J Breast Cancer.  2020 Feb;23(1):10-19. 10.4048/jbc.2020.23.e5.

Predicting the Benefit of Adjuvant Aromatase Inhibitor Therapy in Postmenopausal Breast Cancer Patients with Phosphorylated S6K1 Expression Status

• Choi J
• Park CS
• Seong MK
• Seol H
• Kim JS
• Park IC
• Noh WC
• Kim HA

• KMID: 2470878
• DOI: http://doi.org/10.4048/jbc.2020.23.e5

Abstract

PURPOSE
Phosphorylated ribosomal S6 kinase 1 (pS6K1) is a major downstream regulator of the mammalian target of rapamycin (mTOR) pathway. Recent studies have addressed the role of S6K1 in adipogenesis. pS6K1 may affect the outcome of estrogen depletion therapy in patients with hormone-sensitive breast cancer due to its association with adipogenesis and increased local estrogen levels. This study aimed to investigate the potential of pS6K1 as a predictive marker of adjuvant aromatase inhibitor (AI) therapy outcome in postmenopausal or ovarian function-suppressed patients with hormone-sensitive breast cancer.
METHODS
Medical records were retrospectively reviewed in postmenopausal or ovarian function-suppressed patients with estrogen receptor-positive and node-positive primary breast cancer. pS6K1 expression status was scored on a scale from 0 (negative) to 3+ (positive) based on immunohistochemical analysis.
RESULTS
A total of 428 patients were eligible. The median follow-up duration was 44 months (range, 1-90). In patients with positive pS6K1 expression, AIs significantly improved disease-free survival (DFS) compared to selective estrogen receptor modulators (SERMs) (5 year-DFS: 83.5% vs. 50.7%, p = 0.016). However, there was no benefit of AIs on DFS in the pS6K1 negative group (5 year-DFS 87.6% vs. 91.4%, p = 0.630). On multivariate analysis, AI therapy remained a significant predictor for DFS in the pS6K1 positive group (hazard ratio, 0.39; 95% confidence interval, 0.16-0.96; p = 0.041). pS6K1 was more effective in predicting the benefit of AI therapy in patients with ages < 50 (p = 0.021) compared to those with ages ≥ 50 (p = 0.188).
CONCLUSION
pS6K1 expression may predict AI therapy outcomes and serve as a potential predictive marker for adjuvant endocrine therapy in postmenopausal and ovarian function-suppressed patients with hormone-sensitive breast cancer. AIs may be more effective in patients with pS6K1 positive tumors, while SERM could be considered an alternative option for patients with pS6K1 negative tumors.

Keyword

Aromatase inhibitors; Biomarkers, tumor; Breast neoplasms; Ribosomal protein S6kinase, 70kD, polypeptide 1; Tamoxifen

MeSH Terms

Adipogenesis
Aromatase Inhibitors
Aromatase*
Biomarkers, Tumor
Breast Neoplasms*
Breast*
Disease-Free Survival
Estrogens
Follow-Up Studies
Humans
Medical Records
Multivariate Analysis
Retrospective Studies
Ribosomal Protein S6 Kinases
Selective Estrogen Receptor Modulators
Sirolimus
Tamoxifen
Aromatase
Aromatase Inhibitors
Biomarkers, Tumor
Estrogens
Ribosomal Protein S6 Kinases
Selective Estrogen Receptor Modulators
Sirolimus
Tamoxifen

Figure

• 

  Figure 1 Kaplan-Meier DFS curves for adjuvant AIs and SERMs in patients with (A) positive pS6K1 expression status and (B) negative pS6K1 expression status. Patients with positive pS6K1 expression status showed better DFS when treated with AIs than with SERM (p = 0.016). However, in pS6K1 negative patients, there was no difference in DFS between AIs and SERMs (p = 0.630). DFS = disease-free survival; AI = aromatase inhibitor; SERM = selective estrogen receptor modulator; pS6K1 = phosphorylated ribosomal S6 kinase 1.

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