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Background: HER2 is a well established prognostic and predictive factor in invasive breast cancer. The role of HER2 in ductal breast carcinoma in situ (DCIS) is much debated and recent data have suggested that HER2 is mainly related to in situ recurrences. This contrasts the proposed role of HER2 in the progression from in situ to invasive cancer. Our aim was to study HER2 as a prognostic factor in a large population based cohort of DCIS. Methods: All 458 women diagnosed with a primary DCIS 1986-2004 in two Swedish regions were included and tissue microarrays constructed. Silver-enhanced in situ hybridisation (SISH) and immunohistochemistry (IHC) were used for detection of HER2 amplification and IHC expression. HER2 status and its relation to invasive breast cancer recurrence (IBCR) (ipsilateral or contralateral invasive events and regional or distant metastasis) and ipsilateral events (IBE) were studied. Kaplan-Meier survival analyses and Cox proportional hazards regression models were used. Adjustments were made for age, size, radiotherapy and ER status. Results: Mean follow up was 184 months. DCIS was screening detected in 75.5% of cases. Breast conserving surgery (BCS) was performed in 78.6% of whom 44.0% received postoperative radiotherapy. No women had hormonal or chemotherapy. A total of 106 IBCRs and 105 IBEs were identified. 54 IBEs were in situ and 51 invasive cancer. Eighteen women died from breast cancer and another 114 had died from other causes. 420 tumours could be classified using available SISH or IHC data; 132 were HER2 positive (31.4%) and 288 HER2 negative. SISH and IHC data were concordant in 296 of 332 (89.2%) available cases. HER2 positivity was related to size, grade and ER and PR negativity. The risk of IBCR was statistically significantly lower subsequent to a HER2 positive DCIS, hazard ratio (HR) 0.53 (95% CI 0.31-0.90), log rank p=0.01. However, the curves did not separate until after almost ten years. HRs after adjustments were similar to the crude analyses. The risk of any IBE was not statistically differently changed by HER2 status. In women undergoing BCS, HR was 1.18 (0.77-1.82), log rank p=0.44. But interestingly, divided by type of IBE, HER2-positivity showed an increased risk of in situ IBEs, HR 1.64 (0.92-2.90), log rank p=0.09 and, a decreased risk of invasive IBEs, HR 0.76 (0.39-1.50), log rank p=0.43. These correlations were however not statistically significant. Risk of invasive and local recurrence by HER2 status in a population based cohort of women with a primary DCIS HER2 positiveHER2 negativeInvasive Breast Cancer RecurrenceHR (95% CI)Reference 1.0All patients (n=420)(events=101)0.53 (0.31-0.90)RefIpsilateral new Breast Events (IBE) BCS (n=324) (events=94)1.18 (0.77-1.82)RefBCS, in situ IBEs (events=48)1.64 (0.92-2.90)RefBCS, invasive IBEs (events=46)0.76 (0.39-1.50)Ref Conclusions: In this long term follow-up DCIS cohort positive HER2 status in the primary DCIS predicted a statistically lower risk of IBCR. This effect was seen from ten years after primary surgery and onwards. The risk of an in situ IBE was increased and the risk of an invasive IBE was decreased if the primary DCIS was HER2 positive. All together, this challenges the role of HER2 as a driving force of the progression from in situ to invasive cancer. Citation Format: Signe Borgquist, Wenjing Zhou, Karin Jirström, Rose-Marie Amini, Thomas Sollie, Therese Sørlie, Salma Butt, Carl Blomqvist, Fredrik Wärnberg. The prognostic role of HER2 expression in ductal breast carcinoma in situ [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 P6-13-03.

Aim: The importance of the androgen receptor (AR) as a prognostic factor and a possible treatment target is currently debated. However, the impact of lifestyle factors on AR status in breast cancer has not yet been addressed. The aim of this study was to evaluate the influence of hormonal lifestyle factors on AR-defined breast cancer risk. Materials and methods: The population-based prospective Malmö Diet and Cancer Study including 16,459 women were followed using record-linkage with national cancer registries. Baseline data of all women in the cohort included socioeconomic factors, reproductive factors including use of exogenous hormones and anthropometry. During an average follow-up of 12.8 years, 747 cases of invasive breast cancer were diagnosed. AR was assessed immunohistochemically by monoclonal antibody Ab-1 (Clone AR441, Thermo Scientific, USA). A tumor was considered AR positive (AR+) when >10% positive nuclei. A valid AR score was obtained from 516 tumors. The expression of ER, PR, Ki67 along with information on HER2 status, tumor size, histological type, tumor grade and axillary lymph node involvement was obtained. Reproductive factors were compared with tumor characteristics based on AR status. Distribution of clinicopathological data and odds ratios in relation to AR status were analyzed. Hazard ratios (HR) were calculated using Cox's proportional hazards analysis. Survival analyses in relation to AR status were carried out using Kaplan-Meier Log Rank test. Results: A total of 467 tumors (90.5%) were AR+ and 49 tumors (9.5%) were AR negative (AR-). AR positivity correlated significantly to lower tumor grade, lower proliferation and ER and PR co-expression. There was a significant trend of increasing risk of AR- breast cancer by increasing age at first childbirth (HR30 yrs =2.01, Ptrend=0.002 among parous women). The risk for AR+ breast cancer was not affected by age at first birth. Ever oral contraceptive (OC) users had an increased risk of AR- breast cancer (HR=2.10, 95% CI 1.16-3.81, P=0.015) compared to never users. OC use was neither associated with risk for breast cancer in general nor with AR+ breast cancer. The use of combined estrogen and progestin hormonal replacement therapy (cHRT) was significantly associated with increased risk for breast cancer (HRall=2.13, P= Conclusion: In conclusion, reproductive factors and exogenous hormones influenced the risk for AR-defined breast cancer. Specifically, the older the age at first childbirth, the higher the risk for AR- breast cancer. Similarly, ever OC users had a higher risk of AR- breast cancer compared to never users. This study contributes to a deepened understanding of AR in relation to breast cancer risk factors and may yield improved risk stratification tools for breast cancer prevention and treatment. Citation Format: Karin Elebro, Salma Butt, Mozhgan Dorkhan, Helena Jernström, Signe Borgquist. Oral contraceptives and late first childbirth increase the risk of androgen receptor-negative breast cancer: The Malmö Diet and Cancer cohort. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr A126.