Making resistance visible through multidisciplinary teams solving testing barriers in HR+/HER2– advanced breast cancer

In hormone receptor–positive/HER2-negative advanced breast cancer, acquired resistance to endocrine therapy (ET) is driven predominantly by ESR1 mutations, which are present in approximately 30–40% of patients, and alterations in the PI3K/AKT/PTEN pathway, which occur in up to 50% of cases. These mechanisms are directly targetable with oral selective estrogen receptor degraders (e.g., elacestrant) and pathway inhibitors (e.g., alpelisib, inavolisib, or capivasertib). However, patients who urgently require resistance testing are often the hardest to test, including those with bone-only metastases, those lacking access to reimbursement for circulating tumor DNA (ctDNA) testing, and those whose previous testing targeted inadequate specimens. While technological advances, including ultra-sensitive droplet digital polymerase chain reaction and broad liquid biopsy panels, are transformative, their clinical utility is dictated by local hospital infrastructure, funding models, and laboratory capabilities. There is no universally applicable testing algorithm; instead, testing must be adapted to each institution’s specific context. Coordinated multidisciplinary team (MDT) action is essential. This review reframes molecular diagnostics as a team-based, problem-solving exercise. We present three scenarios illustrating how MDTs transform testing obstacles into actionable pathways: (1) a patient with bone-only progression and no ctDNA reimbursement for ESR1 detection; (2) a patient tested on archival primary tissue, where molecular pathology clarifies resistance-mutation timing and redirects to ctDNA; and (3) a patient with false-negative ctDNA due to low tumor fraction, where the MDT reflexes to alternative cytology (pleural effusion). Through strategic specimen selection, pre-analytical optimization, fit-for-purpose assay triage, and resource-aware contingency planning, MDTs increase detection of targetable resistance, shorten turnaround times, and close equity gaps in precision medicine.