Abstract P1-07-01: Ki-67 index after neoadjuvant endocrine therapy as a prognostic biomarker in patients with HR+/HER2- early breast cancer: a systematic review and meta-analysis
Authors: Martins-Branco Diogo , Molinelli Chiara , Marta Guilherme Nader , Ameye Lieveke , Paesmans Marianne , Salgado Roberto , Aftimos Philippe , de Azambuja Evandro 
Published: March 2023

Abstract
Background: Neoadjuvant treatment allows to better distinguish responders from non-responders, and to tailor post-neoadjuvant treatment according to tumor response in patients with HER2+ and triple-negative early breast cancer. For HR+/HER2- tumors, the pathologic complete response is less likely to occur, and residual disease is predictive of inferior recurrence-free or overall survival. Therefore, Ki-67 index, a prognostic biomarker in early breast cancer, is often used in clinical trials as an endpoint for evaluating response to neoadjuvant endocrine therapy (NET). In this systematic review and meta-analysis, we aim to assess if Ki-67 level after NET is associated with disease recurrence and/or survival. Methods: We conducted a systematic literature search of PubMed, Embase, CENTRAL, and conference proceedings (ASCO and ESMO annual meetings, ESMO Breast, and SABCS) up to June 28, 2022, to identify clinical trials or observational studies reporting Ki-67 index after NET in patients with HR+/HER2- early breast cancer treated with NET (PROSPERO number CRD42021282338). We excluded studies in which all patients received neoadjuvant chemotherapy, or from which separate data from patients receiving only NET was not retrieved. Here we report data from studies screened for the availability of the primary endpoint - recurrence-free survival (RFS), and the secondary endpoint - overall survival (OS), comparing patients with low Ki-67 versus high Ki-67 index after NET, as defined per each study. We performed a sensitivity analysis of the studies measuring the post-NET Ki-67 index in a pre-planned core biopsy. We used the Higgins I2 index to evaluate the heterogeneity between included studies, which did not reach statistical significance. Therefore, we used a fixed effects model to combine RFS and OS hazard ratios (HR) with 95% confidence intervals (CI). Results: We included 11 studies reporting data from 4,231 patients: nine clinical trials (n=3,926), one pooled analysis of two clinical trials (n=217), and one retrospective cohort study (n=88). Nine studies included only post-menopausal women (n=4,069), one included both post- and premenopausal women (n=88), and one included only premenopausal women (n=74). NET was aromatase inhibitor (AI) in four studies (n=3,359), tamoxifen or AI in four (n=465), tamoxifen in two (n=190), and one study with AI or fulvestrant (n=217). There were no studies with targeted agents combined with NET. No study restricted the use of adjuvant chemotherapy in high-risk patients. Three studies evaluated post-NET Ki-67 in a pre-planned core biopsy after a window of treatment of two to four weeks (n=3,348), while the other eight evaluated KI67 in the surgery specimen (n=883). The timing of post-NET evaluation ranged from 2 to 24 weeks. The median follow-up for RFS ranged between 37 and 95 months, and between 62 to 84 months for OS. We found a statistically significant association of adverse RFS (HR 2.43, 95% CI 1.99-2.98) and OS (2.66, 95% CI 1.65-4.28) with higher Ki-67 after NET. The sensitivity analysis of the three studies evaluating post-NET Ki-67 in a pre-planned core biopsy showed the same association with RFS (HR 2.41, 95% CI 1.77-3.30). These three studies did not report OS data. Conclusion: Our data reinforce the role of Ki-67 index after NET as a valuable biomarker of response or resistance to endocrine therapy in women with HR+/HER2- early breast cancer. Despite the use of adjuvant chemotherapy in most of the high-risk patients included in this analysis, the reduction of Ki-67 after NET is strongly associated with survival outcomes (RFS/OS), even after a short course of two to four weeks NET. Ki-67 index post-NET might be a useful tool to help tailoring the use of adjuvant chemotherapy in HR+/HER2-negative breast cancer patients, particularly in low-resource settings where the access to genomic assays is limited.
Citation Format: Diogo Martins-Branco, Chiara Molinelli, Guilherme Nader Marta, Lieveke Ameye, Marianne Paesmans, Roberto Salgado, Philippe Aftimos, Evandro de Azambuja. Ki-67 index after neoadjuvant endocrine therapy as a prognostic biomarker in patients with HR+/HER2- early breast cancer: a systematic review and meta-analysis [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-07-01.