HR-positive metastatic breast cancer after CDK4/6 inhibitors

Resistance to first-line endocrine therapy with a CDK4/6 inhibitor follows a few well-mapped routes. Aromatase inhibitors select for mutations in the ligand-binding domain of ESR1 (Y537S, D538G and others) that make the oestrogen receptor active without oestrogen; these are rare in untreated tumours, appear in a third or more of patients at progression and are best detected in circulating tumour DNA. PIK3CA mutations are present from the outset in about 40 percent, and AKT1 mutations and PTEN loss in a further tenth; loss of RB1, cyclin E amplification and FGFR alterations drive CDK4/6 resistance itself. Guidelines now ask for an ESR1 test on plasma at each progression and a PIK3CA, AKT1 and PTEN test on tissue or plasma before the second line.

For ESR1-mutant disease the oral degraders replaced fulvestrant. EMERALD randomised 478 patients to elacestrant or standard endocrine therapy and halved the risk of progression in the ESR1-mutant group (hazard ratio 0.55), giving the first oral SERD approval in January 2023. SERENA-6 changed the timing: 315 patients on an aromatase inhibitor and CDK4/6 inhibitor whose plasma showed a new ESR1 mutation before any scan showed growth were switched to camizestrant while continuing the CDK4/6 inhibitor, and progression-free survival rose from 9.2 to 16.0 months (hazard ratio 0.44). EMBER-3 (874 patients) showed imlunestrant beat standard endocrine therapy in ESR1-mutant disease (hazard ratio 0.62) and that imlunestrant with abemaciclib beat imlunestrant alone whatever the ESR1 status (hazard ratio 0.57); postMONARCH showed a modest gain from continuing CDK4/6 inhibition with abemaciclib and fulvestrant after progression (6.0 against 5.3 months); the PROTAC degrader vepdegestrant followed in 2026, and giredestrant with everolimus improved progression-free survival in evERA.

For the PI3K and AKT pathway, SOLAR-1 showed alpelisib with fulvestrant extends progression-free survival from 5.7 to 11.0 months in PIK3CA-mutant tumours at the cost of severe hyperglycaemia in about 37 percent; CAPItello-291 (708 patients) showed capivasertib with fulvestrant helps after a CDK4/6 inhibitor with a hazard ratio of 0.60 overall and 0.50 in tumours with a PIK3CA, AKT1 or PTEN alteration, and was approved in November 2023; INAVO120 moved the mutant-selective inhibitor inavolisib into the first line for PIK3CA-mutant disease relapsing during or soon after adjuvant endocrine therapy, with palbociclib and fulvestrant, extending progression-free survival from 7.3 to 15.0 months and overall survival from 27.0 to 34.0 months. After endocrine therapy is exhausted, trastuzumab deruxtecan comes before chemotherapy for HER2-low and ultralow tumours (DESTINY-Breast06), sacituzumab govitecan extends survival after chemotherapy (TROPiCS-02, 14.4 against 11.2 months) and datopotamab deruxtecan is an alternative (TROPION-Breast01). The order in which to use degraders, pathway inhibitors and antibody-drug conjugates is the open question.