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Personalized Oncogenetics/Oncology October 8, 2007

Posted by ramunas in cancer genetics, genetic testing, research.
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In one recent article I’ve found a good summary of research approaches in cancer that lead individualized cancer management (research field –> clinical target):

  • Germline mutation analysis –> Personalized risk assessment and guided prevention
  • Gene expression profiling (multigene assays, gene signatures) –> Prognosis optimization, predictive response to specific therapies
  • Tissue single-gene mutation analysis –> Improvement of predictive precision
  • Circulating tumor cells –> Individual prognosis, fine-tuning
  • Single-nucleotide polymorphism analysis –> Host tailored therapy
  • Cancer stem cells –> Cancer eradication therapy

I could add advances in tumor immunology, especially a better understanding of immune editing and immunosuppressive networks (T regs etc) as well as monoclonal therapy (see a picture which I’ve added to Wikipedia a couple years ago) and cancer vaccines.

(Update: e.g., VentureBeat presents innovative Bellicum prostate cancer dendritic cells vaccine based on modified CD40 activation.)

First area is quite well established.:

Among these syndromes, HBOC (Hereditary breast ovarian cancer syndrome) and HNPCC /FAP are of the highest clinical significance because a large body of evidence supports the implementation of genetic analysis in clinical intervention strategies in these clinical situations. Indeed, although HBOC accounts for 5–10% of all breast‑-ovarian cancers and HNPCC for 2–4% of colorectal cancers, the high incidence of these tumor types reflect a substantial number of inherited cancers. It is estimated that in the US among 300,000 new annual breast and ovarian cancer cases, approximately 15,000 to 30,000 are attributed to germline BRCA mutations. Similarly among 150,000 colorectal cancer cases approximately 3300 to 6000 are considered to be familial. It is clear that a sensible number of cancer patients could be offered a life-saving early diagnosis, or optimally tumor prevention if genetic screening programs were applied. The development of such strategies could help prevent cancer onset in mutation carriers (via).

Gene expression profiling have already entered marked as commercial tests but gene expression studies have widely been criticized for methodology, diversity of genes used and the reproducibility outside highly specialized laboratories. However, despite criticism expressed on the validity of gene sets, a recently published study produced encouraging results by confirming that most gene signature models had high rates of concordance in their outcome predictions for the individual samples [ref].

The possible superiority of these tests over standard predictors is assessed in two large randomized prospective trials the TAILORx( designed by the NCI in the USA) and the MINDACT in the European Union, that are currently recruiting patients with the aim to test the validity of the 21-gene recurrence score (as for Oncotype DX) and the 70-gene profile (as for Mammaprint) respectively.

In general it is foreseen by file experts that genomic research will soon be in the position to provide easily applicable versions of gene sets that will give clinicians the opportunity to provide cancer patients a truly personalized treatment (via).

Or just simply state – the future is now! I am convinced, that oncology with cancer genetics in front, will be (or already is) the first truly acknowledged personalized medicine practice.

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1. Sandi Pniauskas - October 10, 2007

Open Invitation:

Dr Yi Pan, (Neurologist) MD, PhD along with Annamarie DeCarlo, Managing Editor, Anne Arundel Medical Center will be moderating the Survivors’ Debates in Detroit (Oct. 27) and Toronto (Nov. 3). The two principals of the debate are 8 & 9-year survivors Sandi Pniauskas and Carolyn Benivegna. We are thankful for the support of Bridget Capo and Pamela J. West, oncology nursing specialists.

These debates are by and for survivors, with an open-arms invitation to physicians, nurses, pharmacists, health care workers, caregivers and the public. There has been no corporate sponsorship.

We would like the general public and healthcare professionals to know about these survivor-led forums; to let them know we are doing these forums. We wish to share the often-lost patient perspective, but also to bring a public voice to our concerns and issues which often times delay or complicate forward progression for the benefit of all.

We ask, simply, that you share the news, share the knowledge, and talk about this with your colleagues and communities. We encourage open and lively discussion.

For background information, below is an interview with Sandi and Carolyn, published in ‘Eye on DNA’ conducted by Dr. Hsien-Hsien Lei.

For registration, downloadable documents and updates please visit: http://ovariancancerdebate.blogspot.com/

A third event has been confirmed for April 2008.

Eye on DNA Exclusive Interview with Cancer Survivors Sandi Pniauskas and Carolyn Benivegna
by Dr. Hsien-Hsien Lei

September 28, 2007

“How times have changed. Cancer has come from being taboo to being a subject of debate. Even better, ever more cancer survivors are now leading the charge for better healthcare.

Two ovarian cancer survivors, Sandi Pniauskas and Carolyn Benivegna, have joined to hold the Survivors Debate: The Past Decade in Ovarian Research. Two events are scheduled for October 27 in Michigan and November 3 in Toronto. Details are available at the Survivors Debate blog, http://ovariancancerdebate.blogspot.com/

Earlier this week, Sandi and Carolyn participated in an exclusive interview with me for Eye on DNA. Learn more about what it’s like to have ovarian cancer and these women’s experiences with genetic testing. Their very personal stories remind us of the realities of cancer.”

http://tinyurl.com/23bs3z

2. Personalized Medicine: Oncogenetics « ScienceRoll - October 12, 2007

[...] Personalized Oncogenetics/Oncology (Cancer Genetics): A good summary of research approaches in cancer that lead individualized cancer management. [...]

3. Gregory D. Pawelski - November 5, 2007

Personalized Cancer Medicine

The genetic analysis of Oncotype DX predicts which women will have a greater chance of breast cancer recurrence. The test looks at 21 genes that influence the behavior of breast cancer cells. Until this test, it had been difficult to pinpoint which women would benefit most from chemotherapy, and those which wouldn’t.

MammaPrint is another genetic test that could help patients with early-stage breast cancer predict their chance of relapse, information that could save many patients from unnecessary chemotherapy. This test looks at the expression of 70 genes linked to breast cancer with an accuracy level of 96.7% as determined by a study published in the NEJM.

These new gene expression profiling tests enable the oncologist and breast cancer surgeon to more accurately determine who should be treated and who should not be treated with chemotherapy, but they cannot predict chemo response.

These laboratory tests are a tool for the oncologist. The oncologist should take advantage of all the tools available to him/her to treat a patient. And since studies show that only 25-30% of patients do respond to chemotherapy that is available to them (and even less for “targeted” drugs), there should be due consideration to looking at the advantage of molecular and cellular assay tests to the resistance that has been found to chemotherapy drugs.

These tests can enhance the ability to distinguish between low risk and high risk patients. Patients in the high-risk group, who would benefit from chemotherapy can then be pre-tested with a “functional” bio-marker to see what treatments have the best opportunity of being successful, and offers a better chance of tumor response resulting in progression-free survival, while those in the lower-risk groups can be spared the unnecessary toxicity, particularly associated with ineffective treatment.

These new genetic tests have enormous implications for the short-term future of cancer research in general, and is one of the truly great cancer breakthroughs of our time. These DNA microarray will prove to be highly complementary to the parellel breakthrough efforts in targeted therapy through cell culture assays like the EGFRx Assay.

The EGFRx Assay can prospectively report to a physician specifically which chemotherapy agent would benefit a high risk cancer patient by testing that patient’s “live” cancer cells. Drug sensitivity profiles differ significantly among cancer patients even when diagnosed with the same cancer. Knowing the drug sensitivity profile of a specific cancer patient allows the treating oncologists to prescribe chemotherapy that will be the most effective against the tumor cells of that patient.

Every breast cancer patient should have her own unique chemotherapy trial based on consultation of pathogenic profiles and drug sensitivity testing data. Research and application of these tests are being encouraged by growing patient demands, scientific advances and medical ethics. These tests are not a luxury but an absolute necessity, and a powerful strategy that cannot be overlooked.

Literature Citation: Eur J Clin Invest 37 (suppl. 1):60, 2007

Presentation: http://weisenthal.org/Weisenthal_ESCIa.pdf

4. hchcec - November 26, 2007

“Every breast cancer patient should have her own unique chemotherapy trial based on consultation of pathogenic profiles and drug sensitivity testing data. Research and application of these tests are being encouraged by growing patient demands, scientific advances and medical ethics. These tests are not a luxury but an absolute necessity, and a powerful strategy that cannot be overlooked.”

there’s not a lick of evidence that these expensive internet marketed chemo. assays are of any benefit.

Please produce the data that they are.

5. Gregory D. Pawelski - December 23, 2007

Mammostrat: Another Molecular Test

In principle, this makes more sense than the Oncotype DX test. It is “validated” with the usual, retrospective, non-randomized study using archival tissues and uniform batch processing and slide interpretation.

In chemotherapy selection, Gene and Protein testing examine a single process within the cell or a relatively small number of processes. The aim is to tell if there is a theoretical predisposition to drug response.

Whole Cell Functional Profiling tests not only for the presence of genes and proteins but also for their functionality, for their interaction with other genes, proteins, and processes occurring within the cell, and for their response to anti-cancer drugs.

Genes create the blueprints for the production of proteins within the cell. A protein is a molecule that makes a cell behave in a certain way. It does so by interacting with other proteins in a complex series of steps.

The goal of Gene testing is to look for patterns of normal and abnormal gene expression which could suggest that certain proteins might or might not be produced within a cell. However, just because a gene is present it does not mean that an associated protein has been produced.

Protein testing goes one step further by testing to see if the relevant protein actually has been produced. However, even Protein testing cannot tell us if a protein is functional or how it will interact with other proteins in the presence of anti-cancer drugs.

Gene and Protein testing involve the use of dead, formaldehyde preserved cells that are never exposed to chemotherapy drugs. Gene and Protein tests cannot tells us anything about uptake of a certain drug into the cell or if the drug will be excluded before it can act or what changes will take place within the cell if the drug successfully enters the cell.

Gene and Protein tests cannot discriminate among the activities of different drugs within the same class. Instead, Gene and Protein tests assume that all drugs within a class will produce precisely the same effect, even though from clinical experience, this is not the case. Nor can Gene and Protein tests tell us anything about drug combinations.

“Whole Cell” Functional Tumor Cell Profiling tests living cancer cells. Functional Tumor Cell Profiling assesses the net result of all cellular processes, including interactions, occurring in real time when cancer cells actually are exposed to specific anti-cancer drugs. Functional Tumor Cell Profiling can discriminate differing anti-tumor effects of different drugs within the same class. Functional Profiling can also identify synergies in drug combinations.

Gene and Protein tests are better suited for ruling out “inactive” drugs than for identifying “active” drugs. When considering a cancer drug which is believed to act only upon cancer cells that have a specific genetic defect, it is useful to know if a patient’s cancer cells do or do not have precisely that defect.

Although presence of a targeted defect does not necessarily mean that a drug will be effective, absence of the targeted defect may rule out use of the drug. Of course, this assumes that the mechanism of drug activity is known beyond any doubt, which is not always the case.

Although Gene and Protein testing currently are limited in their reliability as clinical tools, the tests can be important in research settings such as in helping to identify rational targets for development of new anti-cancer drugs.

As you can see, just selecting the right test to perform in the right situation is a very important step on the road to personalizing cancer therapy.

6. Eva Robertson - May 24, 2010

I am mainly interested in integrated therapy methods that combine chemo and biological methods and would like to receive info on tat subject if possible


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