Abstract
Taxanes are the mainstay of treatment in triple-negative breast cancer (TNBC), with de novo and acquired resistance limiting patient's 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 patient with BRCA1-mutated breast cancer who had progressed on docetaxel treatment. Analysis of clinical data indicates an association between chr12p amplification and patients with TNBC/basal-like breast cancer, 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 preexisting population harboring chr12p amplification is associated with the emergence of docetaxel resistance and carboplatin responsiveness in TNBC/BRCA1-mutated tumors. SIGNIFICANCE: Chr12p copy number gains indicate rapid emergence of resistance to docetaxel and increased sensitivity to carboplatin, therefore sequential docetaxel/carboplatin treatment could improve survival in TNBC/BRCA1 patients. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/79/16/4258/F1.large.jpg.
Highlights
Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer and most tumors display basal-like features [1]
The metastatic samples were collected, both patients had been heavily treated with chemotherapy including taxanes
Analysis of germline variants revealed the presence of a heterozygous frameshift mutation in BRCA1 (p.Q1756Pfs) in both normal lymphocytic DNA and in peritumoral tissue from the patient (Supplementary Table S1.3), which was validated by Sanger sequencing (Fig. 1A)
Summary
Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer and most tumors display basal-like features [1]. As no targetable therapies are available, chemotherapy, mostly taxanes, either alone or in combination with other drugs, is the most common treatment for patients with TNBC [2]. De novo or intrinsic chemoresistance to taxanes consistently occurs in TNBCs, leading to resistant relapse or distant metastasis and mortality [2]. A form of de novo resistance occurs when a preexisting resistant subpopulation already present in the tumor is selected as a consequence of treatment [3, 4]. In such cases, resistance can be thought of as "emergent" in otherwise responsive tumors, leading to partial response. A better understanding of these mechanisms is essential to improve patient outcome
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