Yale Cancer Center Precision Medicine Tumor Board: two patients, one targeted therapy, different outcomes

• Published in: The lancet oncology Vol. 19; no. 1; pp. 23 - 24
• Main Authors: Cecchini, Michael, Walther, Zenta, Sklar, Jeffrey L, Bindra, Ranjit S, Petrylak, Daniel P, Eder, Joseph P, Goldberg, Sarah B
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.01.2018; Elsevier Limited
• Subjects: Aged; Androgens; Apoptosis; Ataxia Telangiectasia Mutated Proteins - genetics; Biomarkers, Tumor - genetics; Cancer; Cancer therapies; Cell cycle; Cell growth; Chemotherapy; Clinical trials; Computed tomography; Deoxyribonucleic acid; Disease Progression; DNA; DNA biosynthesis; DNA damage; DNA repair; Double-strand break repair; Doxorubicin; Epigenetics; Fatal Outcome; Fees & charges; Gene expression; Heterozygosity; Homologous recombination; Humans; Ifosfamide; Kinases; Lethality; Loss of heterozygosity; Lung cancer; Male; Medical imaging; Metastases; Middle Aged; Molecular Targeted Therapy; Mutation; Patients; Phthalazines - therapeutic use; Piperazines - therapeutic use; Poly(ADP-ribose) polymerase; Poly(ADP-ribose) Polymerase Inhibitors - therapeutic use; Precision Medicine; Prostate cancer; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - genetics; Prostatic Neoplasms - secondary; Protein-serine/threonine kinase; Proteins; Radiation therapy; Sarcoma; Sarcoma - drug therapy; Sarcoma - genetics; Sarcoma - secondary; Signal transduction; Toxicity; Transcription factors; Treatment Outcome; Tumor suppressor genes; Tumors
• ISSN: 1470-2045; 1474-5488
• DOI: 10.1016/S1470-2045(17)30916-6

ATM encodes a serine or threonine kinase that has crucial roles in the DNA damage response (DDR) and the homologous recombination (HR) pathway for DNA double-strand break (DSB) repair (appendix p 3). Because of toxicity, the chemotherapy regimen was changed to adriamycin and ifosfamide. 9 months later, a PET-CT scan revealed lung metastases and he received doxorubicin and olaratumab, but the cancer progressed after two cycles. During DNA replication, unrepaired SSBs are converted into DSBs, which are thought to require the HR pathway for repair. [...]PARP inhibition is selectively toxic in HR-deficient cells, and this damaging loss of function in two proteins-one by mutation and one by drug action-is referred to as synthetic lethality. MC, ZW, JLS, and JPE declare no competing interests Supplementary Material For more on DNA repair defects see N Engl J Med 2015; 373: 1697-708 For more on PARP and ATR inhibitor sensitivity in lung cancer see Cancer Res 2017; 77: 3040-56 Table Summary of molecular alterations detected by next-generation sequencing Single-nucleotide variants and insertions or deletions are notated as the nucleotide change in the coding sequence of DNA for the mutated gene, followed by the inferred change in the aminoacid sequence of that gene's protein product.