Targeted next-generation sequencing identifies genomic abnormalities potentially driving the prognosis of early-stage invasive lobular breast carcinoma patients stratified according to a validated clinico-pathological model

Giovanni Scambia, Giampaolo Tortora, Emilio Bria, Luisa Carbognin, Michele Simbolo, Anna Caliò, Caterina Vicentini, Pietro Delfino, Isabella Sperduti, Matteo Fassan, Francesco Schettini, Maria Vittoria Dieci, Gaia Griguolo, Sara Pilotto, Elena Fiorio, Grazia Arpino, Valentina Guarneri, Sabino De Placido, Pierfranco Conte, Erminia ManfrinMatteo Brunelli, Aldo Scarpa

Risultato della ricerca: Contributo in rivistaArticolo in rivista

1 Citazioni (Scopus)

Abstract

Introduction: The clinico-pathological and molecular factors that drive the prognosis of invasive lobular breast carcinoma (ILC) are not entirely explored. In this regard, the development and validation of a prognostic model for ILC and the investigation of the distribution of molecular abnormalities (focusing on CDK4/6 alterations) according to prognosis were the aims of this study. Patients and methods: Two clinico-pathological multi-center data-sets of early-stage ILC patients (Training/Validation Set, TS/VS) were gathered. A 3-class model was developed according to the multivariate analysis for disease-free-survival (DFS) and externally validated. Mutational, copy number variation and transcriptomic analyses by targeted next generation sequencing (NGS) were performed (and validated with quantitative PCR) in an explorative cohort of patients with poor and good prognosis. Results: Data from overall 773 patients (TS/VS: 491/282) were gathered. The developed model significantly discriminated low/intermediate/high risk in the TS (10-years DFS: 76.3%/67.6%/39.8%, respectively, p<0.0001) and in the VS (p<0.0001). In the explorative cohort for molecular analysis (34 patients), CDK4 gain was present exclusively in the poor prognosis group (35.0%, p = 0.03; OR 7.98, 95%CI 1.51–42.1, p = 0.014). Moreover, CDK4 and 6 overexpression showed a trend toward an association with poor prognosis (OR 2.7, 95%CI 0.4–18.1, p = 0.3; OR 3.29, 95%CI 0.56–19.25, p = 0.18). Conclusions: A risk stratification model, able to accurately separate early-stage ILC patients’ prognosis into different risk classes according to clinico-pathological variables, allowed to investigate potential biomarkers of prognosis with targeted NGS. CDK4 gain is suggested for future validation as a prognostic biomarker and a potential therapeutic opportunity in ILC patients.
Lingua originaleEnglish
pagine (da-a)56-63
Numero di pagine8
RivistaTHE BREAST
Volume50
DOI
Stato di pubblicazionePubblicato - 2020

Keywords

  • Breast cancer
  • CDK4
  • Lobular
  • Next-generation sequencing
  • Prognosis
  • Transcriptome analysis

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