Abstract P6-08-34: p16INK4a expression and chemotherapy toxicity in women with early stage breast cancer
Authors: Muss Hyman , Deal Allison , Hurria Arti , Mitin Natalia , Torrice Chad , Janakiraman Krishnamurthy , Jolly Trevor , Williams Grant , Alston Shani , West Jerard , Zavala Laura , Katheria Vani , Sharpless Norman 
Published: May 2015

Abstract
Background: Increased expression of p16INK4a, a molecular marker of aging, is a hallmark of increased cellular senescence in most mammalian tissues. In human peripheral blood T-lymphocytes, expression of p16INK4a increases 10-fold between 20 and 80 years of age (Liu et al, Aging Cell, 2009). We hypothesized that higher "molecular age," as evidenced by increased T-cell expression of p16INK4a at the time of initiation of breast cancer (BC) chemotherapy (CRx), predicts increased treatment-related toxicity.
Methods: Patients (pts) with early breast cancer scheduled to receive neoadjuvant (NA) or adjuvant (Adj) chemotherapy (CRx) had p16INK4a evaluation performed prior to treatment. Expression of p16INK4a mRNA in CD3+ T-lymphocytes was determined using TaqMan real time quantitative reverse transcription polymerase chain reaction. Grade 3 and 4 (G3/4) hematologic (H) and non-hematologic (NH) toxicities (NCI CTCAE version 4) were assessed during and within 4 weeks of completion of CRx. Wilcoxon Rank Sum tests compared p16INK4a between groups.
Results: 93 pts with Stage I-III BC and complete toxicity data during and within 4 weeks after completion of CRx have been accrued. Median age (range) was 52 (25-76). 48 (52%) of pts were hormone receptor (HR) positive, 21 (23%) HER-2 positive, and 24 (26%) triple-negative. 39 (42%) received NA and 54 (58%) received Adj CRx. 57 pts (61%) received an anthracycline containing combination and 21 (23%) cyclophosphamide/docetaxel (TC). 85 pts (91%) received pegfilgrastim. Overall, 69 pts (74%) had a G3/4 toxicity during or ≤4 wks of CRx, 54% NH and 40% H. 22 pts (24%) were hospitalized for CRx related toxicity and 11 (12%) of these admissions were for neutropenic fever (NF). 23 (25%) reported G3/4 fatigue during CRx and had significantly higher p16INK4a values at baseline than those without fatigue (p=0.03). There was no significant association of baseline p16INK4a and other NH or H toxicity or hospitalization in this cohort.
Conclusion: In this small sample of pts treated with anthracycline and non-anthracycline containing NA and Adj CRx regimens, there was a significant association of baseline p16INK4a and G3/4 fatigue. The heterogeneity of treatment and use of pegfilgrastim in almost all pts limits the power of this study to find significant relationships between p16INK4a and other toxicities. The cohort for this study is being expanded to further explore p16INK4a as a predictor for G3/4 toxicity.
Support: Breast Cancer Treatment Foundation, New York, NY; University Cancer Research Fund, University of North Carolina, Chapel Hill.
Citation Format: Hyman Muss, Allison Deal, Arti Hurria, Natalia Mitin, Chad Torrice, Krishnamurthy Janakiraman, Trevor Jolly, Grant Williams, Shani Alston, Jerard West, Laura Zavala, Vani Katheria, Norman Sharpless. p16INK4a expression and chemotherapy toxicity in women with early stage breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-08-34.