Genomic & Tumor DNA sequencing and Chemo-Sensitivity Tests

Chemo-sensitivity, genomic profiling and Tumor DNA sequencing Tests are forms of molecular cancer diagnostics that are part of a new branch of medicine called “Precision Medicine”, whose paradigm goes beyond the “pill for an ill” treatment that is given to all patients who have the same disease. These tests can  be useful when the patient uses chemotherapeutic agents and even some supplements. These tools can help to individualized protocols thereby finding the most effective and safest pharmaceutical and neutraceutical interventions. (1) The three companies that are popular among integrative oncologists are  as follows:

Integrative Oncology

1. The Greek RGCC test has a 2 week turnaround time. It can cost $2700 – $3000 depending on the exchange rate and is not usually reimbursable by insurance.

2. Biofocus (“German Test”) is similar as the Greek one. Its costs is about $3000. See this link for some of the science that supports this detection modality.

3. Dr Nagourney in California proposes a smilar tests, but for more expensive, at around 4000 dollars. Furthermore, Dr Nagourney only tests the primary tumor and usually required a large biopsy.

Conventional Oncology

4. Conventional oncologists like Tampus DNA & RNA Genomics

This company  analyzes DNA, RNA, and proteomic data to understand a patient’s tumor at the molecular level in order to identify treatment options tailored to each patient. Their  platform analyzes thousands of clinical and molecular data points, connecting physicians with up-to-date treatment options and relevant insights for patients based on their unique molecular profile and in terms of the company’s advanced analytics and machine-learning algorithms. These tests can range from 3K to 4,000 dollars and more.

There are dozens of other conventional DNA sequencing companies, many of which are billion dollars corporations. (Source)

What is clinical tumor DNA sequencing?

When mammalian cells are exposed to DNA-damaging carcinogens, cancer can develop. When the immune system does not work well, random DNA mutations can develop into malignant tumors. Each person’s cancer has a unique combination of genetic changes. In this perspective, tumor DNA sequencing is a test to identify these unique DNA changes. Especially in the primary tumor. A few oncologists recommend to also test metastasis DNA.

In some cases, knowledge of the genetic alterations  can help determine a treatment plan. Some treatments, in particular, some targeted therapies, are effective only for people whose cancer cells have specific genetic alterations that cause the cells to grow out of control (these are sometimes called “driver” mutations). For example, mutations in the EGFR gene that make cells divide rapidly are found in some people’s lung cancer cells. A patient whose lung cancer cells harbor an EGFR mutation may respond to treatment with drugs called EGFR inhibitors. Clinical tumor DNA sequencing can reveal whether a patient’s lung tumor has an EGFR mutation. Tumor DNA sequencing is at the crux of precision medicine: care tailored to the molecular characteristics of each patient’s disease.

Tumor DNA sequencing Options

Tumor DNA sequencing is most common for patients with cancer types that may be susceptible to treatment with a targeted therapy. These patients are commonly tested for the genetic mutation the therapy targets. For example, genetic testing is a routine part of care for colorectal and lung cancer.

In addition, some oncologists may recommend tumor DNA sequencing for patients with advanced cancer that is not responding to standard treatment or for which no standard treatment is available. This may help identify other treatments that might be effective given the cancer’s genetic makeup.

In other cases, tumor DNA sequencing may be available for patients who are participating in a clinical trial that includes a sequencing test. Several ongoing precision medicine trials, such as NCI-MATCH and NCI-COG Pediatric MATCH, are using tumor DNA sequencing to assign patients to investigational treatments based on the genetic alterations in their tumors.

How is tumor DNA sequencing done?

A sample of the tumor is removed and, in some cases, a sample of  healthy cells as well. They may obtain these samples during surgery, if it is part of the treatment plan. In other cases, biopsies are done.

These samples will be sent to a specialized lab, where researchers will isolate the DNA and then use a machine called a DNA sequencer to “read” it. They will then analyze the sequence of  the DNA to determine if there are any genetic alterations that make the tumor susceptible to certain treatments. They may also examine the DNA sequence of healthy cells to determine if the patient has any inherited, or germline, mutations that increase risks of cancer and can also influence treatment decisions.

RNA analysis is also starting to be considered.

Based on the tumor’s unique genetic alterations, the specialized lab may generate a report that lists treatments the tumor is likely to respond to.

What kinds of sequencing tests are available?

The Government’s FDA Approved Two Genomic Profiling Tests for Cancer that can identify different cancer-associated genetic alterations. DNA sequencing tests can have a broad or a targeted focus. Targeted DNA sequencing tests, also called multigene panels, are the most frequently used sequencing test for patient care. These tests analyze specific “driver” mutations. Some targeted sequencing tests analyze alterations that are common in a single cancer type, whereas others analyze alterations that may be found in many cancer types.

Broad DNA sequencing tests analyze the sequence of large regions of DNA rather than specific mutations. For example, whole-genome sequencing reads the sequence of all of the DNA in your cells—what’s known as the genome. Another broad test, called whole-exome sequencing, reads the sequence of all of the patient’s genes, known as the exome. Most cancer-causing DNA changes occur in genes, but DNA changes outside of genes can also drive cancer growth. Because whole genome and whole exome tests have not been directly compared, it is not clear if one type of test is more beneficial to patients.

In addition, a quantitative mRNA expression test can also gather information about what treatments may work best for you. For example, one quantitative mRNA test commonly used for cancer care analyzes 21 different genes that can cause breast cancer and predicts whether a patient with breast cancer is likely to benefit from chemotherapy treatment.

What do the results of a tumor DNA sequencing test mean?

Multigene panel tests indicate whether the patient has a genetic alteration in the tumor that can be targeted by an existing therapy. Because broad tumor DNA sequencing tests analyze more regions of DNA, they may be more difficult to interpret. For example, they may identify genetic alterations that do not cause cancer (benign) or whose effects are not known (of unknown significance). Alterations that are benign or of unknown significance do not aid patient care.

Tumor DNA sequencing tests may also uncover the presence of inherited alterations that increase cancer risk (hereditary cancer syndromes) or that are associated with diseases or conditions other than cancer. These are known as incidental, or secondary, findings. Finding that a patient carries an inherited genetic alteration may have implications for the patient and his or her family. Genetic counselors are usually hired to help interpret the results of DNA sequencing tests.

Discussion

What are the limitations of tumor DNA sequencing tests?

Genetic testing is still in its infancy, one patient I know had multiple genetic testing from six different DNA sequencing companies and they were all dissimilar. The biggest problem with DNA sequencing is based on unreliability, given the dynamic and changing nature of genetic expression. The genetic alterations in a tumor that changes over time only captures a “snapshot” of the alterations present at one point in time. This means that the results of a sequencing test obtained a few months ago may not accurately reflect the genetic alterations present in the patient’s cancer cells when he or she will be ready for the treatment. Furthermore, most companies will only test the primary tumor. Yet, most patients dont die from the primary tumor. They succomb to metastasic tumors and those tend to have a different genetic make-up. Worse, from the Institute’s holistic viewpoint, most genetic alternations in the cell’s nucleus are a function of the cross-talk with mitochondria’s genome, which, to my knowledge is never tested. Lastly, even the mitochondria’s genome can change, given one’s lifestyle, food, climate and other factors. Therefore, the ACR Institute can’t recommend these expensive tests, unless the patient is commited to a chemotherapeutic approach, in which case the best of these tests may be useful. However, even here,  not every patient will benefit, DNA alteration that is driving the growth of the tumor may not even have been identified. Or the Lab may find such an alteration but it cannot be targeted by existing therapies. And even if the patient has an alteration that can be targeted by an existing therapy, other unique aspects of the patient’s biology (such as how your body breaks down a drug or the immune system responds to the immune checkpoint inhibitors) can influence how the patient can actually respond to the therapy.

Another limitation is that tumors are composed of cancer cells with varied, or heterogeneous, genetic alterations. Therefore, a small sample of cancer cells obtained from a biopsy may not accurately represent a heterogeneous tumor. This could mean that DNA sequencing tests may identify a potential treatment that can act against some, but not all, of your cancer cells. Cancer cells that are not targeted by the treatment have the potential to continue growing, causing the tumor to come back. Furthermore, cancer stem cells are not even targeted. More often than not, these Master cells just spur the regrowth of the tumor the targeted therapy will have shrunk.

How much does tumor DNA sequencing cost?

The cost of tumor DNA sequencing varies by the type of test. For example, one commercial test that analyzes genetic alterations in more than 300 genes for patients with solid tumors, currently costs around 6 thousand dollars.

Clinical whole-exome sequencing tests cost between $1,000 and $5,000, and whole-genome sequencing could cost over $10,000. However, biotechnology companies are constantly developing faster and cheaper sequencing techniques that could eventually bring the price down.

Insurance coverage of tumor DNA sequencing depends on the patient’s insurance provider and the type of cancer. Insurance providers typically cover a DNA sequencing test if there is sufficient evidence to support that the test is necessary to guide patient treatment. Tests without sufficient evidence to support their utility may be considered experimental and are likely not covered by insurance.

Many clinical trials involve tumor DNA sequencing. If the patient participates in one of these clinical trials, the cost of tumor sequencing might be covered.

Conclusion

Genomic sequencing can provide insights into the etiology of both simple and complex diseases. The enormous reductions in cost for whole genome sequencing have allowed this technology to gain increasing use. Whole genome analysis has impacted research of complex diseases including cancer by allowing the systematic analysis of entire genomes in a single experiment, thereby facilitating the discovery of somatic and germline mutations, and identification of the function and impact of the insertions, deletions, and structural rearrangements, including translocations and inversions, in novel disease genes. Whole-genome sequencing can be used to provide the most comprehensive characterization of the cancer genome, the complexity of which we are only beginning to understand.

However, from the point of view of Holistic Oncology and un-biased Science, these billion dollars companies’ DNA sequencing technologies are not relevant. First off, from the holistic point of view, cancer is less a genetic disease then a metabolic disorder where the mitochondria’s energy system is flawed. By first fixing this aspect of the cancer process, nuclear genetic expression will often get “naturally” restored. Hence, the Institute prefers to approach cancer more upstream, on what causes cancer DNA alterations. Furthermore, most targeted therapies are short-lived, spur resistance and don’t get to the root of the problem.

Be that as it may, every patient should not assume anything in medicine, ask loads of questions and decide with his or her  cancer team what is the best testing and treatment approach. The patient should do this with three different cancer schools, not three different oncologists from the same school. Traditional Chinese Medicine, Allopathic school and Holistic Oncology would be recommended. One must realize that medicine is as much a cultural and economic phenomenon as a scientific one.  A few decades ago, in the 50s and 60s,  it was the standard of care for schizophrenic patients to be forced to endure three months of insuline shock thereapy where the vitamin and nutrient deficient “mentally ill” patient would go into near-death coma experiences dozens of time. Dozens of similar “standards of care” exist, including the mercury and blood letting standard of care for throat infection. This is the standard of care that killed America’s first president, G. Washington. If chemo is chosen, then yes, sequencing testing would make sense, but both DNA and mRNA testing as well as metastatic tumor testing. The more data the better given the high error rates of most of these sequencing billion dollars companies. Treatments should not be delayed too much after the testing, given the dynamic and changing nature of genetic expression and metastatic invasion.

Pr. Joubert (ACR Institute director)

Reference note

(1). One of the problems with conventional oncology is that the doctors have used a “one-size-fits-all” approach and therefore the drugs too often fail with life altering consequences. With chemo-sensitivity and genomic testing,  some semblance of “precision” and individualized medicine is achieved.  The personalized approach is to identify the circulating Tumor Cells, (CTCs) and Cancer Stem Cells (CSCs) to see what natural and chemical substances they are most sensitive to. The procedure consists in remove some of the patient’s blood which can then be harvested so that cancer cells and the cancer stem can be grown in petri dishes, where various pharmaceutical and natural substances are introduced. After 48 hours, each substance is measured to see how effective it is in terms of cancer cell and cancer stem cell apoptosis or necrosis. In this realm, the most popular test is the GreekTest which checks 49 chemo drugs and 50 natural biologic substances such as enzymes, Poly MVA, Vitamin D3, fermented soy extract, mistletoe, SOD, burdock complex, B 17. The patient also have the option of sending 2 specific natural substances that are not on the Greek test list. Based on the results of the test, the practitioner can learn the following: (a) which specific genes are involved in the growth of the cancer, (b) the effectiveness of drugs and natural substances. Thanks to this data, a precise and individualized protocol can be ascertained. Sloane Kettering and the University of Texas MD Anderson Cancer Center in Houston are beginning to use the test after have received a $15 million dollar grant from the Stand up to Cancer Telethon.  For more details, see this Source.

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