A large comprehensive overview of synchronous bilateral breast cancers that integrated clinical and pathological data with immune infiltration and genomic profiles generated using modern whole exome sequencing and RNA sequencing technologies provides important insights to understand the relationships among tumour, host, immunity and response to treatment. The findings indicate that synchronous bilateral breast cancers represent two distinct and independent diseases occurring incidentally at the same time.
The study team found that the immune infiltration was not determined purely by local tumour microenvironment properties, but was different according to the subtype of the contralateral tumour. In luminal breast cancers, response to neoadjuvant chemotherapy was significantly higher in the case of discordant subtypes of contralateral tumour than in concordant pairs, as with tumour infiltrating lymphocyte (TIL) levels. T cell receptor (TCR) analyses identified that patient was the main source of variability of TCR, and TCRs were not differentially shared between pairs of left and right tumour than they were between pairs of primary tumour and residual disease. The findings are published by Joshua J. Waterfall and Fabien Reyal of the Translational Research Department, Institut Curie, Université de Paris Cité in Paris, France and colleagues on 6 March 2023 in the Nature Medicine.
Bilateral breast cancers represent 2–11% of breast cancers, and their incidence is increasing due to advances in breast cancer imaging. This entity includes both synchronous bilateral breast cancers that is occurring synchronously in both breasts and metachronous bilateral breast cancers that is a tumour occurring in the contralateral breast at a later time period from the primary index cancer.
In several studies, synchronous bilateral breast cancers are associated with poorer survival than unilateral cancer. Neither synchronous nor metachronous breast cancer is associated with strong genetic determinants, and only 5% of patients with bilateral breast cancers carry BRCA1 or BRCA2 mutations. From the genomic point of view, several studies, although with old technologies, investigated clonal relationships among bilateral breast cancers, with most reaching the conclusion that most, if not all, of bilateral breast cancers were independent events.
Synchronous bilateral breast cancers occur after both breasts have been affected by the same germline genetics, reproductive life factors and environmental exposures for several decades. Two tumours arising concomitantly in a host mimic a model where extrinsic factors are almost fully shared by the same host, intrinsic factors are specific to the tumour of each side, and the immune tumoural microenvironment resulting from the interaction between the same host and two different tumours can be compared.
Little evidence exists regarding immune infiltration and response to treatment in synchronous bilateral breast cancers. In the current study, the investigators identified a rare resource of 20 tumours deriving from 6 patients with synchronous bilateral breast cancers treated by neoadjuvant chemotherapy with left and right pre- and post-neoadjuvant chemotherapy with frozen material available. They performed whole exome sequencing, copy number alterations and RNA sequencing to comprehensively analyze somatic alterations, the immune microenvironment and the tumour evolution under treatment.
Out of 17575 patients with breast cancer identified in the Institut Curie clinical database, 404 patients had synchronous bilateral breast cancers (2.3%). Slight differences existed in patient and tumour characteristics between patients with unilateral breast cancers and patients with synchronous bilateral breast cancers. Out of 313 patients with invasive synchronous bilateral breast cancers, most of the tumours were luminal (87.6%), whereas triple-negative breast cancer (TNBC) (7.2%) and HER2-positive breast cancers (5.2%) were rare. Only 13 patients were carriers of a genetic germline BRCA1 or BRCA2 predisposition. They were significantly younger and more likely to be diagnosed with large, palpable and high-grade tumours, more frequently of TNBC subtype.
Overall, the 313 paired invasive synchronous bilateral breast cancers shared more common characteristics than expected by chance. Most (84.7%) of the tumor pairs were concordant regarding clinical and pathological patterns, notably regarding the subtype of breast cancer. A minority of pairs of tumours belonged to different breast cancer subtypes (discordant pairs: 15.3%), and both the proportion of pairs (18%) and their relative repartition were similar in the validation cohort of 8367 patients with synchronous bilateral breast cancers from the Surveillance, Epidemiology, and End Results database.
The study investigators showed that the impact of the subtype of breast cancer on levels of TILs (n = 277) and on pathologic complete response (pCR) rates (n = 140) differed according to the concordant or discordant subtype of breast cancer of the contralateral tumour. Luminal breast tumours with a discordant contralateral tumour had higher TIL levels and higher pCR rates than those with a concordant contralateral tumour.
Tumour sequencing revealed that left and right tumours (n = 20) were independent regarding somatic mutations, copy number alterations and clonal phylogeny, whereas primary tumour and residual disease were closely related, both from the somatic mutation and from the transcriptomic point of view. The study findings indicate that tumour-intrinsic characteristics may have a role in the association of tumour immunity and pCR and demonstrate that the characteristics of the contralateral tumour are also associated with immune infiltration and response to treatment.
The authors wrote that their study has several strengths, such as the use of modern technologies. Whole exome sequencing is more informative than targeted sequencing for determining clonal relationships. The investigators studied a very rare and unique cohort of patients, enabling direct comparison of left versus right primary tumour together with a temporal analysis comparing paired samples before versus after neoadjuvant chemotherapy. Beyond the challenges in analyzing tumour evolution from bulk sequencing data, the investigators were able to leverage multiple tumour samples to reconstruct a clonal phylogeny from germline data to left and right synchronous bilateral breast cancers both before and after treatment. Data on immune infiltration are novel contributions to the literature and provide insights into the immune mechanisms underlying the biology of synchronous bilateral breast cancers.
The authors concluded that both tumour immune infiltration and response to treatment are differentially associated with the subtype of breast cancer according to the concordant or discordant character of the contralateral tumour. They underlined that pairs of tumours from different subtypes of breast cancers should be considered as singular entities before primary systemic treatment is considered, as observed responses might deviate from well-known profiles of response to chemotherapy.
This work was funded by the Site de Recherche Integrée en Cancérologie/Institut National du Cancer and Association d’aide à la recherche cancérologique de Saint-Cloud.
Hamy A-S, Abécassis J, Driouch K, et al. Evolution of synchronous female bilateral breast cancers and response to treatment. Nature Medicine; Published online 6 March 2023. DOI: https://doi.org/10.1038/s41591-023-02216-8