Mitochondrial DNA analysis efficiently contributes to the identification of metastatic contralateral breast cancers

Abstract

Purpose In daily practice, a contralateral breast cancer (CBC) is usually considered as a new independent tumor despite the indications of several studies showing that the second neoplasia may be a metastatic spread of the primary tumor. Recognition of clonal masses in the context of multiple synchronous or metachronous tumors is crucial for correct prognosis, therapeutic choice, and patient management. Mitochondrial DNA (mtDNA) sequencing shows high informative potential in the diagnosis of synchronous neoplasms, based on the fact that somatic mtDNA mutations are non-recurrent events, whereas tumors sharing them have a common origin. We here applied this technique to reveal clonality of the CBC with respect to the first tumor. Methods We analyzed 30 sample pairs of primary breast cancers and synchronous or metachronous CBCs with detailed clinical information available and compared standard clinico-pathological criteria with mtDNA sequencing to reveal the metastatic nature of CBCs. Results MtDNA analysis was informative in 23% of the cases, for which it confirmed a clonal origin of the second tumor. In addition, it allowed to solve two ambiguous cases where histopathological criteria had failed to be conclusive and to suggest a clonal origin for two additional cases that had been classified as independent by pathologists. Conclusion Overall, the mtDNA-based classification showed a more accurate predictive power than standard histopathology in identifying cases of metastatic rather than bilateral breast cancers in our cohort, suggesting that mtDNA sequencing may be a more precise and easy-to-use method to be introduced in daily routine to support and improve histopathological diagnoses.

Association of molecular subtype concordance and survival outcome in synchronous and metachronous bilateral breast cancer

“…Some pathological features could be used to help define a contralateral breast cancer as independent or suspected metastasis of the primary, such as different/identical histological type/histological grading, presence/absence of an in situ component, different/identical bioprofiles, or the presence/absence of distant metastasis. However, some of the criteria are not considered fully reliable, due to the tumor heterogeneity, evolution of metastases and some inherent ambiguities regarding histological type and/or IHC [ [43] , [44] , [45] ]. In the CBHC cohort, comprehensive evaluations were carried out to distinguish a second primary tumor from metastasis.…”

Mitochondrial DNA mutations in ageing and cancer

“…The same methodology has since been applied to breast and borderline ovarian tumours. In both cases, this has allowed the distinction between synchronous tumours and metastases, which have originated from the primary tumour, by virtue of whether or not they share a common mtDNA genotype [142,143].…”