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An RNA-Based Digital Circulating Tumor Cell Signature Is Predictive of Drug Response and Early Dissemination in Prostate Cancer

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An RNA-Based Digital Circulating Tumor Cell Signature Is Predictive of Drug Response and Early Dissemination in Prostate Cancer Published OnlineFirst January 4, 2018; DOI: 10.1158/2159-8290.CD-16-1406 RESEARCH ARTICLE An RNA-Based Digital Circulating Tumor Cell Signature Is Predictive of Drug Response and Early Dissemination in Prostate Cancer David T. Miyamoto1,2, Richard J. Lee1,3, Mark Kalinich1, Joseph A. LiCausi1, Yu Zheng1, Tianqi Chen4, John D. Milner1, Erin Emmons1, Uyen Ho1, Katherine Broderick1, Erin Silva1, Sarah Javaid1, Tanya Todorova Kwan1, Xin Hong1, Douglas M. Dahl1,5, Francis J. McGovern1,5, Jason A. Efstathiou1,2, Matthew R. Smith1,3, Lecia V. Sequist1,3, Ravi Kapur1, Chin-Lee Wu1,6, Shannon L. Stott1,3,7, David T. Ting1,3, Anita Giobbie-Hurder4, Mehmet Toner7,8, Shyamala Maheswaran1,8, and Daniel A. Haber1,3,9 Downloaded from cancerdiscovery.aacrjournals.org on September 28, 2021. © 2018 American Association for Cancer Research. Published OnlineFirst January 4, 2018; DOI: 10.1158/2159-8290.CD-16-1406 Digital Expression Signatures of Prostate CTCs RESEARCH ARTICLE ABSTRACT Blood-based biomarkers are critical in metastatic prostate cancer, where charac- teristic bone metastases are not readily sampled, and they may enable risk strati- fication in localized disease. We established a sensitive and high-throughput strategy for analyzing prostate circulating tumor cells (CTC) using microfluidic cell enrichment followed by digital quantita- tion of prostate-derived transcripts. In a prospective study of 27 patients with metastatic castration- resistant prostate cancer treated with first-line abiraterone, pretreatment elevation of the digital CTCM score identifies a high-risk population with poor overall survival (HR= 6.0; P = 0.01) and short radiographic progression-free survival (HR = 3.2; P = 0.046). Expression of HOXB13 in CTCs identifies 6 of 6 patients with ≤12-month survival, with a subset also expressing the ARV7 splice variant. In a second cohort of 34 men with localized prostate cancer, an elevated preoperative CTCL score predicts microscopic dissemination to seminal vesicles and/or lymph nodes (P < 0.001). Thus, digital quantita- tion of CTC-specific transcripts enables noninvasive monitoring that may guide treatment selection in both metastatic and localized prostate cancer. SIGNIFICANCE: There is an unmet need for biomarkers to guide prostate cancer therapies, for curative treatment of localized cancer and for application of molecularly targeted agents in metastatic disease. Digital quantitation of prostate CTC-derived transcripts in blood specimens is predictive of abirater- one response in metastatic cancer and of early dissemination in localized cancer. Cancer Discov; 8(3); 1–16. ©2018 AACR. See related commentary by Heitzer and Speicher, p. 269. INTRODUCTION including potent suppressors of androgen synthesis (e.g., abiraterone), inhibitors of the androgen receptor (AR) itself The application of blood-based biomarkers is emerging as (e.g., enzalutamide), vaccine therapy (sipuleucel-T), cytotoxic an important strategy for individualizing therapeutic choices chemotherapy (docetaxel or cabazitaxel), bone-tropic radio- in prostate cancer in the settings of both metastatic and isotopes such as radium-223, and PARP inhibitors (4, 5). In localized disease. In advanced prostate cancer, typically char- this context, circulating tumor cell (CTC) quantitation has acterized by bone metastases that cannot be readily biopsied been proposed as a potential surrogate endpoint to facilitate for tumor sampling (1), multiple increasingly potent thera- the selection of treatment algorithms (6), although the small peutic regimens have been recently approved, resulting in a number of cells identified visually in blood specimens from pressing need for noninvasive tumor-specific predictors of patients with prostate cancer and the lack of specific molecular response (2, 3). In virtually all cases, metastatic prostate cancer determinants of response have limited its clinical utility (7). initially responds to androgen deprivation therapy (ADT), To date, most molecular alterations in prostate cancer which suppresses the primary driver of proliferation in this that have potential therapeutic implications have been cen- tissue. Responses, however, are limited in duration and the tered around the AR gene itself, including gene amplifica- development of metastatic castration-resistant prostate cancer tion or overexpression, activating mutations, or alterations (mCRPC) necessitates the application of alternative therapies, in transcriptional coactivators (8). Measuring AR signal- ing output through expression ratios of androgen-induced 1Massachusetts General Hospital Cancer Center, Boston, Massachusetts. versus androgen-repressed transcriptional targets has been 2Department of Radiation Oncology, Massachusetts General Hospital, Harvard proposed as an integrated readout for these complex AR Medical School, Boston, Massachusetts. 3Department of Medicine, Massa- pathway alterations (9). Multiple AR gene splicing variants chusetts General Hospital, Harvard Medical School, Boston, Massachusetts. encoding aberrant ligand-independent transcriptional acti- 4Department of Biostatistics & Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts. 5Department of Urology, Massachusetts vators have also been described in mCRPC (10). These AR General Hospital, Harvard Medical School, Boston, Massachusetts. 6Depart- isoforms are rarely expressed in primary prostate cancer, but ment of Pathology, Harvard Medical School, Boston, Massachusetts. 7Center they are readily detected in mCRPC, with single-cell RNA for Engineering in Medicine, Massachusetts General Hospital, Boston, sequencing (RNA-seq) of CTCs identifying multiple variants Massachusetts. 8Department of Surgery, Harvard Medical School, Boston, Massachusetts. 9Howard Hughes Medical Institute, Chevy Chase, Maryland. within different tumor cells from the same patient and even within individual CTCs (11). One of the most common vari- Note: Supplementary data for this article are available at Cancer Discovery Online (http://cancerdiscovery.aacrjournals.org/). ants, ARV7, is noteworthy in that it encodes a novel cryptic D.T. Miyamoto and R.J. Lee contributed equally to this article. exon, CE3, which may be detected using either CE3 exon- specific RNA-based PCR amplification or CE3 exon-targeted Corresponding Authors: Daniel A. Haber, Massachusetts General Hospital Cancer Center, Building 149, 13th Street, Boston, MA 02129. Phone: 617- IHC staining. In patients with mCRPC receiving AR-target- 726-7805; Fax: 161-7726-5637; E-mail: [email protected]; and ing therapies, detection of ARV7 in CTCs has been correlated Shyamala Maheswaran, [email protected] with a poor outcome (12–14). In addition to alterations in doi: 10.1158/2159-8290.CD-16-1406 AR signaling, additional pathways have been implicated ©2018 American Association for Cancer Research. in the progression toward androgen-independent disease, March 2018 CANCER DISCOVERY | OF2 Downloaded from cancerdiscovery.aacrjournals.org on September 28, 2021. © 2018 American Association for Cancer Research. Published OnlineFirst January 4, 2018; DOI: 10.1158/2159-8290.CD-16-1406 RESEARCH ARTICLE Miyamoto et al. including expression of the glucocorticoid receptor (15), digital PCR quantitation could provide a higher through- activation of the noncanonical WNT pathway (11), and evolu- put, more sensitive, and more specific readout of prostate tion of tumor cells toward a neuroendocrine phenotype (16). CTCs. We recently established such an assay for detection of In contrast to mCRPC, early-stage localized prostate cancer is liver-derived CTCs in patients with hepatocellular carcinoma often characterized by good prostate cancer–specific outcomes (28), and we reasoned that prostate-derived CTCs may also regardless of treatment modality, including radical prostatec- express specific transcripts that are unique to this tissue of tomy, radiotherapy, or active surveillance (17). However, a sub- origin and are undetectable in normal blood cells, even using set of patients is at high risk of tumor dissemination outside a highly sensitive digital PCR assay (Supplementary Fig. of the prostate gland, most often to the seminal vesicles and S1A). Microfluidic (CTC-iChip) depletion of hematopoietic pelvic lymph nodes, and eventually to bone. Standard clinico- cells from blood samples achieves 104 to 105 purification pathologic parameters including Gleason score, serum PSA, of CTCs, with approximately 500 white blood cells (WBC) and clinical T-stage (18, 19) and clinical nomograms (20, 21) remaining per 1 mL of initially processed whole blood (27). provide estimates for risk stratification, but they rely primarily The high quality of RNA within the purified CTCs allows on pathologic assessment of prostate core biopsies, which are the application of ddPCR, in which rare cDNA templates are subject to undersampling errors and often underestimate the encapsulated within lipid droplets, followed by PCR amplifi- true pathologic stage of the cancer (22, 23). Interestingly, CTCs cation and fluorescence scoring of positive droplets (29). The have been detected in the blood of a fraction of men with local- combination of initial microfluidic whole-cell enrichment ized prostate cancer, which are cleared within 24 hours of surgi- of CTCs from blood, followed by RNA-based digital PCR cal resection of the prostate, although the clinical significance of CTC-derived transcripts, thus allows exceptionally high- of these findings has not been established (24–26). sensitivity
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