Background: As new systemic therapies emerge for the treatment of breast cancer, new prognostic markers are required to help stratify patients into higher and lower risk groups to aid treatment decision making. Features of the tumour microenvironment, such as tumour necrosis, tumour-stroma percentage (TSP), and tumour budding have been shown to have prognostic value in some cancers. However, their role in breast cancer is unclear. Methods: Patients who underwent surgery for primary operable breast cancer in 2 centres between 1995-2007 and who had paraffin-embedded tissue blocks available were identified. Clinicopathological details and survival data were obtained from patient records. Haematoxylin & Eosin-stained slides were visually assessed within a set visual field for TSP (<50% or >50% tumour stroma), tumour necrosis (<25% or >25% necrosis) and tumour budding (<20 buds or >20 buds). A combined score of tumour necrosis and tumour budding was then created. A score of 0 was assigned to tumours where both components were low, 1 to those where only one component was high, and 2 to those where both were high. Multivariate cox regression analysis was carried out for cancer specific survival (CSS). Results: A breast cancer cohort of 1301 patients was utilised, from which 1186 H&E slides were scored for necrosis, TSP and tumour budding. Median follow up was 158 months (26-183) and there were 234 breast cancer deaths. In the full cohort, necrosis (p<0.0001), high TSP (p=0.010) and high budding (p<0.0001) were associated with CSS and all 3 were independently prognostic on multivariate analysis (necrosis HR 1.54, 95%CI 1.15-2.07, p=0.004; high TSP HR 1.49, 95%CI 1.12-1.98; p=0.006; high budding HR 1.38, 95%CI 1.02-1.87, p=0.035). In ER positive disease (n=826), necrosis was associated with worse CSS (p<0.0001) and was independently prognostic (HR 1.46, 95%CI 1.03-2.08, p=0.033). In ER negative disease (n=359), necrosis, high TSP and high budding were associated with worse CSS (p=0.001, p=0.002, p<0.0001 respectively) and were independently prognostic (necrosis HR 2.44, 95%CI 1.34-4.43, p=0.003; high TSP HR 1.64, 95%CI 1.06-2.53, p=0.026; high budding HR 2.47, 95%CI 1.56-3.89, p<0.0001) . To assess if combining these markers added additional prognostic power a combined budding/necrosis score was established. This was associated with worse CSS in ER positive disease (p<0.0001) and a score of 2 was independently associated with worse CSS compared to a score of 0 (HR 1.96, 95%CI 1.19-3.23, p=0.008). This was potentiated in node-negative patients (HR 5.14, 95%CI 2.18-12.08, p<0.0001). In ER negative disease, an increasing score was associated with worse CSS (p<0.0001) and was independently prognostic (combined score 1 vs. 0: HR 2.37, 95%CI 1.13-5.00, p=0.023; score 2 vs. 0: HR 5.93, 95%CI 2.62-13.40, p<0.0001). Conclusions: A combined score of tumour necrosis and budding shows promise as a readily-available prognostic tool to aid treatment decision making in primary operable breast cancer, both by stratifying risk in ER negative disease, and by identifying a high-risk group in ER positive, node negative disease. Citation Format: Morrow ES, Gujam F, Mohammed Z, McMillan DC, Horgan PG, Roseweir AK, Edwards J. A combined score of tumour budding and tumour necrosis has prognostic value for cancer specific survival in both ER positive and ER negative primary operable breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-08-23.
Background There are limited treatments for triple negative breast cancer (TNBC) patients and an unmet need for targeted approaches in these patients. In the last 4-5 years, the prevalence of high androgen receptor (AR) expression in TNBCs has been noted in up to 50% of tumors suggesting it has clinical relevance. The non-canonical NF-kB pathway is also upregulated in this patient group and it has been reported that that there is crosstalk between these pathways. Therefore the aim of this study was to examine the expression of IKKα and AR in breast cancer tissue samples, to assess if combining these markers increased prognostic power. Methods Immunohistochemistry was performed on tissue microarray of 410 patients to assess proteins level of IKK alpha and AR. Protein expression levels were assessed using the weighted histoscore (WHS) method. The median was employed as the cut off for IKK alpha and 1% as cut off for AR. Expression was analyzed for associations with cancer-specific survival (CSS) and recurrence-free survival (RFS). Results In a cohort of 370 breast cancers nether AR nor IKK alpha alone or combined were associated with CSS or RFS. Stratifying patients by ER status did not impact CSS or RFS. However, in TNBC patients (n=82) high expression of AR was associated with shorter CSS (HR 2.55 95 CI 1.61-5.59, p=0.013). To assess if combining AR and IKK alpha increased prognostic power, AR and IKK alpha were combined into a single score: 0= low expression of both or high expression of one and 1= high expression of both. In the full cohort or when stratified by ER status the score was not associated with CSS or RFS, however in TNBC the combined score potentiated the effect observed with AR alone, (HR 1.68 95 CI 1.20-2.33, p=0.001). Patient CSS was stratified from 11.5 years to 4.6 years and was independently associated with CSS when compared with common clinicopathological factors (HR 1.56 95CI 1.11-2.21, p=0.011). In addition, the combined score was associated with decrease radiotherapy use (p=0.032), increased recurrence rate (p=0.014), decreased cytotoxic T cells (p=0.007), B cells (p=0.043) and macrophages (p=0.037). Conclusions A combined AR and IKK alpha score is an independent prognostic classification for patients with TNBC. Patients with high expression of both AR and IKK alpha a significantly reduced survival and were immune cell cold. This study suggests that this patient group will not benefit from immunotherapy but dual targeting with anti-androgens and IKK alpha selective inhibitors could offer a novel therapeutic strategy for this patient group. Citation Format: Roseweir AK, Khongthong P, Dickson K, Bennett L, Edwards J. Dual targeting of androgen receptor and IKK alpha is a potential therapeutic strategy for triple negative breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-10-13.
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