Biology and Medicine

Biology and Medicine
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ISSN: 0974-8369

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Short Communication - (2020) Volume 12, Issue 1

Retrospective Review of 374 Samples, Circulating DNA; As a Biomarker Assay to Support Clinical Management in Solid Tumors Treated with Multi Targeted Epigenetic Therapy (MTET)

Nezami M1*, Klowsowski C2 and Hager SJ3
 
*Correspondence: Nezami M, Research Cancer Institutes of America, Sahel Oncology, Newport Beach, California, USA, Email:

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Abstract

Here in this abstract we retrospectively review preliminary findings on 374 samples of circulating DNA extracted from 173 patients treated by multi targeted epigenetic therapy (MTET), which is a combination of natural histone deacetylase inhibitors and DNMT methyltransferase inhibitors. This therapy could dynamically interrupt the expression of altered genes, in a variety of solid tumor types, both in in vitro and in vivo models. We hypothesize that serial monitoring of the circulating DNA provides a feasible option for therapeutic decisions making based on presence of the driver genes in these cases. We also were able to track the antineoplastic response in these groups of patients by monitoring their tumor circulating DNA mutated allele fractions and propose a direct correlation with interim epigenetic therapy effectiveness.

Keywords

Epigenetics; Liquid biopsy; Circulating DNA

Introduction

Our current understanding of cancer biology and the epigenetic science has transformed our ability to deliver therapies more precisely to the genetic and epigenetic targets driving the tumor growth and disrupting its behavior. In concert with our efforts to regulate the transcription of altered genes involved in tumor biology, we have emphasized a range of epigenetically regulated driver genes that control the tumor key molecular targets, involved with its growth and metastasis [1]. Statistical analysis on epigenetically driven targets had shown improved outcome compared to historical control [2].

Unfortunately epigenetic targets are dynamically expressed [3] and no single drug can clinically be used to target the epigenome as drugs have static mechanism of action. This limiting factor has caused researchers in the field to admit their failure in development of an epigenetic formula or product that has significant clinical impact in majority of cancer types, mainly solid tumors. As a result, the effort on epigenetic drug development has shifted in recent years to hematological cancers, such as lymphomas and leukemia where these drugs can make a difference in the clinic [4-13].

We earlier had shown that a combination of histone and DNA selective demethylators used in a specific protocol was able to significantly produce meaningful results in our experimental therapeutic models. Although cytotoxic therapies and targeted drugs have been studied in the recent years to correlate with such relevance, using liquid biopsy in different types of cancer, including lung [14-16], lymphoma [17], renal cancer [18], breast cancer [19-21], colon cancer [22-26], ovarian cancer [27,28], this is to our knowledge the first time this correlation with epigenetic drugs have been explored.

Materials and Methods

173 cases treated by MTET were collectively selected without selection bias. These cases were treated all in associated clinics of Medical centers of Hope.

The biomarker assays were performed through liquid biopsy through 374 samples. Amongst them 300 samples were positive for circulating DNA. 74 were negative. 66 patients had one sample and 63 patients had at least two samples (Tables 1 and 2).

Table 1: 374 samples sent through the end of May 2018 on 173 patients. More than 1/2 patients in the practice (61%) have had serial testing (2 or more G360 tests).

Number of tests Number of patients
1 66
2 63
3 17
4 13
5 9
6 2
7 2
8 1
Total 173

Table 2: Other and miscellaneous category.

Other/MISC Count of cancer type
Anal Squamous Cell Carcinoma 2
Anaplastic Thyroid Carcinoma 1
Cancer, Other 2
Carcinoma of Unknown Primary (CUP) 7
Glioblastoma 3
Glioma 1
Neuroendocrine Carcinoma 1
Other 17
Other Squamous Cell Carcinoma 1
Thyroid Carcinoma 4
Grand Total 42

Detection rate was 86 percent. The most and least common tumor types: 134 cases had breast cancer. 4 had glioblastoma. 20 cases carried BRCA alterations.

In average 64 percent of such cases were stage four and had no other viable options left.

Results

Serial monitoring of mutated allele fraction in circulating DNA analysis is feasible and clinically meaningful, when epigenetic drugs are applied in clinic and show positive clinical outcome based on such biomarker driven approach to epigenetic targets.

Further analysis as of April of 2019, for 491 cases is currently on going and preliminary findings are consistent with this article with common genetic mutations reflected in breast cancer responding to the epigenetic therapies. (Tables 3 and 4).

Table 3: Samples to date by cancer type, through end of April, 2019

Cancer Category Count of samples
Bladder 7
Bone/Soft Tissue 14
Breast 186
Cervix 5
Endometrial/Uterine 11
GI 59
Head Neck 16
Kidney 7
Lung 34
Prostate 50
Miscellaneous/Other* 42
Ovarian 34
Skin 26
Grand Total 491

Table 4: FGFR4436 Common gene mutations breast cancer samples (genes identified 10 or more times in breast cancer samples to date).

Gene Observed in data
Grand Total 644
PIK3CA 61
TP53 44
ERBB2 36
ESR1 32
NF1 32
EGFR 27
ARID1A 26
KIT 23
MYC 22
CCND1 21
BRCA1 20
BRCA2 20
FGFR1 20
MET 20
APC 18
RAF1 16
FGFR2 15
PDGFRA 14
BRAF 12
GATA3 12
CCNE1 11
CKD6 10
NOTCH1 10
ERBB2 36
CNV 14
SNV 22

Conclusion

We conclude that such biomarker based epigenetic approach in cancer therapy could replace the current standard of care which is mainly blind shot and type specific.

References

Author Info

Nezami M1*, Klowsowski C2 and Hager SJ3
 
1Research Cancer Institutes of America, Sahel Oncology, Newport Beach, California, USA
2Guardant Health, Genomic Specialist, Medical Affairs, Redwood City, California, USA
3California Cancer Associates for Research and Excellence, Fresno, California, USA
 

Citation: Nezami M, Klowsowski C, Hager SJ (2020) Retrospective review of 374 sample, circulating DNA; as A biomarker assay to support clinical management in solid tumors treated with multi targeted epigenetic therapy (MTET). Biol Med (Aligarh) 12: 462. doi: 10.35248/0974-8369.20.12.462

Received Date: Sep 07, 2019 / Accepted Date: Sep 25, 2019 / Published Date: Oct 03, 2019

Copyright: © 2020 Nezami M, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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