Abstract P2-09-09: Breast cancer arising on the left side is biologically more aggressive and has worse outcomes compared to the right side
Authors: Abdou Yara , Gupta Medhavi , Asaoka Mariko , Attwood Kristopher , Mateusz Opyrchal , Gandhi Shipra , Takabe Kazuaki 
Published: March 2020

Abstract
Background: Previous studies have shown that breast cancer (BC) occurs more frequently in the left breast with the ratio of left to right ranging from 1.05 to 1.26. In spite of the difference in frequency, prior studies have failed to show any significant differences in clinical characteristics or outcomes between left and right sided BC. We hypothesize that left BC have distinctive clinical features and cancer biology compared to right BC. We aim to further evaluate the difference in clinical characteristics by laterality utilizing a large patient cohort, to analyze the difference in cancer biology by transcriptome profiles, and to investigate the clinical relevance by a neoadjuvant cohort.
Methods: Using SEER database, we analyzed a total of 858,001 BC patients. Cancer specific survival (CSS) and overall survival (OS) were analyzed by Kaplan-Meier methods. Multivariable analyses were conducted using Cox regression models. The Cancer Genome Atlas (TCGA) BC cohort was used to analyze genomic and clinical features from a total of 1081 patients. LVI status, mitotic rate, nuclear score and tubular score were collected from pathology reports in TIES client 5.8. Cytolytic activity (CYT) and gene set enrichment analysis (GSEA) were conducted. 155 BC patients treated with neoadjuvant chemotherapy from 2009-2013 at Roswell Park Comprehensive Cancer Center were retrospectively analyzed using Logistic and Cox regression models to evaluate associations between rates of pathological complete responses (pCR) and cancer laterality.
Results: In SEER database, left and right sided BC were seen in 50.8% and 49.2% respectively. Poorly differentiated tumors and hormone negative tumors were more common on the left. The left BC demonstrated poorer outcomes in both OS and CSS (both p&lt;0.001). The left side had poorer outcomes in stage II (p=0.035) and stage III (p=0.005) disease. On multi-variate analysis, the left sided BC was associated with worse OS (left vs right HR 1.03, 95% CI 1.02-1.04; p&lt;0.001). There was a significant correlation between laterality and age; in older patients left sided BC was a poor prognostic indicator (p=0.017). Furthermore, there was a significant correlation between laterality and positive lymph nodes; as the number of positive nodes increased, the left-right side HR increased in magnitude, trending towards poorer survival in left sided BC. In the TCGA database, left and right sided BC were seen in 51.8% and 48.2% respectively. The tumor grade was significantly higher in the left (p=0.02). No statistically significant differences were observed in the tumor immune microenvironment and CYT. GSEA revealed cell-cycle related gene sets such as G2M checkpoint, Mitotic spindle, E2F targets and MYC targets that were significantly enriched in left sided tumor. Furthermore, out of the 865 genes that were highly expressed on the left side, we identified specific genes that are associated with breast tumorigenesis; including BRCA1, BRCA2, BRIP1, CHEK2, FANCC, PALB2, TP53 and MSH6. Neoadjuvant chemotherapy cohort showed that left and right sided BC were found in 50.3% and 49.7% patients respectively. Left BC were associated with a lower pCR rate compared to right (15.4% vs 29.9%, p=0.036). This held true when adjusted for receptor status (OR 0.43 (0.18-0.99), P = 0.048).
Conclusion: We observed that left BC have more aggressive biology and pathology as compared to right BC, resulting in worse outcomes in multiple patient cohorts. The differences in response to neoadjuvant chemotherapy suggest distinctive underlying biologic characteristics between the two sides. This is the first study that looked into differences in cancer biology between right and left sided BC. Future similar studies will help confirm this observation in order to better understand BC biology and make best treatment decisions for our patients.
Citation Format: Yara Abdou, Medhavi Gupta, Mariko Asaoka, Kristopher Attwood, Opyrchal Mateusz, Shipra Gandhi, Kazuaki Takabe. Breast cancer arising on the left side is biologically more aggressive and has worse outcomes compared to the right side [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-09-09.