Evolution of ER-cut-off definition in clinical trials for triple negative breast cancer: trends and patterns over 15...

Triple negative breast cancer (TNBC) is historically defined as oestrogen receptor (ER) < 1% and HER2-negative. Increasing evidence supports that ER-low breast cancer (BC) (ER 1-10%) shares similar clinical behaviour and biology with classic TNBC. However, how ER cut-off definitions have been applied as eligibility criteria in clinical trials for TNBC over time remains unclear. In August 2024, the Clinicaltrials.gov database was systematically queried using the following string: "breast cancer" AND "interventional studies" AND "phase II-III-not applicable". We included trials started from January, 1, 2010 to August, 7, 2024 restricted to TNBC, using either ER<1% or any other ER cut-off up to 10%. Differences across study descriptors were assessed using Mann-Whitney U and χ² tests. A total of 6747 studies were retrieved. Of 620 eligible trials, 474 (76.5%) restricted the inclusion to TNBC and 146 (23.5%) included ER-low tumours. The percentage of trials allowing ER-low was lower for phase III versus phase I and phase II (16.8%, 17.5%, and 27.2%, respectively; p = 0.018); in industry versus investigator-driven studies (11.6% vs 29.1%, p < 0.001), and in metastatic versus early-stage settings (18.0% vs 33.5%, p < 0.001). ER-low inclusion increased over time, particularly in investigator-driven trials (since 2015), while remaining limited in industry-sponsored studies. We evaluated the ER cut-off adopted in trials testing therapies for TNBC. Although more inclusive criteria have been applied in recent years, patients with ER-low disease remain largely excluded from registrational trials, particularly in the metastatic setting, potentially limiting access to effective therapies. Broadening inclusion criteria could improve treatment opportunities for this high-risk population.