Doctors prescribe chemotherapy drugs based on their experience and the data documented in clinical trials. While these methods are sensible, there are too many other variables between individuals that can produce a-typical results more often than one would think. Chemosensitivity testing can help lower instances of cancer recurrence by guiding patients in choosing the most effective drug the first time around. Because it targets residual cells that are actually different in their genetic makeup than cells from the primary tumor, chemosensitivity testing is a more targeted approach to cancer treatment. By eliminating drugs that show resistance, chemosensitivity testing can help you make the best choices for your treatment. As with anything, absolute certainty is impossible, but the use of diagnostic testing and tools to complement chemotherapy can greatly minimize instances of cancer recurrence.
You’re more than halfway through the worst part of cancer – chemotherapy, only to find out the cancer cells were resistant to the drugs. With only 3 treatments remaining you begin to wonder if it will be enough …
Testing For Chemotherapy Drug Effectiveness – Before Treatment
Sunridge Medical believes all patients should make the most informed decisions about what’s best for them in terms of their health. In cases of serious illness like cancer these decisions can have a significant impact on the end result of their treatments.
Choosing chemotherapy as a first line of defense against cancer or as an adjuvant therapy, may be the best treatment option for you, but can also have varying degrees of effectiveness for different people. For example, certain types of cancers have shown to respond better or worse to certain types of chemotherapy drugs. Doctors prescribe chemotherapy drugs based on their experience and the data documented in clinical trials. While these methods are sensible, there are too many other variables between individuals that can produce a-typical results more often than one would think.
Gene Profiling and Drug Resistance “The cells responsible for cancer recurrance are different in their genetic makeup than those of the primary tumor”
When we consider the complexity of disease, especially cancer, along with the biological complexity of each individual patient, it’s nearly impossible to determine drug resistance with absolute certainty. But while predicting such reactions may be impossible, testing for them prior to actual treatment is not. By testing the patient’s cancer cells with various chemotherapy drug types we can observe the reactions and see a bit clearer into the patient’s future treatment. In fact, we can test combinations of drugs and pinpoint those showing the best response ex-vivo using a tissue or blood sample from the patient. Using a method called “gene profiling” we look at micrometasteses which are cancerous cells shed in the blood after a primary tumor has been removed.
These particular cells are responsible for cancer recurring or a relapse and may differ in their genetic alterations from those of the primary tumor. [Georgia Institute of Technology (2013, August 12). Cancer cells appear to change while moving throughout body. ScienceDaily. Retrieved September 10, 2013, from http://www.sciencedaily.com/releases/2013/08/130812154102.htm]. For this reason their chemo resistance may also be different from the actual tumor.
Chemosensitivity testing can help lower instances of cancer recurrence by guiding patients in choosing the most effective drug the first time around. Because it targets residual cells that are actually different in their genetic makeup than cells from the primary tumor, chemosensitivity testing is a more targeted approach to cancer treatment. By eliminating drugs that show resistance, chemosensitivity testing can help you make the best choices for your treatment. As with anything, absolute certainty is impossible, but the use of diagnostic testing and tools to complement chemo-therapy can greatly minimize instances of cancer recurrence.
 An adjuvant therapy is a term used to describe a secondary therapy used in conjunction with a primary therapy such as the removal of a tumor, which is sometimes followed by chemotherapy. In this case chemotherapy is used as a secondary, and precautionary therapy to kill any remaining cancer cells left behind after surgery and would be considered the adjuvant therapy, however it isn’t always an adjuvant therapy. Ex-vivo- A term used to describe a location outside of the organism where something takes place, usually testing or experimental in nature such as testing a sample of cancerous tissue taken from a patient.
Technical Information On Chemosensitivity Testing
A fundamental treatment option for cancer is chemotherapy. For each type of tumor, different chemotherapy regimes (drugs or drug combinations) exist. The efficacy of these regimes is usually determined by clinical trials and those regimes showing statistically to have the best success-rates are classified the most effective. However, an individual patient may respond differently to each therapy and it is a difficult task for the physician to choose the most appropriate from the available treatment regimes. Chemosensitivity testing can aid to select those drugs more likely to be effective than others for an individual patient.
Our chemosensitivity testing is based on genetic profiling of drug-metabolizing genes and cellular drug-target genes in the isolated tumor cells. The expression of these genes is determined by accurate technique of real-time quantitative PCR. From the academic literature it is known that the expression of drug metabolizing genes in tumor cells is influencing the action of the drug*1,2. Some drugs act directly on specific cellular molecules, so called drug targets. An effective response of such drugs requires the presence of these drug targets in the cells, which we can assess by measuring the gene expression of the drug target gene.
Several chemo-drugs (e.g. cyclophosphamide, capecitabine, irinotecan, dacarbazine) are virtually inactive in its parent form and need prior activation in the body, e.g. by liver enzymes. Such drugs are rather problematic to test ex-vivo on tumor-tissues with the widely used cell-viability chemosensitivity assays.
In contrast, chemosensitivity testing by our genetic profiling does not depend on prior activation of the test drugs by liver enzymes. The aim of adjuvant therapies is the elimination of residual cancer cells (micrometastases) which are responsible for relapse or metastasis after the primary tumor has been removed. Our philosophy is therefore to use isolated micrometastases for the resistance analyses, since these residual tumor cells should be actually killed by the therapy. It is well known from the literature that tumors are very heterogeneous. They do not consist of identical cancer cells, but are rather composed of groups of cells which may differ in regard of their genetic alterations. The cells shed in the blood stream forming micrometastases may consequently not be genetically identical with the average primary tumor, recently proven by academic work*3. Therefore, a targeted therapy against the disseminated cancer cells may be a more straightforward way to prevent the emergence of relapse and metastases.
Mechanisms of Drug Resistance and Susceptibility
Tumors may become resistant to multiple drugs by activation of functions like MDR or GST, leading to increased detoxification and efflux of chemotherapeutic drugs. We can measure the levels of these multidrug-resistance conferring functions in the tumor cells.
Some drugs need metabolic activation within the tumor cells by enzymatic functions. A reduced expression of these enzymes in the tumor cells may lead to diminished sensitivitiy to those drugs.
It has also been observed that a tumor might better respond to certain drugs, if the molecules which are inhibited by these drugs are increased (overexpressed) in the tumor cells. Such molecules are called drug-targets. The main drug-target for anthracycline drugs (e.g. doxorubicine) is topoisomerase II. Tumors with higher levels of topoisomerase II generally show better sensitivity to anthracyclines.
Her2 (ERBB2) is the drug-target for Herceptin, an antibody specifically directed against ERBB2. Besides breast cancer, Her2 can be detected in many different types of malignancies. Usually, effective treatment of breast cancer with Herceptin requires overexpression of Her2 in the tumor cells, which can be determined by genetic testing. Discordance of Her2 status between primary tumor and metastases can occur by acquiring Her2 activation during tumor progression. In breast cancer patients, circulating tumor cells have shown to overexpress Her2 despite Her2-negative primary tumor. Importantly, after such cases had been treated with Herceptin, clinical responses could have been achieved*4.
Especially in hematological malignancies, genetic malfunction induced by chromosomal rearrangements leads to the uncontrolled production of molecules which are targets for specifically designed anti-cancer agents. Leukemia positive for the bcr-abl chromosomal rearrangement can be efficiently treated with Gleevec. Whereas most cases of chronic myeloid leukemia (CML) are positive for bcr-abl and have a good prognosis, acute myeloid leukemia (AML) positive for bcr-abl is a rare disease, characterized by a poor prognosis, with resistance to induction chemotherapy and frequent relapses in responsive patients. Genetic testing for the presence of bcr-abl can identify those patients which profit from Gleevec treatment. As ever more specifically designed anticancer agents are developed and clinically used, the determination of the target molecules in the tumor cells gets more and more important to stratify patients for the appropriate use of expensive therapies. Examples of recently applied drugs are Sutent or Bortezomib, all known to attack certain molecules frequently altered in many different tumors.
The treatment success of our clinical partners, who guide therapies according to our analytical findings convinces us that our methods are sensible. Evidence from the academic literature is supporting the principles of our strategy.* Beside the metabolic properties of the tumor cells, there are several other critical factors why the chemosensitivity tests cannot always predict that the tumor will respond as supposed by the results of our analyses:
The drug administered systemic must reach all the tumor cells
Patient-to-patient differences may exist how the drug is metabolized and excreted from the body
Subsets of disseminated tumor cells may be present which behave differently
Some cells may have yet unknown genetic mechanisms which render them resistant.
During therapy, tumor cells accumulate further mutations which may result in the selection of resistant clones.
Consequently, partial responses may occur and not necessarily a complete remission despite the results of in vitro testing has not indicated resistance. Since in vitro testing can not be absolutely accurate because of the mentioned reasons, our assay results should not be used as a reason to refuse giving chemotherapy. If a proven effective therapy has not yet been tried, the assay results should not determine that this therapy should not be used. However, the tests can help to choose drugs from the available therapy options that might be more effective than others . If resistance occurs to a drug, the tests can help to identify another agent that might work better.
What Types of Tumors Can Be Tested?
Most types of tumors can be tested, including tumors originating from lung, colon, breast, ovary, cervix, prostate, skin, intestine (stomach, gastric), esophagus, liver, kidney. In addition to these most prominent tumor diseases, other less frequent tumors can also be tested. Please inquire for special cases.
Hematological tumors can be assayed for typical rearrangements of hematological tumor cells to permit detection of minimal residual leukemia cells in the bloodstream and to monitor the success of treatment. If the therapy is effective, residual leukemia cells should disappear from the bloodstream.