The discovery of various new molecular mechanisms of transcription factors may help to make treatment regimens more effective. The transcription factor SALL4 has been related to aggressiveness and resistance therapy in cancer. Its molecular mechanisms and involvement in various signaling pathways are unknown in the HER2+ breast cancer subtype. In this study, we have evaluated the implication of SALL4 in the HER2+ subtype through its expression in patients’ samples and gain and loss of function in HER2+ cell lines. We found higher SALL4 expression in breast cancer tissues compared to healthy tissue. Interestingly, high SALL4 expression was associated with disease relapse and poor patient survival. In HER2+ cell lines, transient overexpression of SALL4 modulates PI3K/AKT signaling through regulating PTEN expression and BCL2, which increases cell survival and proliferation while reducing the efficacy of trastuzumab. SALL4 has also been observed to regulate the epithelial–mesenchymal transition and stemness features. SALL4 overexpression significantly reduced the epithelial markers E-cadherin, while it increased the mesenchymal markers β-catenin, vimentin and fibronectin. Furthermore, it has been also observed an increased expression of MYC, an essential transcription factor for regulating epithelial-mesenchymal transition and/or cancer stem cells. Our study demonstrates, for the first time, the importance of SALL4 in the HER2+ subtype and partial regulation of trastuzumab sensitivity. It provides a viable molecular mechanism-driven therapeutic strategy for an important subset of HER2-overexpressing patients whose malignancies are mediated by SALL4 expression.

HER2DX is a clinically available genomic assay that provides prognostic (relapse risk score), predictive [pathological complete response (pCR) likelihood score], and ERBB2 expression data in stage I-III human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC). This real-world study evaluated its clinical impact. This prospective study enrolled newly diagnosed patients with stage I-III HER2-positive BC across 12 hospitals in Spain (November 2021-September 2024). Thirty-four oncologists ordered HER2DX and completed questionnaires before and after receiving results to assess treatment changes (primary objective). Secondary objectives included evaluating the HER2DX pCR likelihood score association with pCR, test turnaround time, changes in physician confidence regarding treatment decisions, and cost-effectiveness. Among 297 recruited patients, 48.1% (95% confidence interval 42.5% to 53.7%) experienced treatment adjustments after HER2DX. Within these cases, 73.5% involved reduced treatment intensity, 24.5% involved increased treatment intensity, and the remaining cases (2.0%) involved mixed adjustments. Of the cases with reduced treatment intensity, 56.2% had a reduction in chemotherapy intensity, 26.7% had a reduction in anti-HER2 therapy, and 17.1% in both. Among the 182 patients with available pathological data at surgery, the pCR likelihood score was a significant predictor of pCR (P < 0.001). In 69 patients with pCR-high disease, less intensive treatment achieved similar pCR rates compared with multi-agent chemotherapy (81.5% versus 69.0%; odds ratio = 1.97, P = 0.256). Physician confidence improved (P < 0.001) and the estimated total cost savings, including direct drug costs, vein access devices, and HER2DX costs, amounted to €98 031. HER2DX impacts clinical management in stage I-III HER2-positive BC by supporting treatment adjustments, enhancing physician confidence, maintaining pCR rates, and reducing health care costs.

Purpose: HER2DX is a validated genomic assay used to support treatment decisions in early-stage HER2-positive (HER2+) breast cancer. It provides three scores: relapse risk, likelihood of pathologic complete response (pCR), and ERBB2 mRNA expression. This study aimed to evaluate the association between HER2DX and histopathologic features and assess its relationship with pCR after neoadjuvant therapy. Experimental Design: Patients with newly diagnosed stage I to III HER2+ breast cancer were analyzed based on available HER2DX results during routine care in Spain (January 2022–June 2025). Centralized HER2DX testing was performed on formalin-fixed, paraffin-embedded tumor samples. Histopathologic analysis included tumor grade, hormone receptor status, histologic subtype, Ki67 index, HER2 IHC score, stromal tumor-infiltrating lymphocytes (TIL), tertiary lymphoid structures, and spatial immune distribution. Univariate and multivariable logistic regression analyses were conducted to identify factors associated with pCR after neoadjuvant trastuzumab-based therapy. Results: A total of 410 HER2+ tumors were analyzed, and 250 patients received neoadjuvant trastuzumab-based therapy with available surgical outcomes (36% achieved a pCR). HER2DX pCR scores were significantly associated with all eight histopathologic features, whereas relapse risk and ERBB2 scores were associated with five and two, respectively. TIL correlated with the immune/immunoglobulin signature (r = 0.59), and Ki67 with the proliferation signature (r = 0.50). The HER2DX pCR score remained the only independent predictor of pCR in multivariable analysis (OR, 1.77; 95% confidence interval, 1.08–2.97; P = 0.030). Conclusions: HER2DX reflects key biological and pathologic features of HER2+ breast cancer and independently predicts pCR, supporting its utility for individualized treatment decision-making.