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.

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.

A comparative dosemetric study of bilateral breast cancer after modified radical mastectomy with HT and VMAT

Background: The purpose of this study was to compare the dosimetric differences in helical tomotherapy (HT) and volumetric modulated arc therapy (VMAT) plans of bilateral breast cancer after modified radical mastectomy.Methods: Ten patients with synchronous bilateral breast cancer (SBBC) who received modified radical mastectomy were selected for study. Two radiotherapy treatment plans, including HT and VMAT, were created for each patient. The prescribed doses of bilateral breast cancer and dual target volumes were given 25 times at 50Gy. The dosemetric parameters of planning target volume (PTV) and organs at risk (OARs) between HT and VMAT plans were compared and evaluated. Results: For PTV, HT had a higher V95 than that of VMAT plans (99.23 ± 0.61 % vs 98.17± 1.08 %, p=0.024). The conformity index (CI) between two techniques was statistically equivalent (0.812 ± 0.03 vs 0.793 ± 0.04, p=0.322) and the homogeneity index (HI) was reduced from 0.127 to 0.105 (p=0.007) when compared with that of VMAT. For OARs, HT had significantly lower Dmax for spinal cord and V5 for heart when compared with those of VMAT plans (16.68 Gy and 20.93% vs 38.82 Gy and 30.26%, respectively) (p<0.001). HT plans showed significantly lower V5, V10 and V20, that resulted in lower Dmean for the lungs (13.38 Gy vs 14.28Gy, p=0.013). However, VMAT showed specific advantages on V10, V20 and V30 for the heart and V5 and V10 for the liver when compared with those of HT plans (p<0.01). The Dmean for the heart and liver between the two techniques was not significantly different (p>0.05). HT plans also showed greater monitor units (MUs) and beam on time. Conclusion: HT had better PTV coverage and HI and showed better protections for the spinal cord and lungs compared with those of VMAT plans. HT plans effectively reduced the low-dose volume (V5) of the heart, while VMAT plans reduced V10, V20 and V30 for the heart. Both HT and VMAT plans exhibited similar Dmean for the heart and liver. The treatment efficiency of VMAT is higher than that of HT plans, and therefore, physicians need to choose a reasonable radiotherapy plan according to patient's conditions.

Retrospective Analysis of Clinicopathological Features and Familial Cancer History of Synchronous Bilateral Breast Cancer

Bilateral breast cancer is a strong predictor of BRCA 1/2 mutation and hence one criterion indicated for hereditary genetic testing. The purpose of this study is to assess the characteristics of synchronous bilateral breast cancer (SBBC) and its association with personal and familial cancer traits. Patients diagnosed with SBBC in our institute between 1992 and 2018 were retrospectively reviewed, and the information of clinicopathological features, personal and family cancer history were analyzed. Of the 307 SBBCs enrolled, the growing case number generally aligned with the regional breast cancer incidence after the era of population-based mammography screening. SBBC patients had similar cancer stages but worse survival outcomes than those in the standard scenario. A total of 42.0% had mixed pathological diagnoses, and 22.8% had discordant immunohistochemistry (IHC) subtypes from both sides, which contributed to treatment challenges. The correlation of SBBC with hereditary breast and ovarian cancer (HBOC) syndrome was strongly implied, as 20.7% of our SBBC patients with known familial cancer histories had HOBC-related familial cancers (breast, ovarian, or prostate cancers). These findings highlight the need for genetic counseling and germline mutation testing in patients with SBBC. Early PARP inhibitor treatment should also be considered in high-risk cases for outcome improvement.

Quantitative and dosimetric analysis for treating synchronous bilateral breast cancer using two radiotherapy planning techniques

Objective: We compared mono-isocenter and dual-isocenter plans in synchronous bilateral breast cancer (SBBC), which is defined as tumours occurring simultaneously in both breasts, and evaluated the effects of these differences in plans on organs-at-risk (OARs). Materials and methods: We evaluated 10 women with early stage, nod negative (Tis-2N0M0) SBBC. The treatment dose was determined to be 50 Gy. We used mean dose and VXGy to evaluate the OARs. To evaluate the effectiveness of treatment plans, Homogeneity index (HI), conformity index (CI) and sigma index (SI) and monitor units (MU) of monoisocenter (MIT) and dual-isocenter (DIT) plans were compared. During bilateral breast planning, for the single-centre plan, the isocenter was placed at the center of both breasts at a depth of 3-4 cm. For the two-center plan, dual-isocenters were placed on the right and left breasts. Results: No significant difference between the techniques in terms of the scope of the target volume was observed. Statistically significant results were not achieved in MIT and DIT plans for OARs. Upon comparing MIT and DIT, the right-side monitor unit (MU) value in DIT (p = 0.011) was statistically significantly lower than that in MIT. Upon comparing right-left side MIT and DIT, the MU value (p = 0.028) was significantly lower in DIT than MIT. Conclusion: SBBC irradiation is more complex than unilateral breast radiotherapy. No significant difference between both techniques and OARs was observed. However, we recommend MIT as a priority technique due to the ability to protect OARs, ease of administration during treatment, and the fact that the patient stays in the treatment unit for a shorter period of time.

Molecular Imaging Reveals a High Degree of Cross-Seeding of Spontaneous Metastases in a Novel Mouse Model of Synchronous Bilateral Breast Cancer

Purpose Synchronous bilateral breast cancer (SBBC) patients present with cancer in both breasts at the time of diagnosis or within a short time interval. They show higher rates of metastasis and lower overall survival compared to women with unilateral breast cancer. Here we established the first preclinical SBBC model and used molecular imaging to visualize the patterns of metastasis from each primary tumor. Procedures We engineered human breast cancer cells to express either Akaluc or Antares2 for bioluminescence imaging (BLI) and tdTomato or zsGreen for ex vivo fluorescence microscopy. Both cell populations were implanted into contralateral mammary fat pads of mice (n=10), and dual-BLI was performed weekly for up to day 29 (n=3), 38 (n=4), or 42 (n=3). Primary tumors and lungs were fixed, and ex vivo fluorescence microscopy was used to analyze the cellular makeup of micrometastases. Results Signal from both Antares2 and Akaluc was first detected in the lungs on day 28 and was present in 9 of 10 mice at endpoint. Ex vivo fluorescence microscopy of the lungs revealed that for mice sacrificed on day 38, a significant percentage of micrometastases were composed of cancer cells from both primary tumors (mean 37%; range 27 to 45%), while two mice sacrificed on day 42 showed percentages of 51% and 70%. Conclusions A high degree of metastatic cross-seeding of cancer cells derived from bilateral tumors may contribute to faster metastatic growth and intratumoral heterogeneity. We posit that our work will help understand treatment resistance and optimal planning of SBBC treatment.