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Page 266 de Kouchkovsky et al. J Transl Genet Genom 2021;5:265-77 https://dx.doi.org/10.20517/jtgg.2021.32

INTRODUCTION
Although novel androgen receptor (AR) targeted therapies have contributed to a recent decline in prostate
[1]
cancer (PC) mortality , metastatic castration-resistant prostate cancer (mCRPC) remains a lethal disease
with over 30,000 yearly deaths in the United States alone . While most cases of PC initially respond to AR-
[2]
targeted therapies, prolonged treatment invariably leads to the development of castration-resistant disease.
Resistance to AR-targeted therapy can arise in the setting of upregulated AR signaling, often driven by
genomic alterations of the AR gene, enhancer, or co-activators. Lineage plasticity constitutes a distinct
mechanism of resistance to AR-targeted therapy, whereby selective treatment pressure induces a phenotypic
switch from an AR-driven adenocarcinoma to an AR-independent variant - morphologically similar to the
rare but highly aggressive de novo small cell prostate cancer. This treatment-emergent variant can present as
pure or mixed small cell carcinoma and has been variously labeled neuroendocrine or aggressive variant
[4]
[3]
prostate cancer. We refer to this entity as “treatment-associated small cell neuroendocrine prostate cancer”
or t-SCNC, recognizing both its similarity to de novo small cell prostate cancer and its emergence following
AR targeted therapy.

t-SCNC is an aggressive PC variant characterized by increased resistance to conventional AR-targeted
therapies . The optimal treatment of t-SCNC has not been established, and although platinum-based
[5]
chemotherapy regimens are commonly used, treatment responses are typically short-lived, and prognosis
remains poor . Recent advances in our understanding of the genomic and epigenetic features of t-SCNC
[4,6]
have improved our ability to identify patients with t-SCNC while simultaneously bringing into focus a
spectrum of aggressive tumor phenotypes with varying levels of AR independence and neuroendocrine
differentiation. In addition, improved characterization of the underlying molecular drivers of t-SCNC has
also helped to identify potential therapeutic targets in a disease with otherwise limited treatment options.

In this review, we explore the genomic, transcriptional, and epigenetic landscape of t-SCNC. We discuss
important genetic drivers of lineage plasticity and some of the mechanisms through which genomic
alterations and epigenetic reprogramming contribute to the emergence of t-SCNC. Finally, we review how
recent advances in our understanding of t-SCNC have contributed to the development of potential new
therapeutic strategies for this aggressive disease.

DIAGNOSIS AND CLINICAL FEATURES
Small cell neuroendocrine carcinoma (SCNC) of the prostate is rarely present at the time of initial diagnosis
(< 2% of all PC) and more commonly arises in patients with a history of prostatic adenocarcinoma and
[7]
prior antiandrogen therapy (i.e., t-SCNC) . Historically thought of as a rare PC variant , an analysis of
[10]
[8,9]
contemporary series suggests that t-SCNC occurs in as many as 20% of mCRPC patients . This rising
[11]
incidence may in part be due to the increasing and earlier use of more intensive AR-targeted therapies, but
also likely reflects an ascertainment bias as biopsies of metastatic disease become more common.
Traditionally, the diagnosis of SCNC has required the presence of small cell histology on biopsy, along with
low AR expression and positive staining for neuroendocrine markers such as chromogranin A or
synaptophysin. In more recent years, however, improved molecular profiling has led to the recognition of a
subset of patients with aggressive PC lacking small cell histology but with molecular and clinical features of
[12]
t-SCNC .

Clinically, t-SCNC is associated with significantly shorter survival and decreased response to AR-targeted
therapies [5,11] . Therefore, a high clinical index of suspicion and prompt initiation of chemotherapy is often
required to impact the natural history of this disease. Unfortunately, no single clinical feature can be used to
reliably distinguish t-SCNC patients from mCRPC patients with adenocarcinoma (hereafter referred to as