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

Giulia Girolimetti,Giuseppe Gasparre,Laura Benedetta Amato,Claudio Ceccarelli,Lorena Marchio,Antonio De Leo,Miriam Mangiarelli,Mario Taffurelli,Simone Zanotti,Donatella Santini

doi:10.1007/s00432-020-03459-5

Abstract

PurposeIn 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.MethodsWe 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.ResultsMtDNA 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.ConclusionOverall, 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.

Highlights

Patients who experienced a breast neoplasia have a higher risk of developing a contralateral breast cancer (CBC) during their lifetime (Chen et al 1999; Peralta et al 2000;1 3 Vol.:(0123456789)Journal of Cancer Research and Clinical Oncology (2021) 147:507–516Goldstein et al 2003; Raymond and Hogue 2006; Hartman et al 2007)
There are no uniform clinical criteria that allow discriminating between bilateral CBC and metastatic cancer spread to CBC
We apply Mitochondrial DNA (mtDNA) sequencing on a cohort of 30 pairs of breast cancer samples to compare its predictive accuracy against standard histopathological criteria used in the daily practice and retrieve the subset of CBC that ought to be classified as metastasis of the primary breast cancer

Summary

Introduction

Patients who experienced a breast neoplasia have a higher risk of developing a contralateral breast cancer (CBC) during their lifetime (Chen et al 1999; Peralta et al 2000;1 3 Vol.:(0123456789)Journal of Cancer Research and Clinical Oncology (2021) 147:507–516Goldstein et al 2003; Raymond and Hogue 2006; Hartman et al 2007). MetCBC is associated to a higher risk of diffuse metastasis and, subsequently, to a poorer survival, whereas a new primary carcinoma is characterized by its own patho-biological features, and a better survival (Haffty et al 1996; Elkhuizen et al 1998; Huang et al 2002) It is suggested the following pathological features be used to define a second CBC as independent or suspected metastasis of the primary: (1) different/identical histotype/ histological grading; (2) presence/absence of an in situ component; and (3) different/identical bioprofiles. We apply mtDNA sequencing on a cohort of 30 pairs of breast cancer samples to compare its predictive accuracy against standard histopathological criteria used in the daily practice and retrieve the subset of CBC that ought to be classified as metastasis of the primary breast cancer

Methods

Results

Conclusion