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Purpose: To analyze whether adding PI3K/AKT/mTOR inhibitors to fulvestrant could restore endocrine therapy sensitivity for the treatment of postmenopausal patients with HR+, HER2- breast cancer. Methods: This meta-analysis was performed using RevMan 5.4 analysis software. Results: Nine studies that included a total of 3199 patients were analyzed. Compared with fulvestrant alone, the addition of PI3K/AKT/mTOR inhibitors significantly prolonged progression-free survival, overall survival and objective response rate of patients in both the total and PI3K-pathway-activated population. The number of grade 3–5 adverse events was also significantly higher. Conclusion: The addition of PI3K/AKT/mTOR to fulvestrant resulted in potential benefits; however, there may be a higher risk, which needs to be carefully managed. [ABSTRACT FROM AUTHOR]

Background: The RxPONDER trial found that among breast cancer patients with estrogen receptor positive (ER+) breast cancer, 1-3 positive axillary nodes, and a recurrence score of =25, only pre-menopausal women benefitted from adjuvant chemoendocrine therapy; postmenopausal women with similar characteristic did not benefit from adjuvant chemotherapy. We aimed to replicate the RxPonder trial using a larger patient cohort with real world data to determine whether a RS threshold existed where adjuvant chemotherapy was beneficial regardless of age. Methods: The National Cancer Database (NCDB) was queried for women with ER+, human epidermal growth factor receptor 2 (HER2) negative breast cancer, 1-3 positive axillary nodes, and RS =25 who received endocrine (ET) only or chemo-endocrine therapy (CET). Cox regression interaction was explored between CET and age as a surrogate for menopausal status. Results: The final analytic cohort included 28,427 eligible women: 7,487 (26.3%) received adjuvant CET and 20,940 (73.7%) ET. In the entire cohort, RS had a normal distribution, with a median score of 14. After correcting for demographic and clinical variables, a threshold effect was observed with RS >20 being associated with a significantly inferior overall survival (OS) (P value range: < 0.001-0.019). In women with RS of 20-25, CET was associated with a significant improvement in OS compared to ET alone, regardless of age (age <=50: HR = 0.334, P=0.002; age>50: HR=0.521, P=0.019). Conclusion: Among women with ER+/HER2- breast cancer with 1-3 positive nodes, and a RS of 20-25--in contrast to the RxPONDER trial--we observed that CET was associated with an OS benefit in women regardless of age. [ABSTRACT FROM AUTHOR]

BackgroundThe RxPONDER trial found that among breast cancer patients with estrogen receptor positive (ER+) breast cancer, 1-3 positive axillary nodes, and a recurrence score of ≤25, only pre-menopausal women benefitted from adjuvant chemoendocrine therapy; postmenopausal women with similar characteristic did not benefit from adjuvant chemotherapy. We aimed to replicate the RxPonder trial using a larger patient cohort with real world data to determine whether a RS threshold existed where adjuvant chemotherapy was beneficial regardless of age.MethodsThe National Cancer Database (NCDB) was queried for women with ER+, human epidermal growth factor receptor 2 (HER2) negative breast cancer, 1-3 positive axillary nodes, and RS ≤25 who received endocrine (ET) only or chemo-endocrine therapy (CET). Cox regression interaction was explored between CET and age as a surrogate for menopausal status.ResultsThe final analytic cohort included 28,427 eligible women: 7,487 (26.3%) received adjuvant CET and 20,940 (73.7%) ET. In the entire cohort, RS had a normal distribution, with a median score of 14. After correcting for demographic and clinical variables, a threshold effect was observed with RS >20 being associated with a significantly inferior overall survival (OS) (P value range: < 0.001-0.019). In women with RS of 20-25, CET was associated with a significant improvement in OS compared to ET alone, regardless of age (age 50: HR=0.521, P=0.019).ConclusionAmong women with ER+/HER2- breast cancer with 1–3 positive nodes, and a RS of 20-25—in contrast to the RxPONDER trial—we observed that CET was associated with an OS benefit in women regardless of age.

OBJECTIVE: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) in combination with endocrine therapy (ET) have been recommended as standard therapeutic strategies for hormone receptor-positive (HR+), human epidermal growth factor receptor type 2-negative (Her2-) advanced breast cancer (ABC). While the benefits to progression-free survival (PFS) rates have been confirmed, whether the combination of CDK4/6i and ET leads to overall survival (OS) rate improvements remains controversial. This study aimed to assess the long-term efficacy and safety of CDK4/6i in HR+, Her2- ABC patients and identify a population suitable for treatment with CDK4/6i by subgroup analysis. MATERIALS AND METHODS: Electronic literature databases (MEDLINE, EMBASE and the Cochrane Library) were searched for relevant randomized controlled trials (rcts) published from Jan 2014 to Jan 2020. In addition, abstracts and presentations from all major conference proceedings were reviewed. All rcts that compared the efficacy and safety of CDK4/6i plus ET with ET alone in HR+, Her2- ABC patients were selected. The pooled analyses of hazard ratios (hrs) for PFS and OS, and risk ratios (rrs) for the objective response rate (ORR) and adverse events (aes) were obtained with the random-effects model. RESULTS: A total of 6 rcts and 3421 HR+, Her2-ABC patients were enrolled for OS outcome analysis, while all 8 trials and 4580 patients were included for PFS outcome analysis. The pooled hrs for the OS and PFS were 0.76 (95% CI: 0.670.84) and 0.55 (95% CI: 0.50-0.59), respectively, and were consistent in the subgroup analysis. Moreover, CDK4/6i meaningfully improved the ORR in both the intention-to-treat population (RR=1.47; 95% CI: 1.29-1.67) and patients with measurable disease (RR=1.47; 95% CI: 1.301.67); however, CDK4/6i increased the incidence of grade 3/4 aes (RR=2.69; 95% CI: 2.43-2.97). CONCLUSIONS: The combination of CDK4/6i and ET was superior to ET alone in terms of OS and PFS regardless of the drugs administered, the treatment line, age distribution, race, PR status, menopausal status, metastasis site and endocrine resistance status. [ABSTRACT FROM AUTHOR]