Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on sleep in brain health

LIVE: Thursday 2nd May 2024, 18:00-19:30 (CEST)

Quality sleep is essential for health. But what happens to our brains when sleep patterns are disturbed? Join our experts to explore the interplay between sleep disruption and neurological diseases, and the questions that you need to be asking your patients to help you prevent the harmful effects of sleep deprivation.
ADVANCED SEARCH
Log in
Top
Journal of Hematology & Oncology
Published in: Journal of Hematology & Oncology 1/2015

Open Access 01-12-2015 | Case report

Comprehensive serial molecular profiling of an “N of 1” exceptional non-responder with metastatic prostate cancer progressing to small cell carcinoma on treatment

Authors: Kunal C. Kadakia, Scott A. Tomlins, Saagar K. Sanghvi, Andi K. Cani, Kei Omata, Daniel H. Hovelson, Chia-Jen Liu, Kathleen A. Cooney

Published in: Journal of Hematology & Oncology | Issue 1/2015

Login to get access

Abstract

Importance

Small cell carcinoma/neuroendocrine prostate cancer (NePC) is a lethal, poorly understood prostate cancer (PCa) subtype. Controversy exists about the origin of NePC in this setting.

Objective

To molecularly profile archived biopsy specimens from a case of early-onset PCa that rapidly progressed to NePC to identify drivers of the aggressive course and mechanisms of NePC origin and progression.

Design, setting, and participants

A 47-year-old patient presented with metastatic prostatic adenocarcinoma (Gleason score 9). After a 6-month response to androgen deprivation therapy, the patient developed jaundice and liver biopsy revealed exclusively NePC. Targeted next generation sequencing (NGS) from formalin-fixed paraffin-embedded (FFPE)-isolated DNA was performed from the diagnostic prostate biopsy and the liver biopsy at progression.

Intervention

Androgen deprivation therapy for adenocarcinoma followed by multiagent chemotherapy for NePC.

Main outcomes and measures

Identification of the mutational landscape in primary adenocarcinoma and NePC liver metastasis. Whether the NePC arose independently or was derived from the primary adenocarcinoma was considered based on mutational profiles.

Results

A deleterious somatic SMAD4 L535fs variant was present in both prostate and liver specimens; however, a TP53 R282W mutation was exclusively enriched in the liver specimen. Copy number analysis identified concordant, low-level alterations in both specimens, with focal MYCL amplification and homozygous PTEN, RB1, and MAP2K4 losses identified exclusively in the NePC specimen. Integration with published genomic profiles identified MYCL as a recurrently amplified in NePC.

Conclusions and relevance

NGS of routine biopsy samples from an exceptional non-responder identified SMAD4 as a driver of the aggressive course and supports derivation of NePC from primary adenocarcinoma (transdifferentiation).
Appendix
Available only for authorised users
Literature
1.
Al-Ahmadie H, Iyer G, Hohl M, Asthana S, Inagaki A, Schultz N, et al. Synthetic lethality in ATM-deficient RAD50-mutant tumors underlies outlier response to cancer therapy. Cancer Discov. 2014;4(9):1014–21.PubMedCentralCrossRefPubMed
2.
3.
Iyer G, Hanrahan AJ, Milowsky MI, Al-Ahmadie H, Scott SN, Janakiraman M, et al. Genome sequencing identifies a basis for everolimus sensitivity. Science. 2012;338(6104):221.PubMedCentralCrossRefPubMed
4.
Subbiah IM, Subbiah V. Exceptional responders: in search of the science behind the miracle cancer cures. Future Oncol. 2015;11(1):1–4.CrossRefPubMed
5.
Grasso C, Butler T, Rhodes K, Quist M, Neff TL, Moore S, et al. Assessing copy number alterations in targeted, amplicon-based next-generation sequencing data. J Mol Diagn. 2015;17(1):53–63.CrossRefPubMed
6.
Warrick JI, Hovelson DH, Amin A, Liu CJ, Cani AK, McDaniel AS, et al. Tumor evolution and progression in multifocal and paired non-invasive/invasive urothelial carcinoma. Virchows Arch. 2015;466(3):297–311.CrossRefPubMed
7.
Hovelson DH, McDaniel AS, Cani AK, Johnson B, Rhodes K, Williams PD, et al. Development and validation of a scalable next-generation sequencing system for assessing relevant somatic variants in solid tumors. Neoplasia. 2015;17(4):385–99.PubMedCentralCrossRefPubMed
8.
Shah RB, Mehra R, Chinnaiyan AM, Shen R, Ghosh D, Zhou M, et al. Androgen-independent prostate cancer is a heterogeneous group of diseases: lessons from a rapid autopsy program. Cancer Res. 2004;64(24):9209–16.CrossRefPubMed
9.
Deorah S, Rao MB, Raman R, Gaitonde K, Donovan JF. Survival of patients with small cell carcinoma of the prostate during 1973–2003: a population-based study. BJU Int. 2012;109(6):824–30.CrossRefPubMed
10.
Yashi M, Terauchi F, Nukui A, Ochi M, Yuzawa M, Hara Y, et al. Small-cell neuroendocrine carcinoma as a variant form of prostate cancer recurrence: a case report and short literature review. Urol Oncol. 2006;24(4):313–7.CrossRefPubMed
11.
Tanaka M, Suzuki Y, Takaoka K, Suzuki N, Murakami S, Matsuzaki O, et al. Progression of prostate cancer to neuroendocrine cell tumor. Int J Urol. 2001;8(8):431–6. discussion 437.CrossRefPubMed
12.
13.
Williamson SR, Zhang S, Yao JL, Huang J, Lopez-Beltran A, Shen S, et al. ERG-TMPRSS2 rearrangement is shared by concurrent prostatic adenocarcinoma and prostatic small cell carcinoma and absent in small cell carcinoma of the urinary bladder: evidence supporting monoclonal origin. Mod Pathol. 2011;24(8):1120–7.PubMedCentralCrossRefPubMed
14.
Han B, Mehra R, Suleman K, Tomlins SA, Wang L, Singhal N, et al. Characterization of ETS gene aberrations in select histologic variants of prostate carcinoma. Mod Pathol. 2009;22(9):1176–85.PubMedCentralCrossRefPubMed
15.
Lotan TL, Gupta NS, Wang W, Toubaji A, Haffner MC, Chaux A, et al. ERG gene rearrangements are common in prostatic small cell carcinomas. Mod Pathol. 2011;24(6):820–8.PubMedCentralCrossRefPubMed
16.
Hansel DE, Nakayama M, Luo J, Abukhdeir AM, Park BH, Bieberich CJ, et al. Shared TP53 gene mutation in morphologically and phenotypically distinct concurrent primary small cell neuroendocrine carcinoma and adenocarcinoma of the prostate. Prostate. 2009;69(6):603–9.PubMedCentralCrossRefPubMed
17.
Beltran H, Rickman DS, Park K, Chae SS, Sboner A, MacDonald TY, et al. Molecular characterization of neuroendocrine prostate cancer and identification of new drug targets. Cancer Discov. 2011;1(6):487–95.PubMedCentralCrossRefPubMed
18.
Lapuk AV, Wu C, Wyatt AW, McPherson A, McConeghy BJ, Brahmbhatt S, et al. From sequence to molecular pathology, and a mechanism driving the neuroendocrine phenotype in prostate cancer. J Pathol. 2012;227(3):286–97.PubMedCentralCrossRefPubMed
19.
Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2012;2(5):401–4.CrossRefPubMed
20.
De Bosscher K, Hill CS, Nicolas FJ. Molecular and functional consequences of Smad4 C-terminal missense mutations in colorectal tumour cells. Biochem J. 2004;379(Pt 1):209–16.PubMedCentralCrossRefPubMed
21.
Maurice D, Pierreux CE, Howell M, Wilentz RE, Owen MJ, Hill CS. Loss of Smad4 function in pancreatic tumors: C-terminal truncation leads to decreased stability. J Biol Chem. 2001;276(46):43175–81.CrossRefPubMed
22.
Forbes SA, Beare D, Gunasekaran P, Leung K, Bindal N, Boutselakis H, et al. COSMIC: exploring the world's knowledge of somatic mutations in human cancer. Nucleic Acids Res. 2015;43(Database issue):D805–11.PubMedCentralCrossRefPubMed
23.
Ding Z, Wu CJ, Chu GC, Xiao Y, Ho D, Zhang J, et al. SMAD4-dependent barrier constrains prostate cancer growth and metastatic progression. Nature. 2011;470(7333):269–73.PubMedCentralCrossRefPubMed
24.
Tan HL, Sood A, Rahimi HA, Wang W, Gupta N, Hicks J, et al. Rb loss is characteristic of prostatic small cell neuroendocrine carcinoma. Clin Cancer Res. 2014;20(4):890–903.PubMedCentralCrossRefPubMed
25.
Chen H, Sun Y, Wu C, Magyar CE, Li X, Cheng L, et al. Pathogenesis of prostatic small cell carcinoma involves the inactivation of the P53 pathway. Endocr Relat Cancer. 2012;19(3):321–31.PubMedCentralCrossRefPubMed
26.
Grasso CS, Cani AK, Hovelson DH, Quist MJ, Douville NJ, Yadati V, et al. Integrative molecular profiling of routine clinical prostate cancer specimens. Ann Oncol. 2015;26(6):1110–8.CrossRefPubMed
27.
Pavese JM, Ogden IM, Voll EA, Huang X, Xu L, Jovanovic B, et al. Mitogen-activated protein kinase kinase 4 (MAP2K4) promotes human prostate cancer metastasis. PLoS One. 2014;9(7):e102289.PubMedCentralCrossRefPubMed
28.
Kim HL, Vander Griend DJ, Yang X, Benson DA, Dubauskas Z, Yoshida BA, et al. Mitogen-activated protein kinase kinase 4 metastasis suppressor gene expression is inversely related to histological pattern in advancing human prostatic cancers. Cancer Res. 2001;61(7):2833–7.PubMed
29.
Yoshida BA, Dubauskas Z, Chekmareva MA, Christiano TR, Stadler WM, Rinker-Schaeffer CW. Mitogen-activated protein kinase kinase 4/stress-activated protein/Erk kinase 1 (MKK4/SEK1), a prostate cancer metastasis suppressor gene encoded by human chromosome 17. Cancer Res. 1999;59(21):5483–7.PubMed
30.
Boutros PC, Fraser M, Harding NJ, de Borja R, Trudel D, Lalonde E, et al. Spatial genomic heterogeneity within localized, multifocal prostate cancer. Nat Genet. 2015;47(7):736–45.CrossRefPubMed
31.
Zhou Z, Flesken-Nikitin A, Corney DC, Wang W, Goodrich DW, Roy-Burman P, et al. Synergy of p53 and Rb deficiency in a conditional mouse model for metastatic prostate cancer. Cancer Res. 2006;66(16):7889–98.CrossRefPubMed
32.
Peifer M, Fernandez-Cuesta L, Sos ML, George J, Seidel D, Kasper LH, et al. Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer. Nat Genet. 2012;44(10):1104–10.CrossRefPubMed
33.
Rudin CM, Durinck S, Stawiski EW, Poirier JT, Modrusan Z, Shames DS, et al. Comprehensive genomic analysis identifies SOX2 as a frequently amplified gene in small-cell lung cancer. Nat Genet. 2012;44(10):1111–6.PubMedCentralCrossRefPubMed
34.
Varghese AM, Zakowski MF, Yu HA, Won HH, Riely GJ, Krug LM, et al. Small-cell lung cancers in patients who never smoked cigarettes. J Thorac Oncol. 2014;9(6):892–6.PubMedCentralCrossRefPubMed
35.
Nieto MA. Epithelial plasticity: a common theme in embryonic and cancer cells. Science. 2013;342(6159):1234850.CrossRefPubMed
36.
Nordin A, Wang W, Welen K, Damber JE. Midkine is associated with neuroendocrine differentiation in castration-resistant prostate cancer. Prostate. 2013;73(6):657–67.CrossRefPubMed
37.
Terry S, Maille P, Baaddi H, Kheuang L, Soyeux P, Nicolaiew N, et al. Cross modulation between the androgen receptor axis and protocadherin-PC in mediating neuroendocrine transdifferentiation and therapeutic resistance of prostate cancer. Neoplasia. 2013;15(7):761–72.PubMedCentralCrossRefPubMed
38.
Cerasuolo M, Paris D, Iannotti FA, Melck D, Verde R, Mazzarella E, et al. Neuroendocrine transdifferentiation in human prostate cancer cells: an integrated approach. Cancer Res. 2015;75(15):2975–86.CrossRefPubMed
39.
Leshem O, Madar S, Kogan-Sakin I, Kamer I, Goldstein I, Brosh R, et al. TMPRSS2/ERG promotes epithelial to mesenchymal transition through the ZEB1/ZEB2 axis in a prostate cancer model. PLoS One. 2011;6(7):e21650.PubMedCentralCrossRefPubMed
40.
41.
Stoehr R, Taubert H, Zinnall U, Giedl J, Gaisa NT, Burger M, et al. Frequency of TERT promoter mutations in prostate cancer. Pathobiology. 2015;82(2):53–7.CrossRefPubMed
42.
Zheng X, Zhuge J, Bezerra SM, Faraj SF, Munari E, Fallon JT, 3rd, et al. High frequency of TERT promoter mutation in small cell carcinoma of bladder, but not in small cell carcinoma of other origins. J Hematol Oncol. 2014;7:47.
43.
44.
Arcaro A. Targeted therapies for small cell lung cancer: Where do we stand? Crit Rev Oncol Hematol. 2015;95(2):154–64.CrossRefPubMed
45.
Ehrlich D, Wang B, Lu W, Dowling P, Yuan R. Intratumoral anti-HuD immunotoxin therapy for small cell lung cancer and neuroblastoma. J Hematol Oncol. 2014;7(1):91.PubMedCentralCrossRefPubMed
46.
47.
Wang S, Sun W, Zhao Y, McEachern D, Meaux I, Barriere C, et al. SAR405838: an optimized inhibitor of MDM2-p53 interaction that induces complete and durable tumor regression. Cancer Res. 2014;74(20):5855–65.CrossRefPubMed
48.
49.
Subbiah V, Naing A, Brown RE, Chen H, Doyle L, LoRusso P, et al. Targeted morphoproteomic profiling of Ewing's sarcoma treated with insulin-like growth factor 1 receptor (IGF1R) inhibitors: response/resistance signatures. PLoS One. 2011;6(4):e18424.PubMedCentralCrossRefPubMed
50.
Haffner MC, Mosbruger T, Esopi DM, Fedor H, Heaphy CM, Walker DA, et al. Tracking the clonal origin of lethal prostate cancer. J Clin Invest. 2013;123(11):4918–22.PubMedCentralCrossRefPubMed
Metadata
Title
Comprehensive serial molecular profiling of an “N of 1” exceptional non-responder with metastatic prostate cancer progressing to small cell carcinoma on treatment
Authors
Kunal C. Kadakia
Scott A. Tomlins
Saagar K. Sanghvi
Andi K. Cani
Kei Omata
Daniel H. Hovelson
Chia-Jen Liu
Kathleen A. Cooney
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Journal of Hematology & Oncology / Issue 1/2015
Electronic ISSN: 1756-8722
DOI
https://doi.org/10.1186/s13045-015-0204-7

Other articles of this Issue 1/2015

Journal of Hematology & Oncology 1/2015 Go to the issue

Review

Competing endogenous RNA networks: tying the essential knots for cancer biology and therapeutics

Review

Role of DNA methylation in renal cell carcinoma

Research highlight

Palbociclib: a first-in-class CDK4/CDK6 inhibitor for the treatment of hormone-receptor positive advanced breast cancer

Research

Deep sequencing and SNP array analyses of pediatric T-cell acute lymphoblastic leukemia reveal NOTCH1 mutations in minor subclones and a high incidence of uniparental isodisomies affecting CDKN2A

Erratum

Erratum to: The serum CXCL13 level is associated with the Glasgow Prognostic Score in extranodal NK/T-cell lymphoma patients

Review

Targeting neoplastic B cells and harnessing microenvironment: the “double face” of ibrutinib and idelalisib
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits