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Cancer Treatment: The Critical Factors

Step Three: Circulating Tumor Cell Testing

Circulating tumor cell (CTC) testing involves the detection of cancer cells in the bloodstream. These circulating tumor cells are the "seeds" that break away from the primary site of cancer and spread to other parts of the body. Understanding circulating tumor cells is critically important since it is the spread of cancer to other parts of the body—and not the primary cancer—that is very often responsible for the death of a person with cancer.

Historically, medical science has been focused on the primary tumor, basing treatment decisions on the specific genetic characteristics of the primary cancer cells—which assumes that the metastatic cancer cells are genetically identical to the primary tumor. This assumption might be ill-advised, as research has demonstrated that metastatic cancer cells can be genetically dissimilar from the primary tumor as they become more highly differentiated.

In an illuminating study conducted with metastatic breast cancer patients, researchers compared the genetic composition of the cancer cells that had formed distant metastasis to the genetic composition of the corresponding cancer cells in the primary breast tumor. The findings were alarming—in 31% of the comparisons, the genetic composition of the metastatic cancer cells differed almost completely from that of the primary breast tumors.11 Amazingly, further analysis revealed that none of the pairs of primary breast tumors with its corresponding metastatic cancer were identical. Based on these findings, the authors remarked that "because metastatic cells often have a completely different genetic composition, their phenotype [biological behavior], including aggressiveness and therapy responsiveness, may also vary substantially from that seen in the primary tumors," leading to their conclusion that "the resulting heterogeneity [genetic variability] of metastatic breast cancer may underlie its poor responsiveness to therapy..." To further support the evidence that metastatic cancer cells can vary genetically from the primary tumor, two additional studies with breast cancer patients have demonstrated that CTC can be HER2 positive while the primary breast tumor can be HER2 negative.12,13

This research suggests that directing treatment towards the cancer cells of the primary tumor can, in some cases, be "barking up the wrong tree." Treatments designed to attack the primary tumor could fail to destroy the circulating tumor cells. For this reason, focusing on the metastatic cancer cells could potentially lead to better results. CTC testing provides us with the means with which we can now focus our attention on these potential metastatic cancer cells.

CTC testing has been shown to improve prognostic accuracy. German scientists studied 35 women with non-metastatic breast cancer who had their levels of CTC measured before they had received any treatment for their cancer.13 Seventeen tested positive for CTC, while 18 tested negative for CTC. The group that tested negative for CTC had a median overall survival of 125 months. The group with five or more CTC present in their blood sample had a median overall survival of only 61 months—less than half as long. In a related study, researchers at the University of Texas M. D. Anderson Cancer Center measured CTC in 151 women with metastatic breast cancer.14 These patients were also evaluated for other prognostic cancer markers, such as hormone receptor status, CA 27.29, and HER2 status. Those who had five or more CTC per blood sample had a median overall survival of 13.5 months. The median overall survival for those with less than five CTC per blood sample was over 29 months. The researchers also discovered that the presence of five or more CTC in a blood sample had the highest predictive value compared to all other tumor markers. The researchers went on to state that "circulating tumor cells have superior and independent prognostic value…"

Furthermore, recent research indicates that CTC evaluation can be used to predict prognosis for men with prostate cancer. Researchers at Thomas Jefferson University compared the levels of CTC in 37 men with metastatic prostate cancer.15 Their findings were remarkable—for the men with five or more CTC per blood sample, the median overall survival was only 8.4 months. For those men with fewer than five CTC the median overall survival was 48 months. Yet another study measured CTC in 55 men with a rising PSA after surgery for prostate cancer.16 A rising PSA after surgery is strongly predictive of prostate cancer recurrence.17 Radiation therapy was administered to 15 patients. 60% of those who were CTC positive had progression of their disease during radiation therapy, while there were no disease progressions in the CTC negative group. Additional studies have confirmed these results.18,19

One of the most exciting potential uses of CTC technology is to allow doctors to evaluate treatment effectiveness during the early phase of therapy. With regard to chemotherapy, doctors have often had to wait at least a few months before they can assess the effectiveness of treatment. This inability to evaluate a treatment’s efficacy during the early phase of therapy can have disastrous consequences for the person with cancer. Those three months of waiting to know if the treatment is working can make the difference between altering therapy to reflect the lack of response, or continuing with an ineffective treatment and allowing the cancer to progress. This waiting may become a thing of the past, as recent studies have demonstrated that CTC testing can reliably predict the response to treatment during the early phase of therapy. In an important study,20 163 women with metastatic breast cancer were tested for CTC at four different times during the course of treatment. The first measurement of CTC was taken approximately four weeks after treatment had begun. At the first measurement the researchers discovered that those patients with less than five CTC per sample had a median overall survival of greater than 18.5 months. Those with five or more CTC per sample had a median overall survival of only seven months. Additionally, 66% of those with five or more CTC per sample had died after one year, compared to only 19% of those who had less than five CTC per sample. Thus, as early as four weeks into therapy CTC testing determined which patients were not responding and whose cancer would continue to progress with ineffective treatment. The authors of this study concluded that "detection of elevated CTC at any time during therapy is an accurate indication of subsequent rapid disease progression and mortality for metastatic breast cancer patients."

In a study published in the Journal of Clinical Oncology in 2008, 430 patients with metastatic colon cancer had CTC testing before and 3‒5 weeks after the initiation of treatment with chemotherapy.21 For patients who initially started with three or more CTC detected in their blood sample, if they converted to less than three CTC then the median survival was 11.0 months. However, if they continued to have three or more CTC on follow-up testing then the median survival was only 3.7 months. For patients whose cancers were deemed to be non-progressing by imaging studies, median survival was 18.8 months if they had less than three CTC on follow-up testing, whereas those with three or more CTC on follow-up testing had a median survival of only 7.1 months. The authors concluded that "the number of CTCs before and during treatment is an independent predictor of…overall survival in patients with metastatic colorectal cancer. CTCs provide prognostic information in addition to that of imaging studies."

CTC testing can also predict the likelihood of recurrence after initial cancer treatment. In 2006, scientists in Spain measured the presence of CTC in 84 high-risk breast cancer patients after they received initial chemotherapy.22 The researchers found dramatic differences in the relapse rates between those who tested positive for CTC, as compared to those that did not have any CTC detected in their blood samples. The group testing positive for CTC had a 269% increased risk of relapse, and a 300% increased risk of death, compared to the group testing negative for CTC. Further analysis showed a striking 53-month difference in the time to relapse between the groups. In a related study, German scientists in 2008 studied 25 women with breast cancer that had not metastasized.23 They measured CTC levels before and after the patients received chemotherapy. The results showed that relapse occurred in only 9% of patients whose CTC levels indicated a decline, no change, or minor increase when compared to baseline CTC levels. There was a substantially higher relapse rate of 40% in the group with a CTC increase at the end of therapy.

Given that CTC can be the seeds that eventually form metastatic disease, then CTC analysis provides medical science with an excellent opportunity to examine the genetic features of these cancer cells before metastasis occurs, when treatment is far more likely to be successful. In addition to detecting the presence and quantity of CTC in the bloodstream, recent advances in technology now allows the examination of CTC for a large number of tumor cell markers and genetic expressions. The information obtained from this analysis can provide vital insight as to which chemotherapy drugs are best suited to exploit the genetic weaknesses of the CTC, as well as which chemotherapy agents are likely to be powerless against the genetic strengths of the CTC.

Let’s illustrate the benefits of CTC analysis of tumor markers and genetic expressions with a few examples. Chemotherapy drugs can exert their therapeutic effects by inhibiting essential enzymes within the cancer cell. The over expression of these enzymes—called drug targets—can enhance the tumor destructive effects of these drugs. Adriamycin is a prime example of this mechanism of action. The main drug target for Adriamycin is topoisomerase 2. Studies have demonstrated that those patients with cancers expressing higher levels of topoisomerase 2 can benefit from treatment with Adriamycin.24 Conversely, those patients with cancers that produce smaller amounts of topoisomerase 2 are less likely to respond to Adriamycin. Cancer cells also have the ability to produce enzymes that convert chemotherapy drugs into less potent forms, which weakens the anti-tumor activity of these drugs. 5-FU is commonly used in the treatment of breast and colon cancer. DPD is an enzyme that degrades 5-FU to an inactive metabolite. Cancer cells expressing higher levels of DPD can be resistant to 5-FU. One study of colorectal cancer patients treated with 5-FU revealed that those with high DPD levels had significantly shorter overall survival compared to patients with low DPD expression.25

As an added benefit, genetic analysis of CTC can inform us as to which natural supplements might be best indicated. For instance, NF-kB promotes the growth of cancer. Curcumin is an inhibitor of NF-kB.26 So, a person whose cancer is expressing high levels of NF-kB might consider including curcumin as part of their supplement program.

Some cancers are able to produce GSTpi, which confers resistance to multiple chemotherapy drugs. Ellagic acid—from pomegranate—inhibits GSTpi.27 Supplementation with ellagic acid may be wise if CTC analysis demonstrates over production of GSTpi.

How to Implement Step Three

To test for the presence and quantity of CTC in your blood, speak with your physician regarding the Veridex CellSearch CTC test. You may also order quantitative CTC tests for breast, colon, and prostate cancer from Life Extension at 800-226-2370.

Note: Qualitative CTC testing is most feasible with any kind of carcinoma (eg, lung, colon, breast, ovary, cervix, prostate, stomach, gastric, esophagus, liver...), mesothelioma or melanoma.

It is also possible to test for synovial sarcoma. However, other types of sarcoma (eg, liposarcoma, leiomyosarcoma, chondrosarcoma...) gave lower success rates for isolation of tumor cells (<50%).

Testing of tumors of the central nervous system (eg, glioblastoma) is limited, because in the majority of cases it is not successful to isolate CTCs, since these tumors rarely shed tumor cells into the bloodstream.

Hematological cancers (eg, Hodgkin- or non-Hodgkin lymphomas, B-cell lymphomas, myelogenous and lymphocytic leukemias) can be assayed as well. Please note that we cannot test for T-cell cancers at all. Testing for multiple myeloma (MM) is not recommended since we observed low detection rates in MM.

For a molecular analysis of your CTC, contact the International Strategic Cancer Alliance at 610-628-3419 to arrange for a blood specimen to be obtained and shipped for testing. Note: this test is qualitative and will not provide the number of CTC present in your blood. You may have to pay out of pocket for this test because not all insurance plans reimburse for it. Please note that this molecular analysis test of circulating tumor cells may not be of benefit to all cancer patients. While it provides a basis for improved treatment, not all cancers are effectively treated with currently available therapies.