Research Papers:

5'-nucleotidase cN-II emerges as a new predictive biomarker of response to gemcitabine/platinum combination chemotherapy in non-small cell lung cancer

Francesca Toffalorio, Mariacarmela Santarpia, Davide Radice, Christopher Adrian Jaramillo, Gianluca Spitaleri, Michela Manzotti, Chiara Catania, Lars Petter Jordheim, Giuseppe Pelosi, Godefridus J. Peters, Carmelo Tibaldi, Niccola Funel, Lorenzo Spaggiari, Filippo de Braud, Tommaso De Pas and Elisa Giovannetti _

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Oncotarget. 2018; 9:16437-16450. https://doi.org/10.18632/oncotarget.24505

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Francesca Toffalorio1,2,*, Mariacarmela Santarpia1,3,*, Davide Radice4, Christopher Adrian Jaramillo5, Gianluca Spitaleri1,6, Michela Manzotti7, Chiara Catania1,6, Lars Petter Jordheim8, Giuseppe Pelosi9,10, Godefridus J. Peters5, Carmelo Tibaldi11, Niccola Funel12,13, Lorenzo Spaggiari14, Filippo de Braud9,10,*, Tommaso De Pas1,* and Elisa Giovannetti5,12,13,*

1Medical Oncology Unit of Respiratory Tract and Sarcomas, New Drugs Development Division, European Institute of Oncology, Milan, Italy

2Medical Affairs, Roche Spa, Monza, Italy

3Medical Oncology Unit, Department of Human Pathology, University of Messina, Messina, Italy

4Epidemiology and Biostatistics Division, European Institute of Oncology, Milan, Italy

5Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands

6Thoracic Oncology Division, European Institute of Oncology, Milan, Italy

7Division of Pathology and Laboratory Medicine, European Institute of Oncology, Milan, Italy

8Centre de Recherche en Cancérologie de Lyon, INSERM 1052/CNRS UMR 5286, Lyon, France

9Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy

10Inter-Hospital Pathology Division, Science and Technology Park, IRCCS MultiMedica, Milan, Italy

11Division of Oncology, Department of Oncology, S. Luca Hospital, Lucca, Italy

12CNR-Nano, Institute of Nanoscience and Nanotechnology, Pisa, Italy

13Cancer Pharmacology Laboratory, AIRC Start-Up Unit, University of Pisa, Pisa, Italy

14Thoracic Surgery Division, European Institute of Oncology, Milan, Italy

*These authors equally contributed to the work

Correspondence to:

Elisa Giovannetti, email: [email protected]

Keywords: lung cancer; pharmacogenetics; response; gemcitabine; nucleotidase

Received: May 30, 2017     Accepted: February 02, 2018     Epub: February 16, 2018     Published: March 27, 2018


A number of pharmacogenetic studies have been carried out in non-small-cell lung cancer (NSCLC) to identify and characterize genes involved in chemotherapy activity. However, the results obtained so far are controversial and no reliable biomarker is currently used to predict clinical benefit from platinum-based chemotherapy, which represents the cornerstone of treatment of advanced NSCLC. This study investigated the expression levels of ERCC1 and of six genes (RRM1, RRM2, hENT1, dCK, cN-II and CDA) involved in gemcitabine metabolism in locally/advanced NSCLC patients treated with gemcitabine/platinum combination. Gene expression was assessed by quantitative-PCR in laser-microdissected specimens and correlated with tumor response. Frequency distribution of responses above and below the median expression level of biomarkers was compared using a two-sided Fisher’s test. 5′-nucleotidase (cN-II) was the only gene differently expressed (p = 0.016) in the responders (complete/partial-response) compared to non-responders (stable/progressive disease). In the multivariate analysis, overexpression of this catabolic enzyme of gemcitabine remained a significant negative predictive factor. Patients with low cN-II had a modest trend toward increased survival, while both survival and progression-free survival were significantly longer in a more homogenous validation cohort of 40 advanced NSCLC (8.0 vs. 5.1 months, p = 0.026). Moreover, in vitro studies showed that silencing or pharmacological inhibition of cN-II increased the cytotoxicity of gemcitabine. This is the first study demonstrating the role of cN-II as a predictor of response to gemcitabine/platinum combinations in NSCLC. Its validation in prospective studies may improve clinical outcome of selected patients.

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