Saturday, March 26, 2016

Biomarkers - blood components, circulating tumor cells AND of the tumor itself

Biomarkers.  Sounds important.  What are they?  What can they really tell us? 

Researchers have been seeking to find a connection between nonspecific biomarkers (things we ALL have circulating in our blood) like LDH, various white blood cells (neutrophils and monocytes - whether as an absolute count or as a neutrophil to lymphocyte ratio), myeloid-derived suppressor cells (MDSCs) and T-regs (See post with links about all that here:   Blood markers associated with clinical outcomes).  And while many meaningful correlations have been drawn between these components and response to treatment (or lack thereof); the fact that they are all affected by numerous circumstances other than melanoma and its treatment, create limitations in the clarity with which they can be used to PREDICT responses.

With recent scientific advances, PCR testing (Polymerase chain reaction) has become more efficient and cost-effective, allowing labs to copy or "amplify" small segments of DNA or RNA though screening blood or other biological specimens.  This ability allows the cellular identification of whatever may be floating in that blood sample....whether it is a virus or fungus, or actual bits and pieces of tumor cells themselves, to allow a determination of  disease burden, prognosis, and response to treatment.  Here is an earlier post:  Circulating tumor cells: how they may eventually impact melanoma diagnosis and evaluation of response

Now there are these reports:

Liquid biopsy utility for the surveillance of cutaneous malignant melanoma patients.  Haung and Hoon.  Mol Oncol. 2015 Dec 17.

Cutaneous melanoma is one of the highest incident-rate cancers with increasing prevalence in Western societies. Despite the advent of new approved therapeutics, the 5-year overall survival rate of stage IV melanoma patients remains below 15%. Current treatments for late stage disease have shown higher efficacy when treated at a lower disease burden. Thus, blood-based biomarkers capable of detecting melanoma prior to clinically evident distant metastasis, will improve the treatment and outcomes for melanoma patients. To that end, effective treatment of melanoma necessitates identification of patients at risk for developing distant metastases. Furthermore, employing blood biomarkers that monitor cancer progression over the course of treatment is a promising solution to post-treatment drug resistance often developed in melanoma patients. Non-invasive blood biomarker assays allow for regular dynamic monitoring of disease. "Liquid Biopsy" of blood, which exploits circulating tumor cells (CTCs), cell-free circulating tumor DNA (ctDNA) and cell-free circulating microRNA (cmiRNA), has been shown to detect prognostic factors for relapse in AJCC stage III and stage IV melanoma patients. Moreover, molecular characterization of CTC and analysis of various forms of ctDNA present promising potential in development of individualized therapy for melanoma patients. New approaches such as massive parallel sequencing (MPS) provide a comprehensive view of the disease progression, allowing for the selection of therapeutic options for individual patients. With advancements of improving molecular assays, liquid biopsy analysis as a powerful, routine clinical assay for melanoma patients, is highly promising prospective.

Circulating melanoma cells as a potential biomarker to detect metastasis and evaluate prognosis.  Hida, Yoneta, Wakamatsu, et al.  Australas J Dermatol. 2016 Mar 1.

TNM staging is mainly used to evaluate the prognosis of melanoma patients. Serum biomarkers such as 5-S-cysteinyldopa (5-S-CD) have occasionally been used but most do not respond until the tumour burden becomes high. Recently, circulating melanoma cells (CMC) have been reported as a possible new biomarker to detect metastasis, monitor treatment response and predict prognosis. The object of this exploratory study was to evaluate the efficacy of CMC to detect metastasis and predict prognosis by cross-sectional and prospective observational analyses, respectively. Altogether 15 patients with stages II-IV melanoma were enrolled and CMC were enumerated by CellSearch system with cut-off values of two cells/7.5 mL. Serum 5-S-CD and lactate dehydrogenase (LDH) were also measured. The sensitivity of CMC and 5-S-CD for the detection of metastasis was 33 and 50%, respectively. The combination of CMC and 5-S-CD showed a sensitivity of 67%, the best performance among CMC, 5-S-CD, LDH and any combination of two of the markers. Additionally, a 30-month prospective observation showed that CMC could segregate patients with poorer prognosis. The median survival time for the patients with less than 2 CMC and those with greater than or equal to 2 CMC was 19.5 and 4.5 months, respectively. The limitation of this study is the small sample size. These preliminary results indicate CMC may complement the efficacy of 5-S-CD to detect metastasis and can be a prognostic marker. Although there is still room for improvement to maximize the sensitivity, the CellSearch system is reproducible, standardized and suitable for multi-center studies.

Then, there's the examination of the properties of the tumor sample itself.  This article talks about looking at the tumor in regard to how well it is being recognized by the immune system....specifically t-cells:
Melanoma-specific MHC-II expression represents a tumour-autonomous phenotype and predicts response to anti-PD-1/PD-L1 therapy.  Johnson, Estrada, Salgado, Sosman, et al.  Nat Commun.  2016 Jan 29.

Anti-PD-1 therapy yields objective clinical responses in 30-40% of advanced melanoma patients. Since most patients do not respond, predictive biomarkers to guide treatment selection are needed. We hypothesize that MHC-I/II expression is required for tumour antigen presentation and may predict anti-PD-1 therapy response. In this study, across 60 melanoma cell lines, we find bimodal expression patterns of MHC-II, while MHC-I expression was ubiquitous. A unique subset of melanomas are capable of expressing MHC-II under basal or IFNγ-stimulated conditions. Using pathway analysis, we show that MHC-II(+) cell lines demonstrate signatures of 'PD-1 signalling', 'allograft rejection' and 'T-cell receptor signalling', among others. In two independent cohorts of anti-PD-1-treated melanoma patients, MHC-II positivity on tumour cells is associated with therapeutic response, progression-free and overall survival, as well as CD4(+) and CD8(+) tumour infiltrate. MHC-II(+) tumours can be identified by melanoma-specific immunohistochemistry using commercially available antibodies for HLA-DR to improve anti-PD-1 patient selection.

Here...the tumor is being characterized by surface molecules that are correlated with prognosis:

Molecular markers to complement sentinel node status in predicting survival in patients with high risk locally invasive melanoma.  Rowe, Tang, Hughes, et al.  Int J Cancer. 2016 Mar 14. 

Sentinel lymph node status is a major prognostic marker in locally invasive cutaneous melanoma. However this procedure is not always feasible, requires advanced logistics, and carries rare but significant morbidity. Previous studies have linked markers of tumour biology to patient survival. In this study we aimed to combine the predictive value of established biomarkers in addition to clinical parameters as indicators of survival in addition to or instead of sentinel node biopsy in a cohort of high risk melanoma patients. Patients with locally invasive melanomas undergoing sentinel lymph node biopsy were ascertained and prospectively followed. Information on mortality was validated through the National Death Index. Immunohistochemistry was used to analyse proteins previously reported to be associated with melanoma survival, namely Ki67, p16, and CD163. Evaluation and multivariate analyses according to REMARK criteria were used to generate models to predict disease-free and melanoma-specific survival. 189 patients with available archival material of their primary tumour were analysed. Our study sample was representative of the entire cohort (N=559). Average Breslow thickness was 2.5 mm. 32 (17%) patients in the study sample died from melanoma during the follow-up period. A prognostic score was developed and was strongly predictive of survival, independent of sentinel node status. The score allowed classification of risk of melanoma death in sentinel node negative patients. Combining clinicopathological factors and established biomarkers allows prediction of outcome in locally invasive melanoma and might be implemented in addition to or in cases when sentinel node biopsy cannot be performed.

Here the tumor is being analyzed for specific genetic variations:   

Genomic and Transcriptomic Features of Response to Anti-PD-1 Therapy in Metastatic Melanoma.  Hugo, Zaretsky, Sun, et al.  Cell. 2016 Mar 15. 

PD-1 immune checkpoint blockade provides significant clinical benefits for melanoma patients. We analyzed the somatic mutanomes and transcriptomes of pretreatment melanoma biopsies to identify factors that may influence innate sensitivity or resistance to anti-PD-1 therapy. We find that overall high mutational loads associate with improved survival, and tumors from responding patients are enriched for mutations in the DNA repair gene BRCA2. Innately resistant tumors display a transcriptional signature (referred to as the IPRES, or innate anti-PD-1 resistance), indicating concurrent up-expression of genes involved in the regulation of mesenchymal transition, cell adhesion, extracellular matrix remodeling, angiogenesis, and wound healing. Notably, mitogen-activated protein kinase (MAPK)-targeted therapy (MAPK inhibitor) induces similar signatures in melanoma, suggesting that a non-genomic form of MAPK inhibitor resistance mediates cross-resistance to anti-PD-1 therapy. Validation of the IPRES in other independent tumor cohorts defines a transcriptomic subset across distinct types of advanced cancer. These findings suggest that attenuating the biological processes that underlie IPRES may improve anti-PD-1 response in melanoma and other cancer types.

While none of these (other than those that are simple measures of recognized blood components) are validated and ready for daily screening of cancer patients across this country....every step is important in helping docs...eventually....determine the best treatment options for the individual and monitor their response to that treatment in ways that are specific, easily measured, and less invasive and damaging to that patient.  What a beautiful day that will be!!!  Minimized only by the day we figure out how to avoid cancer entirely!  Hey....might as well live large and dream big!!! - c

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