Blood Based Biomarkers for Melanoma

There are new promising pre-treatment blood based biomarkers coming from liquid
biopsies that can determine the possible effectiveness of anti-PD1 and/or anti-CTLA4 treatment
in melanoma. Only 50% of melanoma patients respond to anti-PD1 or anti-CTLA4 treatment so
having a prognostic biomarker would be extremely beneficial for improving clinical decisions.
One of the biomarkers that are being investigated is the “diversity evenness” of the T-cell
receptor (TCR) repertoire in pre-treatment peripheral blood mononuclear cells from melanoma
patients treated with anti-PD1 and/or anti-CTLA4. Here “diversity evenness” refers to ratio of
how many clonotypes amongst the most frequent in the liquid biopsy were necessary to account
for 50% of the total counts. This assessment is carried out by conducting a multi-N-plex PCR
assay on genomic DNA. The results of a study which investigated the evenness of the TCR
repertoire showed that samples with lower DE50 had longer progression free survival and good
responses to a PD-1 blockade, but at the same time predicted a poor response to CTLA4
inhibition. 1
Others studies have suggested that TGF-β1 and oxidative stress in the blood of patients
with melanoma could be used as a biomarker to predict melanoma progression. It well known
that TGF-β1 and oxidative stress are involved in many types of cancer progression but their role
in melanoma is still not well understood. On recent study found that lower levels of TGF-β1 in
the blood of patients with metastatic melanoma was correlated with oxidative stress, giving new
evidence that TGF-β1 acts as a tumor suppressor in melanoma and inhibits tumor relapse.2
Another study has identified free floating micro-RNAs (miRNA) in the plasma as a
candidate for an ideal biomarker. miRNA’s are the circulating copies of non-coding RNA that
play a key role in gene regulation. miRNA’s have many features of ideal biomarkers; they are
stable outside the cell, found in the blood, vary along with tumor advancement and are accessible
through non-invasive means. In one 2013 paper an experiment was conducted that analyzed the
levels of 6 miRNAs (miR-9, miR-145, miR-150, miR-155, miR-203, and miR-205) using real
time PCR in 11 patients with metastatic melanoma and 16 patients without. The expression of
the six miRNAs was significantly different in the group of patients with metastasis and those
without.3 Some mechanisms have been identified for why up or down regulation of these
miRNAs effect cancer metastasis. In 2017 Guo et al., showed that down regulation of miR-23a
contributes to the metastasis of cutaneous melanoma by promoting autophagy.4
Another blood based biomarker that has recently been investigated is the neutrophil-
lymphocyte (NLR) and platelet-lymphocyte (PLR) ratio in cutaneous melanoma. Worse overall
diagnosis was correlated with an NLR lower than 2.5 and baseline PLR 100. Melanoma specific
survival was also lower when the NLR was lower than 2.5 and PLR lower than 100. It was also
found the that 5-year survival rate for melanoma was 50% for patients who had either NLR
lower than 2.5 and PLR lower than 100.5
A biomarker that is also currently being explored is using circulating tumor cells as a
prognostic tool for malignant melanoma. The response rates for interferon-α, the standard
therapy for non-metastatic melanoma, is not as high as desired and having prognostic tools to
predict individualized response rates are necessary. Over the past decade numerous studies have
shown free circulating tumor cells as a promising biomarker in many types of cancer, but in 2018
as study was released that showed its possible use in malignant melanoma. This study showed
that patients with higher numbers of freely circulating epithelial tumor cells (CETCs) had
significantly higher chance for relapse. The Kaplan Meier curves for these patients also showed a
significant different between patients with increasing CETC numbers (mean survival time: 2.6
years) and those with decreasing or stable CETC numbers (mean survival time :12.6 years).
These results demonstrate that CETC numbers can be used as a prognostic marker for patients
with melanoma receiving interferon gamma therapy. However, further studies must be conducted
to determine whether CETCs can be as a prognostic tool for other types of therapies, for example
immune checkpoint inhibition. 6

References:
1. Hogan SA, Courtier A, Cheng PF, et al: Peripheral Blood TCR Repertoire Profiling May
Facilitate Patient Stratification for Immunotherapy against Melanoma. Cancer Immunol Res 7:77-85,
2019
2. Santos Bernardes S, de Souza-Neto FP, Pasqual Melo G, et al: Correlation of TGF-beta1
and oxidative stress in the blood of patients with melanoma: a clue to understanding melanoma
progression? Tumour Biol 37:10753-61, 2016
3. Polini B, Carpi S, Romanini A, et al: Circulating cell-free microRNAs in cutaneous
melanoma staging and recurrence or survival prognosis. Pigment Cell Melanoma Res, 2018
4. Guo W, Wang H, Yang Y, et al: Down-regulated miR-23a Contributes to the Metastasis of
Cutaneous Melanoma by Promoting Autophagy. Theranostics 7:2231-2249, 2017
5. Wade RG, Robinson AV, Lo MCI, et al: Baseline Neutrophil-Lymphocyte and Platelet-
Lymphocyte Ratios as Biomarkers of Survival in Cutaneous Melanoma: A Multicenter Cohort Study. Ann
Surg Oncol 25:3341-3349, 2018
6. Pachmann K, Willecke-Hochmuth R, Schneider K, et al: Circulating epithelial tumor cells
as a prognostic tool for malignant melanoma. Melanoma Res 28:37-43, 2018