Abstract 2723: Defective homologous recombination DNA repair as therapeutic target in advanced chordoma

• Published in: Cancer research (Chicago, Ill.) Ill.), 2019-07, Vol.79 (13_Supplement), p.2723-2723
• Main Authors: Gröschel, Stefan, Hübschmann, Daniel, Raimondi, Francesco, Horak, Peter, Warsow, Gregor, Fröhlich, Martina, Klink, Barbara, Gieldon, Laura, Hutter, Barbara, Kleinhenz, Kortine, Bonekamp, David, Marschal, Oliver, Chudasama, Priya, Mika, Jagoda, Groth, Marie, Uhrig, Sebastian, Krämer, Stephen, Heining, Christoph, Heilig, Christoph, Richter, Daniela, Reisinger, Eva, Pfütze, Katrin, Eils, Roland, Wolf, Stephan, Kalle, Christof von, Brandts, Christian, Scholl, Claudia, Weichert, Wilko, Richter, Stephan, Bauer, Sebastian, Penzel, Roland, Schröck, Evelin, Stenzinger, Albrecht, Schlenk, Richard, Brors, Benedikt, Russell, Robert, Glimm, Hanno, Schlesner, Matthias, Fröhling, Stefan
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2019-2723

Chordomas are rare tumors of the axial skeleton and skull base with few therapeutic options and no clinically validated molecular drug targets. The value of comprehensive genomic analyses for guiding medical therapy of patients with advanced-stage chordoma is unknown. We performed whole-exome and genome sequencing of tumor and matched germline control samples from 11 patients with locally advanced or metastatic chordoma within the MASTER program, a prospective clinical sequencing program of the German Cancer Consortium. All patients were pretreated and had progressive disease prior to molecular analysis. Genomic profiling showed that advanced chordomas are frequently characterized by genomic patterns indicative of defective homologous recombination (HR) DNA repair. First, DNA copy number profiles showed high numbers of structural variants greater than 10 million base pairs in size in the majority of cases. Second, all patients harbored somatic aberrations of at least 2 genes known to be involved in HR, and 10/11 cases harbored somatic alterations in 3 or more HR pathway genes. For example, 8 patients showed heterozygous BRCA2 deletions, which were associated with heterozygous deletions of ERCC6 in 6 patients and RAD54L in 7 patients, as well as PTEN alterations (heterozygous deletion, heterozygous mutation and deletion of the wildtype allele or loss of heterozygosity). Other recurrently altered HR genes included ATR, CHEK2, FANCC, FANCD2, FANCG, RAD18, RAD51B, and XRCC3. Third, pathogenic germline alterations were detected in 3 patients. A heterozygous BRCA2 frameshift mutation (p.T3085fs*26; ACMG Class 5), a heterozygous NBN frameshift mutation (p.K219Nfs*16; ACMG Class 5), and a heterozygous CHEK2 missense mutation (p.R145W; ACMG Class 4) were accompanied by somatic deletion of the respective wildtype alleles. Fourth, a mutational signature associated with HR deficiency was significantly enriched in 72.7% of samples and coincided with genomic instability. The high prevalence of an HR deficiency “footprint” in chordoma patients prompted us to explore the clinical efficacy of the poly(ADP-ribose) polymerase(PARP) inhibitor olaparib, which is preferentially toxic to HR-incompetent cells. Olaparib treatment of a patient whose tumor showed a prominent exposure to an HR deficiency-associated mutational signature, a high degree of genomic instability, and 13 heterozygous HR gene alterations halted tumor growth for 10 months. Whole-genome analysis at progression