Life Extension Magazine®

Issue: Apr 2010

Designing an Individually Tailored Cancer Treatment Utilizing Advanced CTC Molecular Analysis

Using sophisticated molecular analysis, scientists can now design tailored cancer treatment protocols by profiling genetic differences among circulating tumor cells within each patient. Life Extension® hopes even the most indifferent oncologists will abandon the conventional “one-size-fi ts-all” approach and utilize this superior technology.

By Steven Nemeroff, ND.

Designing an Individually Tailored Cancer Treatment Utilizing Advanced CTC Molecular Analysis

For decades, traditional medicine has made cancer treatment decisions based on the “one size fits all” approach—in which everyone with a particular cancer received the same treatment. Tragically, this approach has failed to benefit the vast majority of women with breast cancer who received standard chemotherapy protocols. 

This approach has refused to acknowledge the individual differences inherent in the cancer that could have affected treatment. Now, exciting new advances in circulating tumor cell (CTC) technology can allow medical science to finally move away from this outdated approach and towards an individually tailored cancer treatment program. 

The basic circulatory tumor cells (CTC) test you learned about in the previous article measures the number of CTC in the bloodstream.

In this article, we’ll examine an even more advanced circulating tumor cell test available in Europe that measures the genetic characteristics of circulating tumor cells and makes specific conventional and natural treatment suggestions based on the individual patient’s CTC profile. This technology offers great potential to optimally design an individualized treatment, targeting the specific weaknesses of these potential metastatic cancer cells.

Exposing the Flaws of the “One Size Fits All” Approach

When a person is prescribed a treatment for their cancer, they might assume that the treatment was chosen based on the uniqueness of their cancer. For instance, when a woman with early-stage breast cancer is told that her chemotherapy treatment regimen will consist of the drugs Adriamycin®, Cytoxan®, and Taxol®, (ACT), she might think this treatment was individually tailored for her cancer. In actuality, ACT is a standard chemotherapy protocol given to breast cancer patients. This “one size fits all” approach to breast cancer treatment would work well if superior results were obtained from this routine practice. Sadly, this has not been the case. The “one size fits all” approach to prescribing chemotherapy has failed to improve survival for the vast majority of women with breast cancer. In a shocking study of women with breast cancer over the age of 50 who had cancer present in their lymph nodes, standard chemotherapy regimens were shown to increase 10-year survival by only 3%.1

In a related study of breast cancer patients receiving tamoxifen, researchers at the Dana-Farber Cancer Institute in Boston determined that those over age 50 with cancer in their lymph nodes did not receive any statistically significant survival benefits from receiving generic chemotherapy regimens compared to tamoxifen alone!2

A critical flaw of the “one size fits all” approach rests in treating all breast cancers as if they are one and the same. Although traditional oncology does make distinctions in a few obvious qualities, such as size of the cancer, lymph node status, and estrogen receptor status, we now know there can be substantial individual differences in cancer cell genetics among those with “similar” breast cancers. These differences can dramatically affect the response to treatment.

Exposing the Flaws of the “One Size Fits All” Approach

A powerful illustration of the lack of appreciation for individual differences in cancer treatment was clearly revealed in a landmark study published in the New England Journal of Medicine in 2007. Researchers compared women with lymph node-positive breast cancer who received ACT chemotherapy to those who did not receive chemotherapy. Their HER2 status was also determined—which refers to a genetic characteristic of the cancer. The researchers discovered that the group of women who were HER2 negative and estrogen receptor positive did not benefit at all from taking Taxol®!3 The ramifications of this study are immense, as approximately two thirds of women with breast cancer fall into this category. In recognition of the failure of Taxol® to benefit this large group of women with breast cancer, oncologist Anne Moore, MD, Professor of Clinical Medicine at the Weill Medical College of Cornell University in New York stated, “The days of ‘one size fits all’ therapy for patients with breast cancer are coming to an end.”4

A further indictment of the “one size fits all” approach was prominently displayed in a study published in the Journal of the National Cancer Institute in 2008. In this investigation, scientists measured the effectiveness of an anthracycline-based chemotherapy regimen in 5,354 women with early-stage breast cancer. Anthracyclines are a class of chemotherapy drugs of which Adriamycin® is a key member. The scientists determined that women with early-stage breast cancer who were HER2 negative derived absolutely no benefit from taking Adriamycin® or other anthracycline drugs!5 Given that approximately 80% of breast cancers are HER2 negative,4 then only 1 of 5 women with breast cancer can benefit from these drugs that have considerable toxicity associated with their use. In one study, 7% of patients treated with Adriamycin® developed congestive heart failure.6

Another fundamental flaw of the current cancer treatment model is the exclusive focus on the primary tumor. However, it is the spread of cancer to other parts of the body that is very often lethal. Once the primary tumor has been surgically removed, then chemotherapy will often be prescribed in an attempt to kill any cancer cells remaining in the body that could potentially form metastases.

The choice of the appropriate chemotherapy agent to target the metastatic cancer cells is usually based on the characteristics of the primary tumor—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.

Tailoring Cancer Treatment for the Individual

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!7 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 studies8,9 with breast cancer patients have demonstrated that CTC can be HER2 positive while the primary breast tumor can be HER2 negative!

Tailoring Cancer Treatment for the Individual

Clearly, this old-fashioned approach of prescribing the same treatment for everyone with a particular cancer needs to be succeeded by a more enlightened paradigm which tailors treatment towards the individual uniqueness of the cancer. Furthermore, this “person-centered” model places emphasis on directing treatment decisions towards the distinguishing characteristics of the potential metastatic CTC. One of the most exciting applications of CTC technology is its use to facilitate the design of a treatment program that is truly customized to the genetic attributes of the person’s cancer. 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. In essence, CTC testing constructs a genetic fingerprint of these potential metastatic cancer cells. 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.

What You Need to Know: Designing Individually Tailored Cancer Treatment

Traditional cancer care is based on a “one size fits all” approach in which everyone with a certain type of cancer receives the same treatment. This approach fails to consider individual differences that may impact treatment choices and efficacy.

  • Circulating tumor cells are often genetically different from the primary tumor and can be the seeds that eventually form metastatic tumors.
  • Now, an advanced test available in Europe measures the genetic characteristics of circulating tumor cells (CTCs) and provides specific conventional and natural treatment suggestions.
  • The information gathered from an advanced CTC test can be used to design an optimal individualized treatment plan targeting the weaknesses of potential metastatic cells. Since cancer metastases are often deadlier than primary tumors, targeting CTCs is essential to comprehensive cancer treatment.
The Battle is Fought at the Cellular Level

The Battle is Fought at the Cellular Level

Chemotherapy drugs can interact with cancer cells in various ways. These crucial interactions can decide the winner in the battle between the cancer and the chemotherapy drug. For example, some chemotherapy drugs only become fully activated after entering the cancer cell. This process is dependent upon the presence of certain enzymes within the cancer cell. A reduced production of these enzymes can lead to poor activation of the chemotherapy agent, resulting in a diminished anti-cancer effect. One chemotherapy drug which requires enzymatic activation is fluorouracil (5-FU), which is converted into its active form within the cancer cell by the enzyme uridine phosphorylase. Studies have shown that cancer cells resistant to 5-FU have a reduced expression of uridine phosphorylase.10,11

Gemzar® is a chemotherapy drug used in the treatment of lung, pancreatic, bladder, and breast cancer. Gemzar® requires the enzyme deoxycytidine kinase (DCK)—manufactured within the cancer cell—to become fully activated. Cancers that produce lesser amounts of DCK are protected from the effects of Gemzar®.12

Chemotherapy drugs can also exert their therapeutic effects by inhibiting essential enzymes within the cancer cell. The overexpression of these enzymes—called drug targets—can enhance the tumor destructive effects of these drugs. Adriamycin® (doxorubicin) 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®.13

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. Dihydropyrimidine dehydrogenase (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.14

Cyclophosphamide (Cytoxan®) is utilized in the treatment of lymphoma, leukemia, and cancers of the breast, ovary, and bladder. Cancer cells produce an enzyme called gamma-glutamylcysteine synthetase (GCS), which metabolizes and inactivates cyclophosphamide. Cancer cells that manufacture greater amounts of GCS can possess a tactical advantage in the battle against cyclophosphamide.15

Other genetic expressions within the cancer cell can have a significant impact upon the effectiveness of chemotherapy drugs. The platinum drugs—cisplatin, carboplatin, oxaliplatin—are used in the treatment of ovarian, bladder, testicular, and lung cancer. These drugs inflict damage upon the cancer cell by attacking DNA. Cancer cells produce the excision repair cross-complementation 1 (ERCC1) protein, which is able to repair the damage caused by these drugs. Greater production of ERCC1 offers cancer cells a degree of immunity from platinum drugs.

A team of researchers in Italy measured ERCC1 mRNA levels in lung cancer patients receiving cisplatin.16 The researchers found a dramatic difference in survival based on the levels of ERCC1. Patients with cancers expressing lower levels of ERCC1 had a median overall survival of 23 months, compared to a median overall survival of 12.4 months in those with higher ERCC1 levels.

Methotrexate is a member of the “one size fits all” chemotherapy regimen for breast cancer. Methotrexate wields its tumoricidal activity by blocking an enzyme within the cancer cell called dihydrofolate reductase (DHFR). Cancer cells can compensate by producing more DHFR. Overproduction of DHFR provides cancer cells with a defense against methotrexate.17

In the battle against chemotherapy drugs, some cancers have developed a very clever mechanism to shift the balance of power in their favor. Multidrug resistance 1 (MDR1) is able to conveniently transport chemotherapy drugs out of the cancer cell, which drastically reduces their cancer-killing ability. Cancers that generate greater amounts of MDR1 are resistant to multiple chemotherapy drugs, such as vincristine, Taxol®, mitomycin C, and Adriamycin®.18,19

Advanced CTC Analysis is Now Available

As an added benefit, genetic analysis of CTC can inform us as to which natural supplements might be best indicated. For instance, nuclear factor-kappaB (NF-kB) promotes the growth of cancer. Curcumin is an inhibitor of NF-kB.20 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 glutathione S-transferase pi (GST-pi), which confers resistance to multiple chemotherapy drugs. Ellagic acid—from pomegranate—inhibits GST.21 Supplementation with ellagic acid may be wise if CTC analysis demonstrates overproduction of GST-pi.

Advanced CTC Analysis is Now Available

When taking into consideration the numerous characteristics of the cancer that create its unique genetic fingerprint, we can now fully appreciate the radical differences that can occur between individuals with the “same” cancer, which may require distinctly different treatments. CTC analysis can now allow medical science to take the next step in cancer treatment by uncovering the key distinctions within the cancer—which ultimately distinguishes those with the “same” cancer from one another. The results of CTC analysis can help to ensure the design of a therapy best suited for an individual’s cancer. Fortunately, advanced CTC assays are now available.

CTC analysis can now allow medical science to take the next step in cancer treatment by uncovering the key distinctions within the cancer—which ultimately distinguishes those with the “same” cancer from one another.

If you have any questions on the scientific content of this article, please call a Life Extension® Wellness Specialist at 1-866-864-3027.

References

1. Polychemotherapy for early breast cancer: an overview of the randomised trials. Early Breast Cancer Trialists’ Collaborative Group. Lancet. 1998 Sep 19;352(9132):930-42.

2. Gelber RD, Cole BF, Goldhirsch A, et al. Adjuvant chemotherapy plus tamoxifen compared with tamoxifen alone for postmenopausal breast cancer: meta-analysis of quality-adjusted survival. Lancet. 1996 Apr 20;347(9008):1066-71.

3. Hayes DF, Thor AD, Dressler LG, et al. Cancer and Leukemia Group B (CALGB) Investigators. HER2 and response to paclitaxel in node-positive breast cancer. N Engl J Med. 2007 Oct 11;357(15):1496-506.

4. Moore A. Breast-cancer therapy—looking back to the future. N Engl J Med. 2007 Oct 11;357(15):1547-9.

5. Gennari A, Sormani MP, Pronzato P, et al. HER2 status and efficacy of adjuvant anthracyclines in early breast cancer: a pooled analysis of randomized trials. J Natl Cancer Inst. 2008 Jan 2;100(1):14-20.

6. Swain SM, Whaley FS, Ewer MS. Congestive heart failure in patients treated with doxorubicin: a retrospective analysis of three trials. Cancer. 2003 Jun 1;97(11):2869-79.

7. Kuukasjärvi T, Karhu R, Tanner M, et al. Genetic heterogeneity and clonal evolution underlying development of asynchronous metastasis in human breast cancer. Cancer Res. 1997 Apr 15;57(8):1597-604.

8. Meng S, Tripathy D, Shete S, et al. HER-2 gene amplification can be acquired as breast cancer progresses. Proc Natl Acad Sci U S A. 2004 Jun 22;101(25):9393-8.

9. Wülfing P, Borchard J, Buerger H, et al. HER2-positive circulating tumor cells indicate poor clinical outcome in stage I to III breast cancer patients. Clin Cancer Res. 2006 Mar 15;12(6):1715-20.

10. Chung YM, Park S, Park JK, et al. Establishment and characterization of 5-fluorouracil-resistant gastric cancer cells. Cancer Lett. 2000 Oct 16;159(1):95-101.

11. Inaba M, Mitsuhashi J, Sawada H, et al. Reduced activity of anabolizing enzymes in 5-fluorouracil-resistant human stomach cancer cells. Jpn J Cancer Res. 1996 Feb;87(2):212-20.

12. Sebastiani V, Ricci F, Rubio-Viqueira B, et al. Immunohistochemical and genetic evaluation of deoxycytidine kinase in pancreatic cancer: relationship to molecular mechanisms of gemcitabine resistance and survival. Clin Cancer Res. 2006 Apr 15;12(8):2492-7.

13. Di Leo A, Gancberg D, Larsimont D, et al. HER-2 amplification and topoisomerase IIalpha gene aberrations as predictive markers in node-positive breast cancer patients randomly treated either with an anthracycline-based therapy or with cyclophosphamide, methotrexate, and 5-fluorouracil. Clin Cancer Res. 2002 May;8(5):1107-16

14. Ciaparrone M, Quirino M, Schinzari G, et al. Predictive role of thymidylate synthase, dihydropyrimidine dehydrogenase and thymidine phosphorylase expression in colorectal cancer patients receiving adjuvant 5-fluorouracil. Oncology. 2006;70(5):366-77.

15. Richardson ME, Siemann DW. Thiol-related mechanisms of resistance in a murine tumor model. Int J Radiat Oncol Biol Phys. 1994 May 15;29(2):387-92.

16. Ceppi P, Volante M, Novello S, et al. ERCC1 and RRM1 gene expressions but not EGFR are predictive of shorter survival in advanced non-small-cell lung cancer treated with cisplatin and gemcitabine. Ann Oncol. 2006 Dec;17(12):1818-25

17. Takemura Y, Kobayashi H, Miyachi H. Cellular and molecular mechanisms of resistance to antifolate drugs: new analogues and approaches to overcome the resistance. Int J Hematol. 1997 Dec;66(4):459-77.

18. Borst P, Evers R, Kool M, et al. A family of drug transporters: the multidrug resistance-associated proteins. J Natl Cancer Inst. 2000 Aug 16;92(16):1295-302.

19. Litman T, Druley TE, Stein WD, et al. From MDR to MXR: new understanding of multidrug resistance systems, their properties and clinical significance. Cell Mol Life Sci. 2001 Jun;58(7):931-59.

20. Siwak DR, Shishodia S, Aggarwal BB, et al. Curcumin-induced antiproliferative and proapoptotic effects in melanoma cells are associated with suppression of IkappaB kinase and nuclear factor kappaB activity and are independent of the B-Raf/mitogen-activated/extracellular signal-regulated protein kinase pathway and the Akt pathway. Cancer. 2005 Aug 15;104(4):879-90.

21. Hayeshi R, Mutingwende I, Mavengere W, et al. The inhibition of human glutathione S-transferases activity by plant polyphenolic compounds ellagic acid and curcumin. Food Chem Toxicol. 2007 Feb;45(2):286-95.