TOPIC: Personalized Oncology Treatment
Karl Rogers, MD: medical oncologist
Monday, June 13, 2011
Cancer chemotherapy is migrating from blunt-instrument drugs that affect both cancer and healthy cells to more focused drugs that hit tumors while doing less damage to normal cells. Individual tumors vary on the genetic level among patients with the same type of cancer. Some genetic defects are found in multiple types of cancer.
Imagine a world in which cancer isn't diagnosed according to where it is found on the body but according to genes found in the tumor itself. Patients with skin cancer, colon cancer and parathyroid cancer, for example, might be reclassified as "B-Raf mutation" patients and be treated with the same mutation-specific drugs. Instead of receiving breast cancer-specific chemotherapy, a breast cancer patient might join those with ovarian, uterine and cervical cancer to receive drugs targeted at inhibiting the PIK3CA mutation found in their tumors.
Courtesy Casey Carleton
Casey Carleton, 32, is pictured here with his... View Full Size
Courtesy Casey Carleton
Casey Carleton, 32, is pictured here with his wife, father and three children. Carleton is now in remission after entering the MD Anderson experimental cancer treatment trial. Instead of treating his melanoma specifically, doctors tailored drug treatment to the specific genetic mutation causing his cancer.
In a world used to dividing up cancers by body part and assigning colored ribbons accordingly, the gene approach to treatment marks a fundamental change in the way we even think about cancer. We classify cancers according to where they start, but each cancer is probably many types of cancer. The bigger picture is what are the genetic abnormalities that make that cancer grow? We've known about these mutations for a long time, but it's only recently that we have new drugs to target [them].
The concept of genetically personalized cancer treatment has been a goal among cancer researchers for years—and trials offer hope that widespread use of these kinds of treatments are within reach. Traditional treatments for cancer, such as chemotherapy, are one size fits all. All lung cancer patients might receive the same type of chemotherapy. While this approach can be effective, it ravages the patient's body by attacking all of a patient's cells in hopes of killing the cancer. Genetically targeted therapy, on the other hand, isolates the abnormal proteins within the cell that only occur in the cancerous tumor itself. This has led to the development of drugs that are less toxic than traditional chemotherapy; and, for patients with identifiable genetic mutations, this type of treatment can be effective when nothing else has worked.
All patients of Baptist, Saint Thomas or Middle TN Medical Center have access to personalized oncology, MiCK Assay™
Chemotherapy of a malignant tumor aims to either completely eliminate the tumor cells or substantially reduce their number. Chemotherapeutic agents' ability to kill tumor cells makes this goal achievable. The tumor cells of an individual patient, however, may be sensitive to one chemotherapeutic agent but not to another. Oncologists currently use an empirical approach to the selection of treatment protocols – the selection of a therapeutic agent is based on statistical data obtained in large clinical studies.
For instance, a clinical study shows that agent A helps 60 leukemia patients out of 100 to keep their disease in check, or, as it is usually said, to achieve complete remission. With agent B, complete remission is seen in 35 patients while with agent C complete remission is achieved in 5 patients. Thus, oncologists selecting between agent A, agent B, and agent C, would rather use agent A because agent A is expected to be effective in 60% of leukemia patients. What about the remaining 40% of patients who are statistically not expected to respond to agent A, but would better benefit from agent B or agent C? For them, the use of agent A will result in treatment failure. In other words, their tumor cells will not be killed effectively enough, complete remission will not be achieved and the disease will progress. It may be reasonable for patients in this group to utilize agent B or agent C after agent A fails. Unfortunately, it is not always possible to use another treatment protocol with the same patient. First, all chemotherapeutic agents are highly toxic substances and patients may not survive another round of treatment. Besides, time is lost and the disease may progress beyond its treatable phase. To complicate the picture, it is unclear whether the patient's tumor cells would be more sensitive to agent B or agent C.
The American Cancer Society estimates that approximately 1.22 million new cancer cases are diagnosed every year. For more than 700,000 of these patients, some form of chemotherapy will be used in the treatment plan.
The treatment outcome for cancer patients could be dramatically improved if oncologists would include agents that are effective against tumor cells of a specific patient in the first line of therapy.
The Microculture Kinetics (MiCK) assay for apoptosis helps oncologist discriminate between effective and ineffective chemotherapeutic agents prior to their use in a patient's treatment. MiCK assay helps oncologists to create an individual treatment protocol that includes a drug or drug combination that is most effective in killing tumor cells of an individual patient.
How does MiCK assay work? Over the last 10 years it has been shown in multiple studies that chemotherapeutic agents exert their antitumor activity by triggering apoptosis, a distinct mode of cell death that is accompanied by dramatic changes in the appearance of tumor cells.
The figure above is a photomicrograph of a "healthy" tumor cell (at left) and three other tumor cells at various stages of apoptotic death cased by exposure to a chemotherapeutic agent. The photo demonstrates that cells dying by apoptosis form big blebs on the outer surface of the cell. Formation of these blebs results in a change in the cells' light scattering properties. A sophisticated device called a spectrophotometer can detect the resulting change in the optical properties of apoptotic cells.
Tumor cells undergoing apoptosis manifest an increased side light scattering as compared to "healthy" tumor cells. The MiCK assay of apoptosis is based on frequent measurements of the optical density of tumor cells exposed to multiple chemotherapeutic agents. If a chemotherapeutic agent kills tumor cells by apoptosis, the spectrophotometer will "see" and report accumulation of apoptotic tumor cells as a steep increase in the optical density. On the computer screen, this steep increase in the optical density appears as a so called "apoptotic curve". Data generated by the spectrophotometer are fed to the computer and automatically analyzed in order to determine the extent of the tumor cells' apoptosis. This allows for the identification of a chemotherapeutic agent which causes the most extensive apoptosis in tumor cells. If a patient has no medical contraindications, this agent may be included in the patient's treatment protocol.
In no way can MiCK assay's results substitute for the medical judgment of an oncologist. The MiCK assay is a powerful tool arming oncologists with valuable information on the drug sensitivity profile of a specific cancer patient. However, the final decision on whether a specific agent should or should not be included in the patient's treatment protocol, is always made by the patient's physician
In the MiCK assay, the tumor cells of an individual patient are exposed to multiple doses of several chemotherapeutic drugs either as single drugs or in combinations. A sophisticated algorithm is used to monitor and compute the amounts of apoptosis caused by each of the drugs to establish a drug sensitivity profile of the patient's tumor cells. Knowledge of a patient's drug sensitivity profile allows the treating oncologists to prescribe chemotherapy that would be the most effective against the tumor cells of that patient.
DiaTech Oncology is a privately held clinical pathology laboratory working to help oncologists and their patients deal with the devastating effects of cancer. DiaTech utilizes a patented technology called the Microculture Kinetic (MiCK) assay. The MiCK assay is the only test available that measures the chemotherapeutic drug effect for a specific patient kinetically and accurately.
Fri Jun 3, 2011: Tailoring cancer drugs to target the molecular signature of a tumor helps patients more than a scattershot approach, according to early-stage research.
The strategy is not an option for every type of cancer, but medical advances have led to the development of a number of drugs that target specific gene mutations in tumors, such as Roche's (ROG.VX) Herceptin for a certain type of breast cancer or Gleevec, sold by Novartis (NOVN.VX).
A phase 1 study conducted at the University of Texas MD Anderson Cancer Center found that matching therapies -- most still experimental -- to genetic markers led to higher rates of tumor shrinkage and survival in patients with advanced cancer.
The results were presented on Friday in Chicago at the annual meeting of the American Society of Clinical Oncology.
"The concept is quite simple ... we think you should match the abnormality with the targeted drug," said Dr. Razelle Kurzrock, professor and chair of MD Anderson's Department of Investigational Cancer Therapeutics.
The study involved 852 patients with cancer that was inoperable or had spread beyond the primary site. It found that 27 percent of the 175 patients with a single gene aberration who were treated with a matched drug had tumor shrinkage.
The response rate was 5 percent in the 438 patients without an aberration. The other patients -- who were treated with drugs that did not match their genetic mutations -- had a response rate of 8 percent.
Median survival was 15.8 months for patients with one mutation who were treated with a matched drug, compared with 9.7 months for those patients who were not matched to a targeted therapy.
Dr. Kurzrock said use of molecular testing for cancer patients is not yet standard clinical practice, although it is becoming more common as new drugs are approved and testing is made available.
Since the signing of the National Cancer Act 40 years ago, the average five-year survival rate for all U.S. cancer patients has risen by 18 percent, according to ASCO.
That has been due largely to improvements in traditional chemotherapy drugs, which work by interfering with the entire body's system of cell replication, causing harsh side effects like nausea, hair loss and fatigue.
Newer targeted drugs, made possible by the decoding of the human genome, aim to block specific pathways that cancer cells use to grow and reproduce. The list of targets is an alphabet soup of genes such as PIK3CA, mTOR, MEK, EGFR, RET and BRAF.
Elaine Silk, 54, was diagnosed nine years ago with melanoma, a deadly form of skin cancer.
She has endured numerous surgeries and drug regimens -- including a round of immune boosters that required hospitalization and caused her brain to swell -- but considers herself cancer-free after a year of treatment with an experimental BRAF-blocking drug.
"There are a few side effects, but nothing like before ... my hair is really curly," said Silk, who lives in rural Texas. "I take three pills twice a day ... I look at it like medication for high blood pressure that keeps the disease under control."
Dr. Kurzrock said more work is needed since the MD Anderson study was an analysis of retrospective data, rather than a randomized trial.
She also said it would make sense to match targeted therapies to patients with earlier-stage cancer.
Millions of cancer patients worldwide will soon be able to receive more effective, personalized treatments for their disease thanks to developments in the understanding of cancer biology.