Abstract P6-07-14: Mutational and transcriptomic characterization of breast cancer (BC) arising in young patients (pts) and during pregnancy and their associations with long-term outcome
Authors: Azim Jr HA , Peccatori FA , Loi S , Lambrechts D , Majjaj S , Renne G , Desmedt C , Rotmensz N , Michiels S , Dell'Orto P , Ignatiadis M , Goldhirsch A , Piccart M , Viale G , Sotiriou C 
Published: August 2014

Abstract
Background: BC arising in young age is biologically distinct. Whether diagnosis during pregnancy has an impact on prognosis and tumor biology remains to be elucidated. We report for the first time mutational and transcriptomic profiling of BC arising in young pts and the impact of diagnosis during pregnancy. We also correlate these findings with clinical outcome.
Methods: 65 pts with BC during pregnancy diagnosed at the European Institute of Oncology in the period 1999–2009 were matched to 130 BC pts who were diagnosed and treated at the same period/institute. We screened for 84 somatic hotspot mutations on 17 cancer-related genes using mass spectroscopy-based sequencing (Sequenom). We evaluated the pattern of mutations in the two cohorts and according to BC subtype defined using central immunohistochemistry as follows: Luminal A (ER+, HER2−, Ki67 &lt;14%), Luminal-B (ER+, HER2−, Ki67 &gt;14%), HER2+ (HER2+ irrespective of ER), and triple negative (ER−, PgR−, HER2−). Survival endpoints included distant relapse free survival (DRFS) and overall survival (OS).
Results: Median age at diagnosis was 36 years (range: 28–47). At a median follow-up of 74 months (IQR: 42–96), 44 (23%) and 29 (15%) pts developed a DRFS and OS event respectively. Pts diagnosed during pregnancy had inferior DRFS (HR: 3.2 [1.5–6.7]) and OS (HR: 2.9 [1.1–7.9]) after adjusting for pT, pN, grade, BC subtype, and therapy. Mutational profiling was successful in 97% of pts. A total of 57 hotspot mutations (30%) were detected in 51 pts (15 [23%] pregnant and 36 [28%] controls). The differences in mutations between the two groups are summarized in the table.

PIK3CA mutations were the most common, occurring in 41 pts overall (21.5%). In a logistic regression model adjusted for BC subtype, pregnancy, pT, pN and grade, only BC subtype was associated with PIK3CA mutations (p = 0.005) but not pregnancy (p = 0.3). No mutations related to ERK signaling were detected (PTEN, KRAS, BRAF, ERBB2, EGFR). No significant association was observed between somatic mutations and breast cancer outcome, probably related to lack of power. Gene expression using Affymetrix are currently ongoing to validate our previous findings (Azim et al; CCR 2012) of a role of mammary stem cells, tumor microenvironment (immune, stroma) and RANKL signaling in BC arising in young breast cancer patients. This could also elucidate further mechanisms underlying differences in outcome between the pregnant and control groups.
Conclusion: This is the first report on mutational profiling of BC arising in young women and during pregnancy. Whilst pregnancy is associated with significantly poor prognosis compared with matched controls, there were no significant differences in the mutational profiles evaluated. Ongoing transcriptomic analysis will be presented at the meeting.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-07-14.