Abstract 3772: Cyclin E as a prognostic marker and predictor of response to neoadjuvant chemotherapy and adjuvant hormonal therapy in patients with stage II-III breast cancer
Authors: Karakas Cansu , Francis Ashleigh , Yi Min , Sahin Aysegul , Keyomarsi Khandan , Hunt Kelly 
Published: August 2015

Purpose: While we know that many cytotoxic chemotherapeutic agents act to modulate the cell cycle, the role of cyclin E as a predictive marker of response to chemotherapy is unknown. Given that the cell cycle is compromised in tumors that overexpress cyclin E, we hypothesized that cyclin E overexpression would predict decreased response to neoadjuvant chemotherapy and increased risk of relapse in the subset of patients with pathologic complete response (pCR).

Experimental Design: 286 women with a diagnosis of clinical stage II-III invasive breast cancer that had received neoadjuvant chemotherapy with paclitaxel (or docetaxel) and FAC, FEC or AC followed by surgery were enrolled into this study. Histological sections from the pre- and post-therapy tissue sections of the patient samples were analyzed for cyclin E using immunohistochemistry (IHC). In breast cancers, high levels of cyclin E result in the expression of its low molecular weight isoforms (LMW-E) which are predominantly cytoplasmic due to the loss of the nuclear localization signal. LMW-E expression can be measured by cytoplasmic staining of cyclin E on IHC. The expression of cyclin E was correlated with response to treatment using multivariable logistic regression. Clinical-Pathological factors, disease-free (DFS), recurrence-free (RFS), and overall survival (OS) rates were also evaluated.

Results: A complete pCR was obtained in 79 of 286 cases (31%). Patients with high pretreatment cytoplasmic cyclin E expression on IHC had a decreased pCR rate as compared to those patients with low cytoplasmic cyclin E levels (32.3% vs 67.7%). On multivariable logistic regression analysis, the strongest predictors of poor response to therapy (failure to attain pathologic complete response) were the cytoplasmic cyclin E expression and negative Her-2 status (p&lt;0.0001, OR: 9.0 and p&lt;0.0001, OR: 6.5 respectively). Patients with high cytoplasmic cyclin E expression were significantly correlated with poor DFS, RFS and OS in both pretreatment and posttreatment groups.

Conclusions: Cytoplasmic cyclin E expression is a strong predictive factor for pCR in breast cancer patients treated with neoadjuvant anthracycline-based chemotherapy. Routine clinical assessment of cyclin E could be used to identify patients at high risk for poor response to neoadjuvant therapy or recurrence and stratified for more personalized therapy.

Citation Format: Cansu Karakas, Ashleigh Francis, Min Yi, Aysegul Sahin, Khandan Keyomarsi, Kelly Hunt. Cyclin E as a prognostic marker and predictor of response to neoadjuvant chemotherapy and adjuvant hormonal therapy in patients with stage II-III breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3772. doi:10.1158/1538-7445.AM2015-3772