J Gómez-Miragaya, A Díaz-Navarro, R Tonda, S Beltran, L Palomero, M Palafox, LE Dobrolecki, C Huang, S Vasaikar, B Zhang, GM Wulf, A Collado-Solé, EM Trinidad, P Muñoz, L Paré, A Prat, A Bruna, C Caldas, J Arribas, MT Soler-Monsó, A Petit, J Balmaña, C Cruz, V Serra, MA Pujana, MT Lewis, XS Puente, E González-Suárez
Taxanes are the mainstay of treatment in triple-negative breast cancer (TNBC), with de novo and acquired resistance limiting patient survival. To investigate the genetic basis of docetaxel resistance in TNBC, exome sequencing was performed on matched TNBC patient-derived xenografts (PDX) sensitive to docetaxel, and their counterparts that developed resistance in vivo upon continuous drug exposure. Most mutations, small insertions/deletions and copy number alterations, detected in the initial TNBC human metastatic samples were maintained after serial passages in mice and emergence of resistance. We identified a chromosomal amplification of chr12p in a human BRCA1-mutated metastatic sample and the derived chemoresistant PDX, but not in the matched docetaxel-sensitive PDX tumor. Chr12p amplification was validated in a second pair of docetaxel-sensitive/resistant BRCA1-mutated PDXs and after short-term docetaxel treatment in several TNBC/BRCA1-mutated PDXs and cell lines, as well as, during metastatic recurrence in a BRCA1-mutated breast cancer patient who had progressed on docetaxel treatment. Analysis of clinical data indicates an association between chr12p amplification and TNBC/basal-like breast cancer patients, a BRCA1 mutational signature, and poor survival after chemotherapy. Detection of chr12p amplification in a cohort of TNBC PDX models was associated with an improved response to carboplatin. Our findings reveal tumor clonal dynamics during chemotherapy treatments and suggest that a pre-existing population harboring chr12p amplification is associated with the emergence of docetaxel resistance, but carboplatin responsiveness in TNBC/BRCA1-mutated tumors.