Cancer is a complex illness; it encompasses more than 100 actual diseases made up of combinations of genetic mutations of more than 100 different genes and is treated with more than 200 different individual therapies. There are virtually innumerable permutations of genomic configuration and combination therapies. Also, cancer is not static, but dynamic — it changes over time within the same individual.
Predictable outcome is something we all strive for in medicine. For cancer, this has been an elusive goal. Patients want to have a drug that they know will work, and that will produce an acceptable result for all of the adverse effects they will have to endure. Clinical trials for cancer drugs look at the response rate (the percentage of people who have either a partial or complete tumor shrinkage) and overall improvement in survival (or a surrogate endpoint that in some way reflects overall survival).
But many therapies are associated with overall response rates in the teens and sometimes even in the single digits. Thus, the overall outcome of cancer treatment has been compared with the roll of dice. Think about it: Patients are treated with very toxic chemotherapy agents that, it is hoped, will kill the cancer cells, but that in fact are toxic to many types of normal cells. The measures of outcome — response rates, overall survival, progression-free survival, etc. — are all dependent on therapy’s ability to kill the cancer cells. In general, the higher the cancer cell kill rate, the better the outcome.
Early attempts to predict the response to chemotherapy relied on placing live cancer cells in the presence of chemotherapy drugs and seeing if they died or failed to reproduce. But even the rather crude results achieved with this method took three to six weeks to produce, and the method had limited reported survival data. For these and other reasons, this approach has not been widely accepted by oncologists.
Much of the advancement in cancer care over the past decade has been focused on the development of targeted therapies based on tumor-associated biomarkers — receptors in or traits of the tumor that predict response to a specific therapy that targets the biomarker.
There has been rapid advancement in biomarker technology and the associated therapies. But for even the most efficacious targeted therapies, existing biomarker-based therapy still lacks 100% response rates. In fact, many targeted therapies are associated with just incremental improvements over existing chemotherapy. In addition, only a handful of tumor biomarkers have proven therapies associated with them. Hence, for most cancers, indiscriminate, nontargeted chemotherapy agents still make up the majority of recommended or accepted therapies.
What is needed is a rapid, predictable, proactive method of testing tumor cells against a wide variety of chemotherapy agents, resulting in a test result that predicts the actual outcome of care in a specific patient — and is accepted by oncologists.
Building on work initially developed by Vanderbilt University scientists, a small, Franklin, Tenn.-based technology company called DiaTech Oncology has developed a test that produces a report showing the sensitivity of tumor cells to therapy — a report physicians can act upon. With results available in 72 hours, this potentially disruptive breakthrough has broad implications for managed care, physicians, pharmaceutical companies and patients alike. The company’s technology is called “Microculture Kinetic Assay” — MiCK Assay for short.
Relying on live cancer tissue, this test measures the morphologic changes of chemotherapy-induced apoptosis, a process of programmed cell death that is the mechanism by which chemotherapy kills cancer cells. The test relies on the discovery that the optical density of cells increases as apoptosis occurs.
The fresh cancer sample is shipped overnight in a coldpack to the DiaTech Oncology CAP/CLIA laboratory, where the specimen is minced and digested with enzymes to release single cells. Multiple steps are taken to purify cancer cells and remove normal host cells. A pathologist confirms the presence and purity of malignant cells in the specimen.
The cancer cells are then added to a 384-well microplate. Individual chemotherapeutic agents, as well as combinations (based upon National Comprehensive Cancer Network guidelines or special requests from the oncologist), are added to the wells, consistent with recommended drug doses. The cells are then incubated. Every five minutes for 48 hours, an optical microplate spectrophotometric reader measures optical density. A validated linear score termed the kinetic unit (KU) is calculated and divides response into five levels according to sensitivity. This score correlates with the cytotoxicity of the drug or drug combination.
The developer of this test has completed 17 national published studies confirming the MiCK assay measurement and validation. In addition, 10 national published peer-reviewed studies confirm MiCK’s patient outcomes and cost savings. Some of these studies involved study design recommendations by UnitedHealthcare and WellPoint’s analytic division, HealthCore.
Initial studies simply measured the KU score in a blinded fashion (meaning that the oncologist was never given the result) and oncologists chose drugs based on patient and tumor characteristics and their own judgment. A retrospective review revealed that when oncologists chose drugs with high KU scores, overall survival and time to relapse showed highly statistically significant improvement. Other studies gave physicians the actual results with no advice on how to use the score. A large percentage of physicians (up to 3 out of 4) used the score to guide therapy, and they found that its use resulted in patients having longer times to relapse and overall survival in every tumor type measured. Of great interest to health plans, in most cases, use of the KU scores enabled prescribers to use older and less expensive generic cancer drugs. Also, one study involving a large self-insured employer demonstrated a 55% savings in drug cost.
The MiCK Assay has been used in over 50 different cancer types in more than 1,500 patients. DiaTech Oncology can test effusions, ascites fluid, surgical and core needle biopsies, bone-marrow aspirates, and blood as well as larger specimens.
This test costs from $6,800 to just over $9,000 and has been approved for payment by UnitedHealthcare. The results of several studies have demonstrated significant savings and improved outcomes in overall survival as well as time to progression.
Some limitations exist. At present, small needle biopsies provide too few cells to test, so larger samples are needed. Also, the tissue must be left alive and not placed in a formaldehyde solution as is usually done for microscopic pathologic exam. Thus, a sample must be large enough to send to the pathologist as well as to DiaTech. Further, DiaTech has not tested tumor cells for response to antibodies, but it has evaluated many of the targeted small molecules and newer chemotherapies such as Alimta, Sprycel, Velcade, and Gleevec. The company has just started its marketing campaign and expects rapid uptake.
If the early results pan out over larger populations, this development may enable the treatment of cancer to become much more predictable and successful with possible savings. Of interest is that this new technology may allow individually selected older therapies to become Tomorrow’s Medicine.
The author is a director in the value-based health department at Genentech. He has had no other industry affiliations in the past three years. The views expressed in Tomorrow’s Medicine are the author’s alone.