Disease evolution and heterogeneity in bilateral breast cancer

Bilateral breast cancers (BBC) are currently treated as independent tumors arising in the same patient. Herein, we investigated whether BBC indeed evolve independently at the genomic level. We examined paired targeted next generation sequencing genotypes from 155 paraffin tumors corresponding to 76 BBC patients (75 women and one man; 52 concurrent and 24 metachronous), for coding mutations (amino acid changing, minor allele frequency <0.1%) and single nucleotide polymorphism (SNP) zygosity. Germline genotypes were available for 29 patients. Mutations were present in 80 tumors (54/76 patients; 71%), were mostly tumor-private (90%), more frequent in TP53 (19%), PIK3CA (14%), CDH1, GATA3, MLL3. TP53 mutations were more frequent in metachronous tumors (P<0.001); hormone receptor negative (P<0.001); with higher Ki-67 (P=0.002); and, in younger patients (P=0.01). Hypermutated tumors, all TP53 mutated, were diagnosed as the first incidence in 5 patients; their metachronous counterparts were mutation poor without TP53 involvement. Paired tumors shared common mutations at intratumoral frequency >20% in 10/54 comparable BBC (18.5%), 8/10 concurrent. SNP zygosity status was less preserved in metachronous, compared to concurrent disease. Pathogenic germline mutations were present in 10/29 patients, 9 in BRCA1 and one in TP53 (p.Phe341Val, first report in the germline). BBC demonstrated extensive inter- and intra-patient heterogeneity in the present thus far largest series of corresponding paired genotypes. The majority evolve independently and unpredictably, supporting current clinical practice. A considerable minority though, retains clonal origin and may be regarded as a distinct group for therapeutic interventions among concurrent BBC.