Evaluation of Tumor Heterogeneity in Prostate Biopsy Samples
Arachchige PD, Carskadon S, Dhamdhere G, Diaz-Insua M, Craig R, Peabody J, Menon M, Williamson S, Gupta N, and Palanisamy N. Evaluation of Tumor Heterogeneity in Prostate Biopsy Samples. Cancer Res 2019; 79(13).
Prostate cancer (PCa) is the second most common cancer among men with more than 25,000 deaths each year. A significant number of PCa patients are known to present with multifocal disease characterized by the presence of more than one tumor nodule. Currently, management decisions for active surveillance are made based on the Gleason grade, tumor stage and volume on initial prostate biopsies. Although morphological heterogeneity has been well recognized, recent studies have revealed that PCa is a heterogeneous disease at the molecular level as well. Importantly, some molecular aberrations have been associated with aggressive disease and clinical outcomes, suggesting that tumor heterogeneity may be a determining factor in the success of active surveillance and other PCa management options. Therefore, we evaluated the incidence of several molecular markers on prostate biopsy samples to understand tumor molecular heterogeneity among PCa cases. A total of 626 biopsy cores were collected from 130 consecutive patients undergoing either standard or double sextant biopsies from July to October 2016 at our institute. Selected cores included benign (n=13), high grade intraepithelial neoplasia (HGPIN, n=124), atypical/ASAP (n=33) and Gleason grade 6-9 tissues (n=447). Of the 626, 119 cores included discontinuous (intervening benign tissue) tumor foci. The presence of the molecular markers, ERG, SPINK1, ETV1 and ETV4 was simultaneously evaluated using a novel, combined approach by dual Immunohistochemistry and RNA in situ hybridization. A total of 281 cores (44.9%) were positive for at least one molecular marker. Of these, ERG+ was more prominent (22.0%), followed by SPINK1+ (14.1%). The incidence of ETV1+ and ETV4+ was low (4.5% and 2.1%, respectively). 253 biopsy cores (56.6%) with Gleason 6-9 cancer were positive for at least one marker. Notably, only 12 cores (9.7%) of HGPIN were positive for any one of the markers while all benign cores were negative. Of note, 13 atypical/ASAP cores (39.4%) were positive for at least one marker, suggesting the potential use of molecular analysis to eliminate ambiguities associated with the diagnosis of cancer in atypical lesions. Of the 119 cores with discontinuous tumor foci, 14 (11.7%) dual marker positive with discordant marker status in each foci. Additionally, 99 cores (83.2%) showed the presence of a single marker either in one or both foci, further emphasizing the independent clonal origin and the presence of distinct driver molecular aberrations in different tumor foci in a subset of PCa cases. Finally, 345 of the 626 cores (55.1%) were negative for all the tested molecular markers indicating hitherto unidentified driver molecular aberrations. In conclusion, our study highlights the presence of significant tumor molecular heterogeneity identified in biopsy samples and emphasizes the importance of considering all tumor nodules in multi focal disease in making clinical decision on active surveillance.