Investigator-Assessed PFS Matches BICR in HR+/HER2-Negative Metastatic Breast Cancer

Why This Study Matters

Hormone receptor-positive, HER2-negative (HR+/HER2-negative) disease is the most common breast cancer subtype, accounting for 70.1% of female breast cancer cases in the United States (SEER Cancer Stat Facts, 2019–2023 data). Progression-free survival (PFS) is the default primary endpoint in metastatic HR+/HER2-negative trials, but because it depends on radiographic interpretation of scans, it is inherently susceptible to assessment bias. Trial sponsors and regulators have increasingly leaned on blinded independent central review (BICR) as a safeguard — at real cost in time, money, and trial complexity. This meta-analysis asks a direct operational question: does BICR actually change the answer, or does investigator assessment get you to the same place?

Study Design

The authors conducted a systematic review and trial-level random-effects meta-analysis, searching PubMed, Embase, CENTRAL, and major conference proceedings from database inception through November 27, 2025. Two reviewers independently extracted data from eligible phase 2 or phase 3 randomized trials. The primary comparison was not a treatment-versus-treatment analysis but an assessment-method-versus-assessment-method analysis: investigator (local site)-read PFS versus BICR-read PFS, within the same set of trials.

In total, 21 randomized trials covering 9,165 pooled patients were included, drawn from an initial screen of 4,989 records. Of these, 11 trials used BICR as their primary assessment method, 13 were open-label, and 7 required prior CDK4/6 inhibitor therapy as an inclusion criterion. Site count, randomization ratio, and dosing regimen are not applicable to this study design — it is a meta-analysis of endpoint-assessment concordance across 21 previously conducted trials, not a single interventional trial with its own randomization scheme or dosing protocol.

Patient Population

The pooled population comprised patients with hormone receptor-positive, HER2-negative metastatic breast cancer enrolled across the 21 included trials. Eligible studies required or permitted prior CDK4/6 inhibitor use, and seven of the 21 trials required prior CDK4/6 inhibitor treatment as an inclusion criterion. Detailed baseline characteristics for the pooled cohort — age, prior lines of therapy, visceral versus non-visceral disease, and performance status — are not specified in the available source.

Primary Endpoint Results

The primary outcome was the discrepancy index (DI) — the ratio of hazard ratios for BICR-assessed versus investigator-assessed PFS — along with the absolute difference in median PFS between the two assessment methods. Across all 21 trials, the pooled DI was 1.02 (95% CI, 0.95–1.10; P=.57), indicating no statistically significant systematic discordance between the two review methods at the trial level. This result held up across meta-regression analyses exploring whether trial-level factors — such as BICR-as-primary status, blinding, or prior CDK4/6 inhibitor requirement — modified the discrepancy, and in sensitivity analyses excluding outlier trials.

When the authors examined the absolute difference in median PFS rather than the hazard-ratio-based DI, a small but statistically significant divergence appeared in control arms only: BICR estimated median PFS 0.44 months longer than investigator assessment (95% CI, 0.09–0.78 months; P=.01). The corresponding difference in interventional arms, 0.26 months (95% CI, −0.16 to 0.68; P=.22), was not statistically significant.

Results of this systematic review and meta-analysis show that despite a trend toward longer median PFS with BICR in recent RCTs of patients with hormone receptor-positive/ERBB2-negative metastatic breast cancer, there was no statistically significant discrepancy index between BICR- and investigator-assessed PFS.
— Ravani et al., JAMA Oncology, 2026 (verbatim from the published abstract)

Subgroup Analyses

Because this is an abstract-only source with the full-text PMC record embargoed until July 2027, subgroup-level statistics are limited to what the abstract itself discloses.

Per this publication's fabrication-avoidance standard, no numeric hazard ratio, confidence interval, or p-value is invented for any subgroup where the primary source does not explicitly state one; only qualitative statements are reported where that is all the abstract provides.

Safety Profile

Not specified in source. This is a methodological systematic review of endpoint-assessment concordance, not a treatment efficacy or safety trial — the abstract does not report adverse event rates, and none are available to summarize.

Interpretation and Broader Context

At the trial level, this meta-analysis finds that investigator-assessed PFS and BICR-assessed PFS produce comparable effect estimates in HR+/HER2-negative metastatic breast cancer trials, with the sole statistically significant gap confined to a sub-month difference in control-arm median PFS. A secondary summary of the findings (OncoDaily) frames the practical implication this way: investigator assessment may reliably serve as a primary endpoint in some trial designs, while BICR is reserved for settings where independent review is needed to reduce bias risk or support regulatory confidence — though this framing comes from secondary commentary rather than being stated as a formal recommendation in the abstract itself.

Because BICR adds meaningful cost, logistical complexity, and time to trial conduct, evidence of concordance at the trial level is operationally relevant to how future HR+/HER2-negative metastatic breast cancer trials are designed — though it does not, on its own, resolve when BICR remains necessary for regulatory purposes.