Abstract P4-09-14: PhosphohistoneH3 as a prognostic marker in breast cancer: High expression is associated with younger age, triple negative subtype, and disease specific survival
Authors: Craig J , Kovatich AJ , Hooke JA , Kvecher L , Liu J , Fantacone-Campbell JL , Rui H , Shriver CD , Hu H 
Published: May 2016

BACKGROUND PhosphohistoneH3 (PPH3) is an emerging marker in breast cancer and has been linked to both patient survival and age. Phosphorylation of HistoneH3 is an important step during the cell cycle leading to proper compaction of the chromatin during late G2 and early mitosis. Here we assessed the use of PPH3 as a prognostic marker within a group of invasive breast cancers in the Clinical Breast Care Project (CBCP).

METHODS CBCP participants and their samples were collected following IRB-approved, HIPAA-compliant protocols. Samples from 157 CBCP patients were selected for tissue whole section immunohistochemistry (IHC), using antibodies to PPH3, ER, PR, Ki67, and Her2. For each sample, staining of PPH3 was assessed across 5 high powered microscope fields and was considered positive if there was on average &gt;2 stained cells per field. ER and PR were considered positive when there was &gt;5% nuclear staining, and Ki67 was positive when there was &gt;15% nuclear staining. Her2 was considered positive with an IHC score of 3+ or 2+ with a FISH score above 2.2. The samples were subtyped as Luminal A (LA: ER+/HER2-/Ki67-), Luminal B1 (LB1: ER+/HER2-/Ki67+), Luminal B2 (LB2: ER+/HER2+), Her2+ (ER-/PR-/HER2+), and Triple Negative (TN: ER-/PR-/HER2-). PPH3 was tested for associations with age and subtype using a stratified univariate Wilcoxon rank-sum analysis and a multivariate analysis controlling for subtype. To test the efficacy of PPH3 as a prognostic marker, Kaplan-Meier curves for disease specific survival were analyzed and the cox proportional hazard regression model was calculated. Further analysis addressing population demographics and additional cancer characteristics is ongoing.

RESULTS Wilcoxon analysis revealed an association between higher PPH3 levels and younger age (P=.0038). Subtype was also found to be associated with PPH3, with the TN subtype 6.26 times more likely to have higher PPH3 expression than LA (P=.005). The association with age was confirmed by repeating the analysis and stratifying into non-TN subtypes (P=.05) and TN only subtype (P=.017). Non-TN subtypes positive for PPH3 expression had median age of 53.18 at diagnosis and 63.29 for negative PPH3 expression; TN subtypes that were positive for PPH3 had a median age of 50.44 and 72.9 for negative PPH3. Multivariate analysis with age and subtype as the variables also supported these results (age P=.017; TN vs LA P=.022). Disease specific survival analysis showed that a shorter survival time was associated with positive PPH3 protein levels (P=0.03; hazard ratio=6.97).

CONCLUSIONS High expression of PPH3 is associated with a younger age, poorer survival rate, and the TN subtype. These results corroborate the use of PPH3 as a prognostic marker for breast cancer patients.

The views expressed in this article are those of the author and do not reflect the official policy of the Department of Defense, or U.S. Government.

Citation Format: Craig J, Kovatich AJ, Hooke JA, Kvecher L, Liu J, Fantacone-Campbell JL, Rui H, Shriver CD, Hu H. PhosphohistoneH3 as a prognostic marker in breast cancer: High expression is associated with younger age, triple negative subtype, and disease specific survival. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-09-14.