Abstract P2-23-13: Highly proliferative estrogen receptor-positive breast cancer is associated with better response to neoadjuvant chemotherapy but worse clinical outcome
Authors: Wu Rongrong , Tokumaru Yoshihisa , Asaoka Mariko , Oshi Masanori , yan Li , Ishikawa Takashi , Takabe Kazuaki 
Published: March 2023

Abstract
Introduction: Highly proliferative cancers are known to respond better to neoadjuvant chemotherapy (NAC), and pathological complete response (pCR) is a surrogate for survival benefit in breast cancer. Ki67 is the most commonly used cell proliferation marker; however, conventional immunostaining is subjected to variability by the assessor and the institution including the antibody used. To this end, we used the Ki67 gene expression to identify highly proliferative breast cancer and investigated whether it is associated with better response to NAC and survival by intrinsic subtype. Materials and Methods: Total of 6623 breast cancer patients from 11 independent cohorts with full transcriptome and clinical data were analyzed. The top 20% of Ki67 gene expression in each cohort were defined as highly proliferative group based on previous studies using immuno-staining. Results: Highly proliferative breast cancer was associated with high proliferation score, and all five cell proliferation-related gene sets in the Hallmark collection; E2F Targets, G2M Checkpoint, Mitotic Spindle, and Myc Targets v1 and v2 were enriched by gene set enrichment analysis in multiple cohorts regardless of subtype. MKI67 gene expression increased with higher grade in both ER-positive breast cancer and TNBC in multiple cohorts, but no clear association with staging was observed. Highly proliferative ER-positive breast cancer was significantly associated with worse disease-free, disease-specific, and overall survival consistently in METABRIC and GSE96058 cohorts, and showed a trend toward worse overall survival in TCGA; however, this was not the case in TNBC. Further, we found that highly proliferative tumor was significantly associated with better pathologic complete response (pCR) rate in six of the eight neoadjuvant chemotherapy cohorts of ER-positive breast cancer, but only two for TNBC. We also found that highly proliferative ER-positive breast cancer was associated with abundant silent and non-silent mutations, increased intra-tumoral heterogeneity, and homologous recombination defect scores when compared to lower proliferation groups, and this was not seen in TNBC in TCGA cohort. Although DNA repair gene set was enriched in the highly proliferative ER-positive breast cancer, it was also associated with higher neoantigen activity, higher infiltration of tumor infiltrating lymphocytes including Th1 cells, Th2 cells, regulatory T cells, and M1 macrophages, as well as with enrichment of Interferon-gamma response gene set consistently in 3 large cohorts. In contrast, several stromal cell fractions were decreased in this group. Conclusions: Highly proliferative ER-positive breast cancer is significantly associated with pCR after NAC with increased tumor infiltrating lymphocytes, but is not a surrogate for survival, which are not the case in TNBC.
Citation Format: Rongrong Wu, Yoshihisa Tokumaru, Mariko Asaoka, Masanori Oshi, Li yan, Takashi Ishikawa, Kazuaki Takabe. Highly proliferative estrogen receptor-positive breast cancer is associated with better response to neoadjuvant chemotherapy but worse clinical outcome [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 P2-23-13.