Abstract P6-08-34: p16^INK4a expression and chemotherapy toxicity in women with early stage breast cancer

Background: Increased expression of p16^INK4a, a molecular marker of aging, is a hallmark of increased cellular senescence in most mammalian tissues. In human peripheral blood T-lymphocytes, expression of p16^INK4a 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 p16^INK4a 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 p16^INK4a evaluation performed prior to treatment. Expression of p16^INK4a 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 p16^INK4a 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 p16^INK4a values at baseline than those without fatigue (p=0.03). There was no significant association of baseline p16^INK4a 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 p16^INK4a 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 p16^INK4a and other toxicities. The cohort for this study is being expanded to further explore p16^INK4a 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. p16^INK4a 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.