Germline mutations in DNA repair genes may predict neoadjuvant therapy response in triple negative breast patients.
Triple negative breast cancers (TNBCs) represent about 15-20% of all breast cancer cases and are characterized by a complex molecular heterogeneity. Some TNBCs exhibit clinical and pathological properties similar to BRCA-mutated tumors, without actually bearing a mutation in BRCA genes. This "BRCAness" phenotype may be explained by germline mutations in other genes involved in DNA repair. Although respond to chemotherapy with alkylating agents, they have a high risk of recurrence and progression. Some studies have shown the efficacy of neoadjuvant therapy in TNBC patients with DNA repair defects, but proper biomarkers of DNA repair deficiency are still needed. Here, we investigated if mutations in DNA repair genes may be correlated with anthracyclines/taxanes neoadjuvant therapy response. DNA from 19 TNBC patients undergoing neoadjuvant therapy were subjected to next generation sequencing of a panel of 24 genes in DNA repair and breast cancer predisposition. In this study, 5 of 19 patients (26%) carried a pathogenic mutation in BRCA1, PALB2, RAD51C and two patients carried a probable pathogenic missense variant. Moreover, VUS (Variants of Unknown Significance) in other genes, predicted to be deleterious by in silico tools, were detected in five patients. Germline mutations in DNA repair genes were found to be associated with the group of TNBC patients who responded to therapy. We conclude that a subgroup of TNBC patients have defects in DNA repair genes, other than BRCA1, and such patients respond favourably to neoadjuvant anthracyclines/taxanes therapy. © 2016 Wiley Periodicals, Inc.
Section of Genetic Oncology, Department of Laboratory Medicine, University Hospital of Pisa, Pisa, Italy.
Laura
L
Spugnesi
Section of Genetic Oncology, Department of Laboratory Medicine, University Hospital of Pisa, Pisa, Italy.
Michele
M
Gabriele
Section of Genetic Oncology, Department of Laboratory Medicine, University Hospital of Pisa, Pisa, Italy.
Rosa
R
Scarpitta
Section of Genetic Oncology, Department of Laboratory Medicine, University Hospital of Pisa, Pisa, Italy.
Mariella
M
Tancredi
Section of Genetic Oncology, Department of Laboratory Medicine, University Hospital of Pisa, Pisa, Italy.
Luisa
L
Maresca
Section of Genetic Oncology, Department of Laboratory Medicine, University Hospital of Pisa, Pisa, Italy.
Gaetana
G
Gambino
Section of Genetic Oncology, Department of Laboratory Medicine, University Hospital of Pisa, Pisa, Italy.
Anita
A
Collavoli
Pisa Science Foundation Onlus, Pisa, Italy.
Paolo
P
Aretini
UO Medical Oncology, Department of Oncology, University Hospital of Pisa, Pisa, Italy.
Ilaria
I
Bertolini
UO Medical Oncology, Department of Oncology, University Hospital of Pisa, Pisa, Italy.
Barbara
B
Salvadori
UO Medical Oncology, Department of Oncology, University Hospital of Pisa, Pisa, Italy.
Elisabetta
E
Landucci
UO Medical Oncology, Department of Oncology, University Hospital of Pisa, Pisa, Italy.
Andrea
A
Fontana
Department of Senology, University of Pisa, Pisa, Italy.
Elena
E
Rossetti
Department of Senology, University of Pisa, Pisa, Italy.
Manuela
M
Roncella
Division of Surgical, Molecular and Ultrastructural Pathology, University of Pisa, Pisa, Italy.
Giuseppe Antonio
GA
Naccarato
UO Medical Genetics, Department of Laboratory Medicine, University Hospital of Pisa, Pisa, Italy. adelaide.caligo@do.unipi.it.
Maria Adelaide
MA
Caligo
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D019313:BRCA1 Protein / Q000235:genetics; D014408:Biomarkers, Tumor / Q000235:genetics*; D016022:Case-Control Studies; D004260:DNA Repair / Q000187:drug effects / Q000235:genetics; D045643:DNA Repair Enzymes / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics; D000076164:Fanconi Anemia Complementation Group N Protein; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D060787:Neoplasm Grading; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D009367:Neoplasm Staging; D009687:Nuclear Proteins / Q000235:genetics; D011379:Prognosis; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D025521:Tumor Suppressor Proteins / Q000235:genetics
D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D000076164:Fanconi Anemia Complementation Group N Protein; D009687:Nuclear Proteins; C512790:PALB2 protein, human; C448305:RAD51C protein, human; D025521:Tumor Suppressor Proteins; D045643:DNA Repair Enzymes