Comprehensive Genomic Profile of Heterogeneous Long Follow-Up Triple-Negative Breast Cancer and Its Clinical Characteristics Shows DNA Repair Deficiency Has Better Prognostic

Abstract

Triple-negative breast cancer (TNBC) presents a marked diversity at the molecular level, which promotes a clinical heterogeneity that further complicates treatment. We performed a detailed whole exome sequencing profile of 29 Mexican patients with long follow-up TNBC to identify genomic alterations associated with overall survival (OS), disease-free survival (DFS), and pathologic complete response (PCR), with the aim to define their role as molecular predictive factors of treatment response and prognosis. We detected 31 driver genes with pathogenic mutations in TP53 (53%), BRCA1/2 (27%), CDKN1B (9%), PIK3CA (9%), and PTEN (9%), and 16 operative mutational signatures. Moreover, tumors with mutations in BRCA1/2 showed a trend of sensitivity to platinum salts. We found an association between deficiency in DNA repair and surveillance genes and DFS. Across all analyzed tumors we consistently found a heterogeneous molecular complexity in terms of allelic composition and operative mutational processes, which hampered the definition of molecular traits with clinical utility. This work contributes to the elucidation of the global molecular alterations of TNBC by providing accurate genomic data that may help forthcoming studies to improve treatment and survival. This is the first study that integrates genomic alterations with a long follow-up of clinical variables in a Latin American population that is an underrepresented ethnicity in most of the genomic studies.

The Evolution of Clinically Aggressive Triple-Negative Breast Cancer Shows a Large Mutational Diversity and Early Metastasis to Lymph Nodes

“…In our cohort none of the patients achieved a complete response with NAC and all of them died within three years. Our findings are consistent with and similar to previously reported mortality rates in Latin America and worldwide [29][30][31].…”

“…TNBC patients showed a heterogenous TMB, with an average of 3.8 mutations (range 0.4-8.9). These results are comparable to other studies [31,38]. The treated tumors and recurrences in our cohort had the highest TMB in comparison to primary treatmentnaïve tumor, lymph node, and skin metastasis samples.…”

“…Given the high degree of genetic heterogeneity in TNBC, it is possible to use this molecular trait to identify candidates for targeted therapy. We detected 17 potential actionable alter-clustered in seven altered signaling pathways, which are consistent with previous findings [5,31,52]. We identified seven groups of tumors and their associated treatments based on the type of mutations detected; these treatments are also used in other subtypes of breast cancer and other tumor types.…”

Comparison of PIK3CA Mutation Prevalence in Breast Cancer Across Predicted Ancestry Populations

“…Additionally, compared with patients of EUR ancestry, patients of EAS ancestry with HER2+ BC and TNBC, as well as patients of SAS ancestry with HER2+ BC, were more likely to have tumors that harbor PIK3CAmut (Figs 2A, 2C and 2E). The ancestry-specific tumor PIK3CAmut prevalences observed across BC subtypes is supported by the findings from studies that sampled substantially fewer participants in Africa, [36][37][38][39] Latin America, [40][41][42][43][44] China or Korea, [45][46][47][48][49][50][51][52] and South Asian countries. [53][54][55][56][57] Inconsistencies between PIK3CAmut prevalences identified in our study and those reported in the literature were observed when sample sizes were small and when differences existed in the clinical characteristics of the populations evaluated and/or assay methodologies.…”

Mutational spectrum of breast cancer by shallow whole-genome sequencing of cfDNA and tumor gene panel analysis

“…Bioinformatic analyses were performed using previously described methods 41,42 . Briefly, BWA 43 and GATK 44 were used for alignment and data processing, respectively.…”