Results from genomic analyses of metastatic tumor specimens collected at pretreatment and autopsy from patients with treatment-refractory metastatic small cell lung cancer (SCLC) showed evidence for tumor heterogeneity, and provided candidate oncogenesis driver genes in the settings of disease metastasis and acquired resistance to treatment. The findings from this study will be presented at the American Association for Cancer Research (AACR) Annual Meeting 2019.

Small cell lung cancer is a neuroendocrine carcinoma that is characterized by rapid growth and the early development of distant metastasis. Although many patients with metastatic SCLC respond to initial platinum-based chemotherapy, almost all develop progressive disease in a relatively short period of time. Furthermore, according to the abstract authors, there is no standard of care for second-line treatment in this disease, which is associated with a poor prognosis.

While genomic characterizations of metastatic SCLC have been previously performed, most of these studies focused on specimens from treatment-naive patients. In this study, whole-exome sequencing was performed on tumor specimens from multiple metastatic sites collected from 5 patients with treatment-refractory metastatic SCLC who underwent research autopsy. In addition, as a means of evaluating the presence and evolution of tumor heterogeneity in this diseases, whole exome-sequencing was also performed on corresponding pretreatment specimens, and was available for 3 of these patients.

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Key study findings of whole-genome sequencing of tumor specimens obtained at autopsy included the identification of inactivating alterations in the tumor suppressor genes TP53 and RB1 in all and some tumor specimens, respectively. Furthermore, deletion of the tumor suppressor gene, APC, was observed in almost all of these specimens, and this result was reported to be consistent with modifications in WNT signaling associated with chemoresistance. In addition, deletion of the PTEN tumor suppressor gene was observed in 1 patient with brain metastasis.


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Importantly, a comparison of the genomic characterization of pretreatment and posttreatment tumor specimens revealed the presence of extensive clonal heterogeneity in both sets of tumors. This result suggested that tumor heterogeneity occurs early and is preserved during the course of the disease.

Reference

  1. Chen H-Z, Bonneville R, Krook MA, et al. Genomic characterization of recurrent small cell lung cancer through research autopsy reveals clonal diversity and candidate driver of chemoresistance. Presentation at: American Association for Cancer Research (AACR) Annual Meeting 2019; March 29–April 3, 2019; Atlanta, GA. Abstract 748/22.