Evolution of synchronous bilateral breast cancers provide insights into interactions between host, tumor and immunity.

Synchronous bilateral breast cancer (sBBC) occurs after both breasts have been affected by the same germline genetics, reproductive life factors and environmental exposures for decades. It represents an opportunity to decipher the complex interplay between host, tumor, immune system and response to neoadjuvant chemotherapy (NAC). On a cohort of 17575 BCs treated between 2005 and 2012, sBBCs (n=404) were associated with less aggressive proliferative patterns and higher rates of luminal breast cancers (BCs) when compared with unilateral BCs (n=17171). The left and right tumors were concordant for the majority of clinical and pathological features. Tumor pairs of concordant BC subtype were more frequent than pairs of discordant BC subtype, with notably a particularly high frequency of pairs of luminal BCs. Intriguingly, both the levels of tumor infiltrating lymphocytes (TILs) and the response to NAC were modified by the subtype of the contralateral tumors. Whole exome sequencing and RNAseq analyses revealed that left and right tumors were independent from a somatic mutation and transcriptomic point of view, while primary tumors (PT) before NAC and specimens with residual disease (RD) after NAC were more closely related. The analysis of the TCR repertoire identified very little overlap between patients, while common clones were shared in bilateral tumors within each patient. After NAC, the TCR repertoire of RD was enriched and expanded with clones edited by the contralateral PT.

Clonal Evolution Characteristics and Reduced Dimension Prognostic Model for Non-Metastatic Metachronous Bilateral Breast Cancer

Background:How to evaluate the prognosis and develop overall treatment strategies of metachronous bilateral breast cancer (MBBC) remains confused in clinical practice.Methods:Data from Surveillance, Epidemiology, and End Results (SEER) database and the first hospital of Jilin university were analyzed for breast cancer-specific cumulative mortality (BCCM) by competing risk model. Whole-exome sequencing was applied for 10 lesions acquired at spatial-temporal distinct regions from 5 patients to reconstruct clonal evolutionary characteristics of MBBC. Dimensional reduction (DR) cumulative incidence function (CIF) curves of MBBC features were established on different point in diagnostic interval time, to build a novel DR nomogram.Results:Significant heterogeneity in genome and clinical features of MBBC was widespread. The mutational diversity of contralateral BC (CBC) was significantly higher than that in primary BC (PBC), and the most effective prognostic MATH ratio was significantly correlated with interval time (R2=0.85, p < .05). In SEER cohort study (n=13304), the interval time was not only significantly affected the BCCM by multivariate analysis (p < .000), but determined the weight of clinical features (T/N stage, grade and ER status) on PBC and CBC in prognostic evaluation. Thus, clinical parameters after DR based on interval time were incorporated into the nomogram for prognostic predicting BCCM. Concordance index was 0.773 (95% CI, 0.769 to 0.776) in training cohort (n=8869), and 0.819 (95% CI, 0.813 to 0.826) in validation cohort (n=4435).Conclusions:Bilateral heterogeneous characteristics and interval time were determinant prognostic factors of MBBC. The DR nomogram may help clinical prognostic evaluation.

Expression of Senescence and Apoptosis Biomarkers in Synchronous Bilateral Breast Cancer: A Case Report

Background: Synchronous bilateral breast cancer (SBBC) provides a special condition where two independent breast tumors are exposed to cancer pharmacotherapy within a uniform pharmacokinetic milieu. Both senescence and apoptosis are established responses to therapy; however, they have potentially variable contributions to the overall outcome of treatment, which are yet to be determined. Methods: In this report, we describe the clinicopathological picture of two SBBC cases that received standard anticancer treatment and assess their expression profile of several molecular hallmarks of senescence and apoptosis. Results: Our analysis identified that synchronous tumors have variable expression profiles of both senescence- and apoptosis-associated biomarkers, despite comparable pathological responses to neoadjuvant chemotherapy and current survival rates. Conclusions: Our results highlight the variable expression of senescence- and apoptosis-associated markers in breast tumors (despite the shared somatic genetic background) and invites a large-scale assessment of both senescence and apoptosis in breast cancer tissue in vivo and their contribution to the pathological response and overall survival.