Neuroendocrine differentiation in prostate cancer: Novel morphological insights and future therapeutic perspectives

Biochimica et Biophysica Acta - Reviews on Cancer

Volumn 1846, Issue 2, 2014, Pages 630-637

  Santoni, Matteo ^a   Conti, Alessandro ^a   Burattini, Luciano ^a   Berardi, Rossana ^a   Scarpelli, Marina ^a   Cheng, Liang ^b   Lopez Beltran, Antonio ^c,d   Cascinu, Stefano ^a   Montironi, Rodolfo ^a  

^a UNIVERSITÀ POLITECNICA DELLE MARCHE   (Italy)

^b INDIANA UNIVERSITY SCHOOL OF MEDICINE   (United States)

^c Universidad de Cordoba   (Spain)

^d CHAMPALIMAUD FOUNDATION   (Portugal)

Author keywords

Androgen deprivation therapy; Carcinoid; Drug resistance; Large cell neuroendocrine carcinoma; Neuroendocrine prostate cancer; Small cell carcinoma

Indexed keywords

ANGIOGENESIS INHIBITOR; CYTOKERATIN 14; CYTOKERATIN 5; INTERLEUKIN 6; MIGRATION INHIBITION FACTOR; PHOSPHATIDYLINOSITOL 3 KINASE; PLATINUM COMPLEX; PROSTATE SPECIFIC MEMBRANE ANTIGEN; PROTEIN KINASE B; PROTEIN P53; SOMATOMEDIN C RECEPTOR; AURKA PROTEIN, HUMAN; AURORA A KINASE;

ACINAR ADENOCARCINOMA; ANDROGEN DEPRIVATION THERAPY; AURKA GENE; AUTOPHAGY; BASAL CELL; CANCER CLASSIFICATION; CANCER PROGNOSIS; CANCER THERAPY; CARCINOGENESIS; CARCINOID; CASTRATION RESISTANT PROSTATE CANCER; CELL DIFFERENTIATION; CELL TYPE; CIRCULATING TUMOR CELL; ERG GENE; HUMAN; IMMUNOHISTOCHEMISTRY; INFLAMMATION; LARGE CELL NEUROENDOCRINE CARCINOMA; LUMINAL CELL; METASTASIS POTENTIAL; MIXED NEUROENDOCRINE CARCINOMA; MOLECULAR BIOLOGY; MYCN GENE; NEUROENDOCRINE PROSTATE CANCER; NEUROENDOCRINE TUMOR; NEUROSECRETORY CELL; NKX3.1 GENE; NONHUMAN; PANETH CELL; PROSTATE CANCER; RB1 GENE; REVIEW; SMALL CELL CARCINOMA; TMPRSS2 ERG GENE; TMPRSS2 GENE; TP53 GENE; CYTOLOGY; DRUG RESISTANCE; MALE; PATHOLOGY; PHYSIOLOGY; PROSTATIC NEOPLASMS; TUMOR EMBOLISM;

ANGIOGENESIS INHIBITORS; AURORA KINASE A; AUTOPHAGY; CARCINOGENESIS; CELL DIFFERENTIATION; DRUG RESISTANCE, NEOPLASM; HUMANS; MALE; NEOPLASTIC CELLS, CIRCULATING; NEUROENDOCRINE CELLS; PROSTATIC NEOPLASMS;

EID: 84909579126     PISSN: 0304419X     EISSN: 18792561     Source Type: Journal    
DOI: 10.1016/j.bbcan.2014.10.008     Document Type: Review

References (81)

1. Pienta K.J., Bradley D. Mechanisms underlying the development of androgen-independent prostate cancer. Clin. Cancer Res. 2006, 12:1665-1671.
2. Komiya A., Yasuda K., Watanabe A., Fujiuchi Y., Tsuzuki T., Fuse H. The prognostic significance of loss of the androgen receptor and neuroendocrine differentiation in prostate biopsy specimens among castration-resistant prostate cancer patients. Mol. Clin. Oncol. 2013, 1:257-262.
3. di Sant'Agnese P.A. Neuroendocrine differentiation in carcinoma of the prostate: diagnostic, prognostic, and therapeutic implications. Cancer 1992, 70:254-268.
4. Komiya A., Yasuda K., Watanabe A., Fujiuchi Y., Tsuzuki T., Fuse H. The prognostic significance of loss of the androgen receptor and neuroendocrine differentiation in prostate biopsy specimens among castration-resistant prostate cancer patients. Mol Clin Oncol. 2013, 1(2):257-262.
5. Bostwick D.G., Qian J., Pacelli A., et al. Neuroendocrine expression in node positive prostate cancer: correlation with systemic progression and patient survival. J. Urol. 2002, 168:1204-1211.
6. Theodorescu D., Broder S.R., Boyd J.C., et al. Cathepsin D and chromogranin A as predictors of long term disease specific survival after radical prostatectomy for localized carcinoma of the prostate. Cancer 1997, 80:2109-2119.
7. Weinstein M.H., Partin A.W., Veltri R.W., et al. Neuroendocrine differentiation in prostate cancer: enhanced prediction of progression after radical prostatectomy. Hum. Pathol. 1996, 27:683-687.
8. Tarle M., Ahel M.Z., Kovacić K. Acquired neuroendocrine-positivity during maximal androgen blockade in prostate cancer patients. Anticancer Res. 2002, 22:2525-2529.
9. Berruti A., Dogliotti L., Mosca A., et al. Effects of the somatostatin analog lanreotide on the circulating levels of chromogranin-A, prostate-specific antigen, and insulin-like growth factor-1 in advanced prostate cancer patients. Prostate 2001, 47:205-211.
10. Ousset M., Van Keymeulen A., Bouvencourt G., et al. Multipotent and unipotent progenitors contribute to prostate postnatal development. Nat. Cell Biol. 2012, 14:1131-1138.
11. Pignon J.C., Grisanzio C., Geng Y., Song J., Shivdasani R.A., Signoretti S. p63-expressing cells are the stem cells of developing prostate, bladder, and colorectal epithelia. Proc. Natl. Acad. Sci. U. S. A. 2013, 110:8105-8110.
12. Kim Y., Nirenberg M. Drosophila NK-homeobox genes. Proc. Natl. Acad. Sci. U. S. A. 1989, 86:7716-7720.
13. Abate-Shen C., Shen M.M., Gelmann E. Integrating differentiation and cancer: the Nkx3.1 homeobox gene in prostate organogenesis and carcinogenesis. Differentiation 2008, 76:717-727.
14. Chen H., Mutton L.N., Prins G.S., Bieberich C.J. Distinct regulatory elements mediate the dynamic expression pattern of Nkx3.1. Dev. Dyn. 2005, 234:961-973.
15. Sciavolino P.J., Abrams E.W., Yang L., Austenberg L.P., Shen M.M., Abate-Shen C. Tissue-specific expression of murine Nkx3.1 in the male urogenital system. Dev. Dyn. 1997, 209:127-138.
16. Bieberich C.J., Fujita K., He W.-W., Jay G. Prostate-specific and androgen dependent expression of a novel homeobox gene. J. Biol. Chem. 1996, 271:31779-31782.
17. Wang X., Kruithof-de Julio M., Economides K.D., Walker D., Yu H., Halili M.V., Hu Y.P., Price S.M., Abate-Shen C., Shen M.M. A luminal epithelial stem cell that is a cell of origin for prostate cancer. Nature 2009, 461:495-500.
18. Wang Z.A., Mitrofanova A., Bergren S.K., et al. Lineage analysis of basal epithelial cells reveals their unexpected plasticity and supports a cell-of-origin model for prostate cancer heterogeneity. Nat. Cell Biol. 2013, 15:274-283.
19. DaSilva J.O., Amorino G.P., Casarez E.V., Pemberton B., Parsons S.J. Neuroendocrine-derived peptides promote prostate cancer cell survival through activation of IGF-1R signaling. Prostate 2013, 73:801-812.
20. Tawadros T., Alonso F., Jichlinski P., Clarke N., Calandra T., Haefliger J.A., Roger T. Release of macrophage migration inhibitory factor by neuroendocrine-differentiated LNCaP cells sustains the proliferation and survival of prostate cancer cells. Endocr. Relat. Cancer 2013, 20(1):137-149.
21. Beltran H., Tomlins S., Aparicio A., Arora V., Rickman D., Ayala G., Huang J., True L., Gleave M.E., Soule H., Logothetis C., Rubin M.A. Aggressive variants of castration-resistant prostate cancer. Clin. Cancer Res. 2014, 20:2846-2850.
22. Zhou Z., Flesken-Nikitin A., Corney D.C., Wang W., Goodrich D.W., Roy-Burman P., et al. Synergy of p53 and Rb deficiency in a conditional mouse model for metastatic prostate cancer. Cancer Res. 2006, 66:7889-7898.
23. Chiaverotti T., Couto S.S., Donjacour A., Mao J.H., Nagase H., Cardiff R.D., et al. Dissociation of epithelial and neuroendocrine carcinoma lineages in the transgenic adenocarcinoma of mouse prostate model of prostate cancer. Am. J. Pathol. 2008, 172:236-246.
24. Beltran H., Rickman D.S., Park K., Chae S.S., Sboner A., MacDonald T.Y., et al. Molecular characterization of neuroendocrine prostate cancer and identification of new drug targets. Cancer Discov. 2011, 1:487-495.
25. Coulson J.M., Edgson J.L., Woll P.J., Quinn J.P. A splice variant of the neuron-restrictive silencer factor repressor is expressed in small cell lung cancer: a potential role in derepression of neuroendocrine genes and a useful clinical marker. Cancer Res. 2000, 60:1840-1844.
26. Epstein J.I., Amin M.B., Beltran H., Lotan T.L., Mosquera J.M., Reuter V.E., Robinson B.D., Troncoso P., Rubin M.A. Proposed morphologic classification of prostate cancer with neuroendocrine differentiation. Am. J. Surg. Pathol. 2014, 38:756-767.
27. Weaver M.G., Abdul-Karim F.W., Srigley J., et al. Paneth cell-like change of the prostate gland. A histological, immunohistochemical, and electron microscopic study. Am. J. Surg. Pathol. 1992, 16:62-68.
28. Adlakha H., Bostwick D.G. Paneth cell-like change in prostatic adenocarcinoma represents neuroendocrine differentiation: report of 30 cases. Hum. Pathol. 1994, 25(2):135-139.
29. Tamas E.F., Epstein J.I. Prognostic significance of paneth cell-like neuroendocrine differentiation in adenocarcinoma of the prostate. Am. J. Surg. Pathol. 2006, 30:980-985.
30. Sarbay B.C., Kir G., Topal C.S., Gumus E. Significance of the cribriform pattern in prostatic adenocarcinomas. Pathol. Res. Pract. 2014, (pii:S0344-0338(14)00090-9). 10.1016/j.prp.2014.03.003.
31. Murali R., Kneale K., Lalak N., Delprado W. Carcinoid tumors of the urinary tract and prostate. Arch. Pathol. Lab. Med. 2006, 130:1693-1706.
32. Reyes A., Moran C.A. Low-grade neuroendocrine carcinoma (carcinoid tumor) of the prostate. Arch. Pathol. Lab. Med. 2004, 128:e166-e168.
33. Ghali V.S., Garcia R.L. Prostatic adenocarcinoma with carcinoidal features producing adrenocorticotropic syndrome. Immunohistochemical study and review of the literature. Cancer 1984, 54:1043-1048.
34. Lipianskaya J., Cohen A., Chen C.J., Hsia E., Squires J., Li Z., Zhang Y., Li W., Chen X., Xu H., Huang J. Androgen-deprivation therapy-induced aggressive prostate cancer with neuroendocrine differentiation. Asian J. Androl. Feb 21 2014, 10.4103/1008-682X.123669.
35. Mazzucchelli R., Morichetti D., Lopez-Beltran A., Cheng L., Scarpelli M., Kirkali Z., Montironi R. Neuroendocrine tumours of the urinary system and male genital organs: clinical significance. BJU Int. 2009, 103:1464-1470.
36. Guo C.C., Dancer J.Y., Wang Y., et al. TMPRSS2-ERG gene fusion in small cell carcinoma of the prostate. Hum. Pathol. 2011, 42:11-17.
37. Lotan T.L., Gupta N.S., Wang W., et al. ERG gene rearrangements are common in prostatic small cell carcinomas. Mod. Pathol. 2011, 24:820-828.
38. Wang L., Williamson S.R., Zhang S., Huang J., Montironi R., Davison D.D., Wang M., Yao J.L., Lopez-Beltran A., Osunkoya A.O., Maclennan G.T., Baldridge L.A., Du X., Cheng L. Increased androgen receptor gene copy number is associated with TMPRSS2-ERG rearrangement in prostatic small cell carcinoma. Mol. Carcinog. 2014, 10.1002/mc.22162.
39. Tan H.L., Sood A., Rahimi H.A., Wang W., Gupta N., Hicks J., Mosier S., Gocke C.D., Epstein J.I., Netto G.J., Liu W., Isaacs W.B., De Marzo A.M., Lotan T.L. Rb loss is characteristic of prostatic small cell neuroendocrine carcinoma. Clin. Cancer Res. 2014, 20:890-903.
40. Macleod K.F. The RB, tumor suppressor: a gatekeeper to hormone independence in prostate cancer?. J. Clin. Invest. 2010, 120:4179-4182.
41. Chen H., Sun Y., Wu C., Magyar C.E., Li X., Cheng L., Yao J.L., Shen S., Osunkoya A.O., Liang C., Huang J. Pathogenesis of prostatic small cell carcinoma involves the inactivation of the P53 pathway. Endocr. Relat. Cancer 2012, 19:321-331.
42. Simon R.A., di Sant'agnese P.A., Huang L.S., et al. CD44 expression is a feature of prostatic small cell carcinoma and distinguishes it from its mimickers. Hum. Pathol. 2009, 40:252-258.
43. Deorah S., Rao M.B., Raman R., et al. Survival of patients with small cell carcinoma of the prostate during 1973-2003: a population based study. BJU Int. 2012, 109:824-830.
44. Rubenstein J.H., Katin M.J., Mangano M.M., et al. Small cell anaplastic carcinoma of the prostate: seven new cases, review of the literature, and discussion of a therapeutic strategy. Am. J. Clin. Oncol. 1997, 20:376-380.
45. Wang W., Epstein J.I. Small cell carcinoma of the prostate. A morphologic and immunohistochemical study of 95 cases. Am. J. Surg. Pathol. 2008, 32:65-71.
46. Amato R.J., Logothetis C.J., Hallinan R., et al. Chemotherapy for small cell carcinoma of prostatic origin. J. Urol. 1992, 147:935-937.
47. Ruscica M., Arvigo M., Gatto F., Dozio E., Feltrin D., Culler M.D., Minuto F., Motta M., Ferone D., Magni P. Regulation of prostate cancer cell proliferation by somatostatin receptor activation. Mol. Cell. Endocrinol. 2010, 315:254-262.
48. Aparicio A.M., Harzstark A.L., Corn P.G., et al. Platinum-based chemotherapy for variant castrate-resistant prostate cancer. Clin. Cancer Res. 2013, 19:3621-3630.
49. Mackey J.R., Au H.J., Hugh J., Venner P. Genitourinary small cell carcinoma: determination of clinical and therapeutic factors associated with survival. J. Urol. 1998, 159:1624-1629.
50. Evans A.J., Humphrey P.A., Belani J., van der Kwast T.H., Srigley J.R. Large cell neuroendocrine carcinoma of the prostate: a clinicopathologic summary of 7 cases of a rare manifestation of advanced prostate cancer. Am. J. Surg. Pathol. 2006, 30:684-693.
51. Friedlander T.W., Weinberg V.K., Small E.J., Sharib J., Harzstark A.L., Lin A.M., Fong L., Ryan C.J. Effect of the somatostatin analog octreotide acetate on circulating insulin-like growth factor-1 and related peptides in patients with non-metastatic castration-resistant prostate cancer: results of a phase II study. Urol. Oncol. 2012, 30:408-414.
52. Mitsiades C.S., Bogdanos J., Karamanolakis D., Milathianakis C., Dimopoulos T., Koutsilieris M. Randomized controlled clinical trial of a combination of somatostatin analog and dexamethasone plus zoledronate vs. zoledronate in patients with androgen ablation-refractory prostate cancer. Anticancer Res. 2006, 26:3693-3700.
53. Mazzucchelli R., Montironi R., Santinelli A., Lucarini G., Pugnaloni A., Biagini G. Vascular endothelial growth factor expression and capillary architecture in high-grade PIN and prostate cancer in untreated and androgen-ablated patients. Prostate 2000, 45:72-79.
54. Spiotto M.T., Chung T.D. STAT3 mediates IL-6-induced neuroendocrine differentiation in prostate cancer cells. Prostate 2000, 42:186-195.
55. Qiu Y., Robinson D., Pretlow T.G., Kung H.J. Etk/Bmx, a tyrosine kinase with a pleckstrin-homology domain, is an effector of phosphatidylinositol 3'-kinase and is involved in interleukin 6-induced neuroendocrine differentiation of prostate cancer cells. Proc. Natl. Acad. Sci. U. S. A. 1998, 95:3644-3649.
56. Xie S., Lin H.K., Ni J., Yang L., Wang L., et al. Regulation of interleukin-6-mediated PI3K activation and neuroendocrine differentiation by androgen signaling in prostate cancer LNCaP cells. Prostate 2004, 60:61-67.
57. Zhu Y., Liu C., Cui Y., Nadiminty N., Lou W., Gao A.C. Interleukin-6 induces neuroendocrine differentiation (NED) through suppression of RE-1 silencing transcription factor (REST). Prostate 2014, 10.1002/pros.22819.
58. Drachenberg D.E., Elgamal A.A., Rowbotham R., Peterson M., Murphy G.P. Circulating levels of interleukin-6 in patients with hormone refractory prostate cancer. Prostate 1999, 41:127-133.
59. Angevin E., Tabernero J., Elez E., et al. A phase I/II, Multiple-dose, dose escalation study of siltuximab, an anti-interleukin-6 monoclonal antibody, in patients with advanced solid tumors. Clin. Cancer Res. 2014, 20:2192-2204.
60. Delk N.A., Farach-Carson M.C. Interleukin-6: a bone marrow stromal cell paracrine signal that induces neuroendocrine differentiation and modulates autophagy in bone metastatic PCa cells. Autophagy 2012, 8:650-663.
61. Chang P.C., Wang T.Y., Chang Y.T., Chu C.Y., Lee C.L., Hsu H.W., Zhou T.A., Wu Z., Kim R.H., Desai S.J., Liu S., Kung H.J. Autophagy pathway is required for IL-6 induced neuroendocrine differentiation and chemoresistance of prostate cancer LNCaP cells. PLoS One 2014, 9:e88556.
62. Inoue K., Slaton J.W., Eve B.Y., Kim S.J., Perrotte P., Balbay M.D., Yano S., Bar-Eli M., Radinsky R., Pettaway C.A., Dinney C.P. Interleukin 8 expression regulates tumorigenicity and metastases in androgen-independent prostate cancer. Clin. Cancer Res. 2000, 6:2104-2119.
63. Veltri R.W., Miller M.C., Zhao G., Ng A., Marley G.M., Wright G.L., Vessella R.L., Ralph D. Interleukin-8 serum levels in patients with benign prostatic hyperplasia and prostate cancer. Urology 1999, 53:139-147.
64. Li Zhen, Chen Clark J., Wang Jason K., Hsia Elaine, Li Wei, Squires Jill, Sun Yin, Huang Jiaoti Neuroendocrine differentiation of prostate cancer. Asian J. Androl. 2013, 15:328-332.
65. Liu X., Peng J., Sun W., Yang S., Deng G., Li F., Cheng J.W., Gordon J.R. G31P, an antagonist against CXC chemokine receptors 1 and 2, inhibits growth of human prostate cancer cells in nude mice. Tohoku J. Exp. Med. 2012, 228:147-156.
66. Verjans E., Noetzel E., Bektas N., Schütz A.K., Lue H., Lennartz B., Hartmann A., Dahl E., Bernhagen J. Dual role of macrophage migration inhibitory factor (MIF) in human breast cancer. BMC Cancer 2009, 9:230.
67. Chen Y.C., Zhang X.W., Niu X.H., Xin D.Q., Zhao W.P., Na Y.Q., Mao Z.B. Macrophage migration inhibitory factor is a direct target of HBP1-mediated transcriptional repression that is overexpressed in prostate cancer. Oncogene 2010, 29:3067-3078.
68. Girard E., Strathdee C., Trueblood E., Quéva C. Macrophage migration inhibitory factor produced by the tumour stroma but not by tumour cells regulates angiogenesis in the B16-F10 melanoma model. Br. J. Cancer 2012, 107:1498-1505.
69. Tawadros T., Alonso F., Jichlinski P., Clarke N., Calandra T., Haefliger J.A., Roger T. Release of macrophage migration inhibitory factor by neuroendocrine-differentiated LNCaP cells sustains the proliferation and survival of prostate cancer cells. Endocr. Relat. Cancer 2013, 20:137-149.
70. Mosquera J.M., Beltran H., Park K., MacDonald T.Y., Robinson B.D., Tagawa S.T., Perner S., Bismar T.A., Erbersdobler A., Dhir R., Nelson J.B., Nanus D.M., Rubin M.A. Concurrent AURKA and MYCN gene amplifications are harbingers of lethal treatment-related neuroendocrine prostate cancer. Neoplasia 2013, 15:1-10.
71. Meulenbeld H.J., Bleuse J.P., Vinci E.M., Raymond E., Vitali G., Santoro A., Dogliotti L., Berardi R., Cappuzzo F., Tagawa S.T., Sternberg C.N., Jannuzzo M.G., Mariani M., Petroccione A., de Wit R. Randomized phase II study of danusertib in patients with metastatic castration-resistant prostate cancer after docetaxel failure. BJU Int. 2013, 111:44-52.
72. Albihn A., Johnsen J.I., Henriksson M.A. MYC in oncogenesis and as a target for cancer therapies. Adv. Cancer Res. 2010, 107:163-224.
73. Ghosh A., Heston W.D. Tumor target prostate specific membrane antigen (PSMA) and its regulation in prostate cancer. J. Cell. Biochem. 2004, 91:528-539.
74. Petrylak D.P., Smith D.C., Appleman L.J., Fleming M.T., Hussain A., Dreicer R., Sartor A.O., Shore N.D., Vogelzang N.J., Youssoufian H., DiPippo V.A., Stambler N., Huang K., Israel R.J. A phase 2 trial of prostate-specific membrane antigen antibody drug conjugate (PSMA ADC) in taxane-refractory metastatic castration-resistant prostate cancer (mCRPC). 2014 ASCO Annual Meeting 2014, (abstract 5023).
75. Kaur G., Singh B., Beltran H., Akhtar N.H., Nanus D.M., Tagawa S.T. Circulating tumor cell (CTC) enumeration in patients with metastatic neuroendocrine prostate cancer (NEPC) and castration-resistant prostate cancer (CRPC). J. Clin. Oncol. 2014, 32. (abstr 204).
76. Jiborn T., Bjartell A., Abrahamsson P.A. Neuroendocrine differentiation in prostatic carcinoma during hormonal treatment. Urology 1998, 51:585-9.
77. Terry S., Maillé P., Baaddi H., Kheuang L., Soyeux P., Nicolaiew N., Ceraline J., Firlej V., Beltran H., Allory Y., de la Taille A., Vacherot F. Cross modulation between the androgen receptor axis and protocadherin-PC in mediating neuroendocrine transdifferentiation and therapeutic resistance of prostate cancer. Neoplasia 2013, 15:761-772.
78. Hirano D., Hasegawa R., Satoh K., Mochida J., Yamanaka Y., Hirakata H., Yamaguchi K., Sugimoto S., Kawata N., Takahashi S. Prospective study on the relationship between clinical efficacy of secondary hormone therapy with flutamide and neuroendocrine differentiation in patients with relapsed prostate cancer after first line hormone therapy. Scand. J. Urol. 2014, 48(5):436-444.
79. Ferrari A.C., Liu X.-M., Alshalalfa M., Gomez-Pinillos A., Sierocinski T., Davicioni E. Effect of enzalutamide (EZ) exposure time on androgen receptor (AR) splice variant (SV) expression and gene transcription correlates in androgen-dependent (AD) prostate cancer (PC) cells. 2014 ASCO Annual Meeting 2014, (abstract e22066).
80. Perez D., Linares E., Almagro E., Cantos B., Mendez M., Maximiano C., Franco F., Rubio J., Palka M., Calvo V., Ramirez P., Salas C., Carballido J., Provencio M. Neuroendocrine differentiation in carcinoma of the prostate: an institutional review. 2014 ASCO Annual Meeting 2014, (abstract e16109).
81. Jimenez R.E., Nandy D., Qin R., Carlson R., Tan W., Kohli M. Neuroendocrine differentiation patterns in metastases from advanced prostate cancer. 2014 ASCO Annual Meeting 2014, (abstract 5085).