HER-2 negative + HR positive + ESR1 mutation

This review outlines the key challenges to validating and implementing ctDNA-guided early endocrine switching in routine clinical practice and discusses its potential to reshape monitoring and decision-making in metastatic hormone receptor-positive, HER2-negative breast cancer.

qPCR, dPCR, and NGS assays can detect common ESR1m with differing sensitivity and specificity depending on the assay and amount of input DNA. Assay selection will vary depending on analytical performance, turnaround times, lab infrastructure and expertise, healthcare setting, and regional variation in market costs.

Sapanisertib plus fulvestrant provided the greatest PFS benefit (HR 0.34, 95% CI 0.14-0.82) but had a high discontinuation rate (>15%). Among the approved therapies, ribociclib plus ET (HR 0.57, 95% CI 0.39-0.84), capivasertib plus fulvestrant (HR 0.62, 95% CI 0.51-0.75), and elacestrant (HR 0.70, 95% CI 0.55-0.89) demonstrated superior efficacy...Ipatasertib and alpelisib showed the greatest benefits in patients with PI3K/PTEN/AKT alterations. Antibody-drug conjugates (ADCs), such as trastuzumab deruxtecan and sacituzumab govitecan, outperformed standard chemotherapy, albeit with higher toxicity...Grant Assignment Decree No. 1369 adopted on 01.09.2023 by the Italian Ministry of University and Research (MUR).

Our results support the strategy of switching the CDK4/6i in the second-line setting and demonstrate persistent benefit even in patients with PIK3CA or ESR1 mutations.

Despite these advances, the identification of robust biomarkers to predict response to chemotherapy and radiotherapy remains a critical unmet need. This review synthesizes current evidence and highlights key challenges and opportunities in the clinical translation of biomarker-driven precision oncology for breast cancer.

P3, N=315, Active, not recruiting, AstraZeneca | Trial primary completion date: Apr 2025 --> Jul 2025

However, reports often failed to address the risk that tumor DNA may not have been tested, and the limitations of the methodologies used by participants were insufficiently discussed. The variability in genotyping accuracy and reporting standards underscores the importance of EQA and educational guidance to ensure the provision of high-quality clinical services.

Endocrine therapies, including fulvestrant and novel oral selective estrogen receptor degraders (SERDs) like elacestrant, show promise, especially in patients with ESR1 mutations. Targeted therapies such as PI3K/AKT/mTOR inhibitors, exemplified by alpelisib and capivasertib, offer potential by addressing downstream signaling pathways involved in resistance. Additionally, FGFR inhibitors like erdafitinib are under investigation for their role in overcoming specific resistance mechanisms...Ongoing clinical trials are expected to provide deeper insights, guiding the development of more effective post-progression therapeutic strategies. This evolving landscape highlights the need for continuous research and individualized patient care to improve survival and quality of life in HR + mBC patients.

Oral SERDs offer enhanced bioavailability and convenience compared to fulvestrant, representing a critical advancement in endocrine therapy...However, other than ESR1 mutations, clinical refinement for patient selection is limited. Further trials are needed to optimize patient selection for oral SERD use and define the most effective combination strategies with oral SERDs.

P3, N=312, Active, not recruiting, AstraZeneca | Recruiting --> Active, not recruiting