Page 36 - Read Online

damage signatures at the genetic level, presumably as a Exome sequencing studies performed on small numbers of
result of UV exposure. [114,115] formalin-fixed, paraffin-embedded MCC samples and also
identified RB1 in MCPyV negative tumors. [135] Another
MCC is highly metastatic and the 5 year survival rate small study conducted on 4 MCPyV positive tumors
is dependent on the stage at which original diagnosis is identified somatic mutations in PDE4DIP, as well as genes
made. Patients with local disease at diagnosis have a 5 within the DNA damage response (PRKDC, AURKB,
year OS of 63-87%, those with regional nodal involvement ERCC5, ATR and ATRX) and epigenetic modifying
39-42% and 0-18% for patients with widespread, distant enzymes (MLL3). [136] Harms et al. [115] performed a slightly
metastases. [116] The annual incidence of MCC in the US larger study of whole exome sequencing of 9 MCPyV
is increasing, with an estimated 1,600 patients diagnosed negative and 7 MCPyV positive MCC samples. Known
per year. [117] The increase in incidence is attributed to mutations were identified in TP53, RB1 and PIK3CA
population aging, more known risk factors associated with along with novel activating mutations in oncogenes
this cancer (such as increased aggregate sun exposure), like HRAS, loss-of-function mutations in PRUNE2 and
and increased diagnostic power with cytokeratin 20 NOTCH family genes, and mutations disrupting the PI3K
immunohistochemical staining, which is positive in 88- signaling pathway in the MCPyV negative tumors. [115,137]
100% of MCC cases. [118] Further, the MCPyV negative tumors also had a higher
overall mutational burden and were characterized by a
There are no FDA-approved agents for the treatment prominent UV-signature pattern with C > T transitions
of MCC, nor are there established, standard of care making up 85% of the mutations. MCPyV positive tumors
chemotherapy regimens. [109] Current first line therapies had a much lower mutational burden and were lacking the
for localized disease include surgical resection followed UV signature, suggesting that MCPyV negative tumors
by postoperative radiation therapy. Radiotherapy plays have increased susceptibility to UV damage. [115] The most
a significant role in both the curative setting, and comprehensive study to date included exome sequencing
palliative care setting when used as a monotherapy in of 49 MCC samples (21 positive, 27 negative). [114] This
advanced metastatic MCC. [119] Systemic chemotherapy study confirmed the previous report that the signature of
regimens used for SCLC are employed and typically MCPyV negative tumors is very different than the MCPyV
include a combination of a platinum agent (cisplatin or positive tumors. MCPyV negative tumors have a higher
carboplatin) and topoisomerase inhibitor (etoposide) [120-122] mutation burden, frequent mutations in TP53 and RB1
or combination cyclophosphamide, doxorubicin and and additional mutations in genes involved in chromatin
vincristine therapy (CAV therapy). [122] Cytotoxic modification (ASXL1, MLL2 and MLL3) and DNA damage
chemotherapies do not produce durable responses and pathways (ATM, MSH2, BRCA1). Interestingly, both
are associated with significant toxicity, highlighting MCPyV positive and negative tumors have mutations
the need for targeted, mechanism-based therapies. predicted to activate the PI3K pathway (HRAS, KRAS,
Immunohistochemical analysis of MCC tumors has led PIK3CA, PTEN and TSC1) and to inactivate the Notch
to development and use of several new mechanism-based signaling pathway (Notch1, Notch2), [114] suggesting these
therapies including SSAs (octreotide, lanreotide), [123,124] pathways as putative points for intervention in MCC
pan-receptor tyrosine kinase inhibitors (pazopanib), [125] regardless of viral status.
PI3K inhibitors, [126,127] vitamin D receptor agonists, [128]
small molecules to downregulate Survivin, [129,130] anti- As discussed for SCLC and enteropancreatic NETs, another
PD-L1 antibody therapy, [131] and an antibody conjugate possible point of intervention is by targeting cancer stem
linking a maytansinoid microtubule assembly inhibitor to cells. However, in the case of MCC, the cell of origin is
CD56 (lorvotuzumab mertansine). [132] Many of these are still under debate. Based on early observation of MCC and
now in clinical trials for MCC and an excellent review of the similarity of expression patterns for neuroendocrine
future potential therapeutic options and current clinical and epithelial markers, it was presumed that MCCs arise
trials for MCC can be found in ref. [118] from the Merkel cell, part of the somatosensory system
located within the basal epidermis. However, with the
In addition to immunohistochemistry, genomic studies observations that Merkel cells and MCC are found in
have also been applied to MCC to identify new therapeutic different regions of the skin and exhibit differential
targets and understand the mechanism of tumorigenesis expression of marker proteins, new data are challenging the
in both MCPyV positive and negative cases. Gene panel concept that MCCs arise from Merkel cells. [138] One theory,
studies on 15 MCPyV negative and 12 MCPyV positive based on pathologic diagnosis of MCC suggests a role for
MCC samples identified mutations in TP53, KIT, PIK3CA pluripotent stem cells in the dermis as the cells of origin,
and EGFR genes, with RB1 mutations only identified facilitated by UV irradiation and MCPyV infection. [139]
in the virus negative samples, suggesting that the Another study proposes that MCCs arise from pro/pre-B or
dysregulation of the RB pathway may be a critical step pre-B cells based on terminal deoxynucleotidyl transferase
in tumorigenesis. [133] Targeted sequencing of 17 MCC and PAX5 expression, as well as the preference for
patient samples with unknown virus status, identified polyomaviruses to preferentially infect undifferentiated
mutations in TP53, RB and NOTCH1, among others. [134] stem cells or progenitor cells. [140] However, in the absence
Journal of Cancer Metastasis and Treatment ¦ Volume 2 ¦ August 17, 2016 ¦ 285