Chemosensitivity/Resistance Assay Part of NCCN Guidelines

gdpawel said:

Chemosensitivity/Resistance Assays
Linda

There are two major cell-based assay technologies.

Cell-growth (proliferation) assay is performed by growing a portion of the cancer tumor specimen in the presence of different chemotherapy drugs in the laboratory. If cancer cells grow in the presence of a very high dosage of a chemotherapy drug, the cancer is unlikely to respond to that drug in the patient's body. Like you say, by eliminating "inactive" drugs from the therapy regime, the use of this assay avoids exposing patients to the toxicity of those drugs that are "unlikely" to be effective in treating the cancer. The results are to be used only for the purpose of drug "de-selection" and not for drug "selection."

Way back then (over twenty years ago) the goal of cancer treatment was to inhibit unregulated cell "growth." In the last twenty years, the goal is to induce cell "death" in order to successfully conquer cancer. The much older cell-growth assays measured a drug's ability to inhibit cell growth and only succeeds in eliminating drugs that would "not" work for a patient. The more more modern cell-death assays measure the ability of chemotherapy drugs to induce cell "death" (apoptosis) in a tumor specimen from a patient.

The cell-death assays are not growing anything. They are testing a drug or combinations of drugs with cells that are in their natural state (live or fresh). Three dimensional (3D) tumor cell clusters. Clusters maintain natural cell-cell interactions. This makes the assays indicative of what will happen in the body (where the old technology sometimes did not). The protocol takes "fresh" patient tumor cells and floats them in newer 3D cell suspensions. As our body is 3D, not 2D in form, undoubtedly, this novel step better replicates that of the human body. Traditionally, in-vitro (in lab) cell-lines have been studied in 2 dimensions (2D) which has inherent limitations in applicability to real life 3D in-vivo (in body) states. Recently, researchers have pointed to the limitations of 2D cell line study and chemotherapy to more correctly reflect the human body.

Most patients are treated with a combination of drugs. When correlating various cell-death assays, the "whole cell" is profiled (entire genome), assessing the activity of a drug (or combinations) upon combined effect of all cellular processes, using several metabolic and morphologic endpoints. This is more important than using tests which identify DNA or RNA sequences or gene expression of individual proteins that often examine only one component of a much larger, interactive process (you've heard about Her2, EGFR, VEGF, etc).

Most likely, the reason your oncologist may not believe the science is mature enough to use maybe NCI's failure at studying assay-directed therapy. I won't go into detail about it right here (you can read about it on the Inspire ovarian site), but good review papers exist on cell-based, cell-death assays and are increasingly appreciated, understood and applied by the private sector and European clinicians and scientists. The literature on these assays have not been understood by many NCI investigators and by NCI-funded university investigators, because their knowledge was almost always geared towards an assay technique (cell-growth) that hasnt' been used in private labs for over twenty years now.

cancer survivor x 4

I realized this technology is hard to understand. Think what it was like to research and study it over the last ten years. I was a spouse/caregiver to an ovarian cancer patient. I became intensely interested in cancer medicine by virtue of working through, enduring and surviving my wife's illness. My college education and experience helped me to gather knowledge by virtue of voluminous reading and hundreds of hours of past and ongoing personal communications with noted authorities and experts in the field.

Although retired, privately, I've been a cancer patient advocate and a researcher of cell function analysis for a number of years, like anyone would have an interest in molecular science or biological science. I do not have any financial conflicts of interest raising the awareness of this technology. My point with respect to this systematic procedure is to educate patients and others (even doctors) that such techniques exist and might be very valuable.

gdpawel said:

Chemosensitivity and chemoresistance testing in ovarian cancer
Chemosensitivity and chemoresistance testing in ovarian cancer

Ian A. Cree
Translational Oncology Research Centre, Queen
Alexandra Hospital, Portsmouth, UK
Correspondence to Ian A Cree, MBChB, PhD,
FRCPath, Translational Oncology Research Centre,
Queen Alexandra Hospital, Portsmouth PO6 3LY, UK
Current Opinion in Obstetrics and Gynecology
2009, 21:39–43

Purpose of review

Sensitivity testing in ovarian cancer to individualize therapy remains an active area of interest and this has been renewed recently by results from several groups. The clinical results of assay-directed therapy are invariably better than would be expected from empirical treatment, but it has proved difficult to get these tests into practice.

Recent findings

Several recent studies suggest that cellular individualized tumour response tests, particularly the ATP-based tumour chemosensitivity assay, can improve the chance of response and probably survival for individual patients. Most tumour response tests show excellent correlation with clinical resistance, but vary in their ability to predict sensitivity. Molecular assays of sensitivity and resistance are less developed in ovarian cancer than in breast cancer, but those using multiple gene signatures show considerable promise.

Summary

Individualized therapy has the ability to guide the use of chemotherapy as well as newer agents. The development of companion diagnostics for drugs used in ovarian cancer has considerable potential for the future and such assays are already proving useful where there is clinical evidence of equivalence between possible treatments.

Conclusion

Clearly one size does not fit all when it comes to cancer treatment, but individualized therapy needs predictive tests to tailor treatment to individual patients. The requirement for such information is new to many pathologists,who tend to think that the job has been done when the diagnosis has been made, and many of the tests available have been developed by motivated researchers working in a variety of settings. It is also difficult to persuade health care managers and politicians of the value of expensive new drugs unless these are matched by considerable improvements in patient survival. Targeting drugs makes good economic sense and patients avoid the side effects of drugs from which they are unlikely to benefit.

The problem of which test to use is still an issue. For some patients, obtaining the amount of tissue required for cellular sensitivity testing requires surgery, which may not be otherwise indicated. Molecular methods may require less cancer tissue, but are often (currently) limited to the assessment of a relatively small number of drugs.

The need for predictive tests is greatest when there is a need to make a treatment decision. In the past, when in some countries guidance only allowed platinum chemotherapy for the treatment of primary ovarian cancer, there was little point in testing such tumours. Chemotherapy leads to adaptation of surviving cells to the drugs used, and cross-resistance to other drugs, depending upon which mechanisms of resistance the cancer cell uses. The problem then becomes one of selecting second-line therapy – and the oncologist has a number of roughly equivalent options from which to choose. Any assistance at this point is usually welcome, and a predictive assay would be very useful.

The failure of the GOG-0182/ICON5 trial to show selective advantage between five arms using different regimens means that primary ovarian cancer is now ready for a clinical trial of sensitivity testing. The question to be answered is whether all those who responded in one arm of the GOG-0182/ICON5 trial would also have responded in another. Crossover data from many previous trials tends to suggest that this is unlikely, and chemoresponse testing provides strong scientific evidence to support the idea that responders in one arm might not have done so well in another arm of the study. It is, therefore, likely that patients will do better if chemoresponse testing is used to provide evidence of the individual likelihood of response to any treatment proposed.

http://v.doing-times.com/doc/pdf/tms/wenxian/Chemosensitivity and chemoresistance testing in ovarian cancer.pdf

lindaprocopio said:

Can you help me understand my new pathology report?
I recently had my original tissue slides from my Oct. 2008 hysteretomy reviewed by a different pathologist. (I did this because they were suggesting Magace or Tamoxifen as a treatment for me, and I didn't think my cancer had been documented as hormone receptive in any way.)

This new pathology report says my cancer cells are "moderately positive for estrogen receptor" (meaning that I could take Megace or tamoxifen as an alternative to chemo as treatment options??). It also says my cancer cells were/are "strongly CK7 positive"; "Weakly vimentin and p53 positive"; "progesterone receptor negative and WT-1 negative."

Could you help me to understand what any of that means? The soonest I could get an apppointment wit my gyne-onc to talk about the new pathology report is May 24th, since he wants me to have a CT/PET and CA125 done prior to seeing me (scan will be May 17th) to also factor into my upcoming treatment decision. You seem so knowledgeable that I thought you might be able to help me translate this medical jargon.

My plan is to have tissue assays done if I need to have any more surgery, as I fear my cancer cells have mutated since 2008, with the 28 rounds of radiation and 18 rounds of chemo I've had since then.