Editors' ChoiceCancer

Treatment Guidance from the Blood

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Science Translational Medicine  25 Jun 2014:
Vol. 6, Issue 242, pp. 242ec109
DOI: 10.1126/scitranslmed.3009598

Animal tumor models derived from human lung cancer cell lines have provided insights into oncogenic alterations, treatment response, and resistance mechanisms. Advanced techniques using matched normal lung, tumor, and post-treatment tumor specimens from non–small-cell lung cancer cases have aided the development of more potent and better tolerated molecularly targeted therapeutics. However, small-cell lung cancer has yet to capitalize on these developments. This aggressive malignancy, which accounts for ~15% of lung cancers, carries one of the highest mutation burdens of any tumor type. Although small-cell lung cancer is initially highly responsive to conventional cytotoxic chemotherapy—with response rates more than double that seen in non–small-cell lung cancer—at the time of progression, response rates to second-line regimens may be less than half that achieved in non–small-cell lung cancer.

Limited access to adequate tissue specimens has hindered advances in this challenging disease. Small-cell lung cancer generally presents with rapidly growing central chest masses that are diagnosed by means of bronchoscopic biopsy, yielding small cytologic specimens. Moreover, patients with small-cell lung cancer have the highest smoking burden of any lung cancer subtype, rendering their normal lung tissue more prone to complications from attempts to pursue more generous core needle specimens. Cases almost never undergo repeat biopsy at the time of progression.

In what may mark a major step forward for these patients, Hodgkinson et al. have reported the successful generation of tumors in animal models using circulating tumor cells (CTCs) from patients with small-cell lung cancer. Specifically, they obtained blood samples from six patients with chemotherapy-naïve advanced small-cell lung cancer, enriched for CTCs, and then injected these cells into the flanks of severe combined immunodeficient mice. Histologic and genomic analyses of these CTC-derived explants resembled those of matched clinical specimens. Treatment efficacy of standard platinum-etoposide chemotherapy in the animal models mirrored that observed clinically in the corresponding patient.

Moving forward, “liquid biopsy” through the analysis of CTCs offers key opportunities for individual patient care and the field of thoracic oncology more broadly. Serial monitoring of CTC molecular phenotype could be used for future treatment decision-making. Blood samples pre- and post-relapse could be used to generate models to provide insight into small-cell lung cancer biology, mechanisms underlying resistance, and potential new druggable targets. Such advances are long overdue.

C. L. Hodgkinson et al., Tumorigenicity and genetic profiling of circulating tumor cells in small-cell lung cancer. Nat. Med. 10.1038/nm.3600 (2014). [Abstract]

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