Multigene expression profile for predicting efficacy of cisplatin and vinorelbine in non-small cell lung cancer

Ida Kappel Buhl (1)(2), Ib Jarle Christensen (3), Eric Santoni-Rugiu (4), Jesper Ravn (5), Anker Hansen (2), Thomas Jensen (2), Jon Askaa (2), Peter Buhl Jensen (2), Steen Knudsen (6), Jens Benn Sørensen (7)

1) Section for Molecular Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark, 2) Medical Prognosis Institute, Hørsholm, Denmark, 3) Department of Gastroenterology, Hvidovre Hospital, Hvidovre, Denmark,

4) Department of Pathology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark, 5) Department of Thoracic Surgery, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark, 6) Medical Prognosis Institute Inc, Scottsdale, Arizona 85258, USA, 7) Department of Oncology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.

Background
There is a need for biomarkers to predict efficacy of adjuvant chemotherapy in resected non-small cell lung cancer (NSCLC). Presented is a combined cisplatin and vinorelbine marker from a previously validated model system [1] tested in two cohorts.

Materials and methods
The profiles consist of correlated in vitro cytotoxicity of cisplatin and vinorelbine and mRNA expressions. Then each profile is correlated to mRNA expression of 3500 tumors.

The cohorts are 1) a publically available dataset with 133 completely resected stage Ib-II NSCLC patients, 71 of whom received adjuvant cisplatin and vinorelbine (ACT) and 62 patients who had no adjuvant treatment (OBS) [2] and 2) 95 stage Ib-IIIb completely resected NSCLC patients who all received adjuvant cisplatin and vinorelbine [3]. Endpoint is cancer specific survival.

Results
The combined cisplatin and vinorelbine profiles scored as a continuous covariate showed 1) a Hazard Ratio (HR) of 0.265 ((95% CI:0.079-0.889), p=0.032) in the ACT cohort (sensitive versus resistant), and no significant discrimination in the OBS cohort (HR=1.328 (95% CI:0.46-3.835), p=0.60). A multivariate model adjusted for stage demonstrated significance for ACT (HR=0.284 (95% CI:0.086-0.944), p=0.040) but not for OBS (HR=1.702 (95% CI: 0.575-5.036), p=0.34). The combined profiles resulted in 2) a significant prediction for up to 3 years from surgery (HR=0.143 (95% CI:0.038-0.542), p=0.004, scored as a continuous covariate). A multivariate model adjusting for stage showed that the predictor remained significant (HR=0.123 (95% CI:0.030-0.512), p=0.004).A pooled analysis of the two treated cohorts resulted in a significant prediction (HR=0.187, (95% CI:0.069-0.508), p=0.001) up to 3 years from surgery using a random effects model.

Conclusion
The combined profiles demonstrate that NSCLC patients who benefit from cisplatin and vinorelbine can be identified. The profiles did not discriminate patients in the untreated arm. This holds promise for a predictive effect of the profiles and it is currently being validated in a prospective study [4].

[1] PLoS ONE 2016, 11(2): e0148070. [2] Zhu et al JCO 2010;28:4417-4424. [3] ASCO 2016 abstract e20007.

[4] AACR 2016 Abstract CT154.

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