Breast Cancer Research最新文献

Background: Estrogen receptor-negative breast cancers are clinically heterogeneous. Two subtypes, Luminal Androgen Receptor and Molecular Apocrine Breast Cancers, are both defined by androgen signaling but identified through distinct transcriptomic classifiers. Their relationship remains unclear despite overlapping features.

Methods: We analyzed transcriptomic and genomic data from public and institutional cohorts using two classification systems. Gene set enrichment and immune deconvolution analyses were performed to characterize differences between overlapping and discordant tumors. A four-gene signature was developed and validated using RNA sequencing and RT-qPCR on both fresh-frozen and formalin-fixed samples.

Results: Substantial overlap was observed between the two subtypes, with shared activation of androgen and PI3K/AKT/mTOR signaling pathways. Discordant tumors were enriched in immune and stromal signals. A four-gene signature (AR, FOXA1, SPDEF, TFF3) identified overlapping tumors with high sensitivity and specificity across datasets and remained accurate in RT-qPCR assays on FFPE material.

Conclusion: Luminal Androgen Receptor and Molecular Apocrine Breast Cancers constitute a single molecular entity within estrogen receptor-negative breast cancers. The validated four-gene signature enables robust clinical identification and may guide future therapeutic stratification.

Context and aims: Everolimus was approved in 2012 for the treatment of advanced hormone-receptor-positive, HER2-negative metastatic breast cancer (MBC) in combination with exemestane. Since then, the first line treatment for these cancers has evolved with the development of CDK4/6 inhibitors.

Methods: Patients with histologically proved MBC and who received everolimus between 2012 and 2022 were included in a multicentric retrospective cohort. Prior exposure to CDK4/6 inhibitors was documented. The purpose of the study was to evaluate the efficacy of everolimus plus endocrine therapy in patients previously treated with CDK4/6 inhibitors and to identify factors associated with improved PFS on everolimus. The primary endpoint was PFS. Secondary outcomes included overall survival (OS), factors associated with improved efficacy, and grade III-IV toxicities.

Results: From 2012 to December 30, 2022, 325 patients were included. Of these, 75 patients (23%) had been pretreated by CDK4/6 inhibitors. In the overall population, median PFS was 6.4 months (95% CI, 5.5-7.1), with a median OS of 25 months (95% CI, 21.8-28.1). Among those previously exposed to CDK4/6 inhibitors, median PFS was 5.3 months (95% CI, 4.6-7.1), compared to 6.7 months (95% CI, 5.8-7.6) for those who had not received CDK4/6 inhibitors (p = 0.046) and the median OS was 27.3 months without CDK4/6 inhibitors before everolimus (95% CI, 23.2-30.2) versus 21.8 months (95% CI,18.5-25.5) when pretreated by CDK4/6 inhibitors (p = 0.01). Sixty-eight patients (21%) had a PFS greater than 12 months. Factors associated with an improved PFS were the lack of liver metastases (p < 0.001), no prior exposure to metastatic chemotherapy (p = 0.001), a lower tumor grade (p = 0.005), no prior treatment with CDK4/6 inhibitors (p = 0.006), and a better performance status (p = 0.008). 89 patients (28%) discontinued everolimus due to toxicity rather than disease progression or death and 23 (25%) patients treated with exemestane alone, after everolimus exposure, maintained a stable disease for at least 6 months.

Conclusion: Patients who had prior exposure to CDK4/6 inhibitors experienced a shorter median PFS benefit from everolimus based-treatment compared to those who were CDK4/6 inhibitor-naive. In this study, they also demonstrated shorter OS, likely due to a more pronounced endocrine-resistant profile. Although a reduction in PFS is expected with successive lines of therapy, the use of everolimus after exposure to CDK4/6 inhibitors and aromatase inhibitors remains an option and allows to propose another endocrine-based therapy and to postpone the use of chemotherapy. Managing endocrine resistance remains challenging and further research is needed to identify predictive biomarkers for improved outcomes.