Intratumoral heterogeneity and chemoresistance in nonseminomatous germ cell tumor of the testis

// Mehmet Asim Bilen 1 , Kenneth R. Hess 2 , Matthew T. Campbell 3 , Jennifer Wang 3 , Russell R. Broaddus 4 , Jose A. Karam 5 , John F. Ward 5 , Christopher G. Wood 5 , Seungtaek L. Choi 6 , Priya Rao 4 , Miao Zhang 4 , Aung Naing 7 , Rosale General 3 , Diana H. Cauley 3 , Sue-Hwa Lin 8 , Christopher J. Logothetis 3 , Louis L. Pisters 5 , Shi-Ming Tu 3 1 Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA, USA 2 Department of Biostatistics the University of Texas MD Anderson Cancer Center, Houston, Texas, USA 3 Department of Genitourinary Medical Oncology the University of Texas MD Anderson Cancer Center, Houston, Texas, USA 4 Department of Pathology the University of Texas MD Anderson Cancer Center, Houston, Texas, USA 5 Department of Urology the University of Texas MD Anderson Cancer Center, Houston, Texas, USA 6 Department of Radiation Oncology the University of Texas MD Anderson Cancer Center, Houston, Texas, USA 7 Department of Investigational Cancer Therapeutics the University of Texas MD Anderson Cancer Center, Houston, Texas, USA 8 Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA Correspondence to: Shi-Ming Tu, email: stu@mdanderson.org Keywords: testicular cancer, intratumoral heterogeneity, chemoresistance, nonseminomatous germ cell tumor, next-generation sequencing Received: August 15, 2016 Accepted: November 07, 2016 Published: November 16, 2016 ABSTRACT Background: Nonseminomatous germ cell tumor of the testis (NSGCT) is largely curable. However, a small group of patients develop refractory disease. We investigated the hypothesis that intratumoral heterogeneity contributes to the emergence of chemoresistance and the development of refractory tumor subtypes. Results: Our institution’s records for January 2000 through December 2010 included 275 patients whose primary tumor showed pure embryonal carcinoma (pure E); mixed embryonal carcinoma, yolk sac tumor, and teratoma (EYT); or mixed embryonal carcinoma, yolk sac tumor, seminoma, and teratoma (EYST). Patients with EYST had the highest cancer-specific mortality rate ( P = .001). They tended to undergo somatic transformation ( P = .0007). Two of 5 patients with clinical stage I EYST who had developed recurrence during active surveillance died of their disease. Materials and Methods: In this retrospective study, we evaluated consecutive patients who had been diagnosed with the three most common histological phenotypes of NSGCT. Chemoresistance was defined as the presence of teratoma, viable germ cell tumor, or somatic transformation in the residual tumor or the development of progressive or relapsed disease after chemotherapy. In a separate prospective study, we performed next-generation sequencing on tumor samples from 39 patients to identify any actionable genetic mutations. Conclusions: Our data suggest that patients with EYST in their primary tumor may harbor a potentially refractory NSGCT phenotype and are at increased risk of dying from disease. Despite intratumoral heterogeneity, improved patient selection and personalized care of distinct tumor subtypes may optimize the clinical outcome of patients with NSGCT.