Arizona Advanced Medicine Clinic

What if there were a test for cancer that had therapeutic as well as predictive value?

Did you ever wonder why some people do well (relatively speaking) with chemotherapy, and others do not respond at all? Why some tumors appear to respond, but then recur a few weeks, months or years later? Why treatment has to be by trial and error instead of being based on rational choices for the individual? After all, we treat pneumonia based on the infecting organism’s sensitivity to antibiotics. Why not treat cancer the same way?

The American Cancer Society website states: “All available chemosensitivity assays are able to report drug ‘resistance’ information. Resistance implies that when a patient’s cancer cells are exposed to a particular chemotherapy agent in the laboratory, the cancer cells will continue to live and grow. Some chemosensitivity assays also are able to report drug ‘sensitivity’ information. Sensitivity implies that when a patient’s cancer cells are treated with a particular chemotherapy agent in the laboratory, that agent will kill the cancer cells or inhibit their proliferation.”[1]

The good news - there is such a test for breast cancer, measuring the genetic predisposition to development of cancer (and, by the way, also to chemical sensitivity, environmental illness, chronic inflammatory disease and poor detoxification capacity). The test measures methylation of DNA, specific sequences, and it uses peripheral blood to do it. No need to do surgery and get tissue biopsies. This test is done through a simple blood draw - like a blood biopsy - measuring the DNA of white cells which are in plentiful supply.[2]

The bad news - this test does not measure chemosensitivity, so it’s no good after you already have cancer. But it may have some predictive value, and might at least give you a heads-up that it’s time to change your diet and lifestyle.

The other bad news - the test will not be available at least until the year 2017. It has to be checked and double checked, with all the statistical analysis validated, to be sure that the correct conclusions are being drawn. At the moment, the American Society of Clinical Oncology recommends against doing such testing.

The really bad news - Tests of chemosensitivity come and go.

The infamous Duke University cancer biomarkers experiment came to a crashing close when two things happened: First, the statistics were found to be poorly done and inaccurate.[3] And second, the lead researcher was found to have falsified his credentials.[4] That was in 2010.

The bright side of that whole sad story is that the Institute of Medicine and the National Cancer Institute are finally looking at such genetic testing with a fresh eye.

Other tests may also have predictive value.

Inflammation is known to be a cause of cancer - or at the very least an early warning sign. There are biomarkers which can be measured in a standard laboratory which contribute to the development of cancer, and which are certainly early warning signs.[5]

At the Arizona Center for Advanced Medicine, we routinely measure c-reactive protein and other biomarkers of inflammation like sedimentation rate and fibrinogen levels, to determine a patient’s state of inflammation and risk of chronic illness.

Diabetes and insulin resistance are also predictive factors for development of cancer. We also routinely measure both fasting blood sugar and fasting insulin, so that we do not allow the patient with insulin resistance to develop full-blown diabetes before we begin to treat them preventively.

No chemosensitivity test using peripheral blood has yet come in to common use in the United States.

There are, however, some companies in the world which provide such a test. Of course it costs money to do the testing. Nevertheless, these tests do give some idea about rational choices of chemotherapy based on the individual’s tumor genetics rather than population results.

Two basic mechanisms of chemosensitivity testing are used: Type I are assays based on cell proliferation or DNA synthesis. Type II are based on cell death. Type I assays predict which agents the tumor should be sensitive to. Type II assays state which chemo agents actually killed the patient’s tumor cells in a petri dish.

We are aware of two laboratories which use peripheral blood to determine the likelihood, by circulating tumor cell genetics, of a cancer’s chemosensitivity or resistance. Both labs isolate peripheral tumor cells and grow them in cell culture before determining their genetic make-up and potential sensitivity to various commonly used chemotherapeutic drugs.

BioFocus Laboratory in Germany and the RGCC Laboratory in Greece both provide culture assays of circulating tumor cells (in peripheral blood), with assay of cell genetics which can provide a reason why these cells should or should not be sensitive to specific chemotherapy agents (Type I). Both companies can test the tumor cells against alternative as well as standard therapies. The biggest difference between the two companies is that the RGCC Laboratory also performs a viability assay (Type II) using specific drugs, to see if there is a correlation between the genetics and the performance of specific drugs against the cultured tumor cells.

Other laboratories use tumor tissue, either fresh from surgery or fixed in a paraffin bloc, to determine likelihood of chemosensitivity to various agents.[6,7] Caris Lifesciences, a private company in Phoenix, AZ, does a test they call “molecular” profiling, based on immunohistochemistry, FISH, RT-PCR, and molecular microarrays. Precision Therapeutics requires fresh tissue for their analysis. Both of these laboratories provide a type I analysis. Neither lab tests alternative treatments, only standard chemotherapy.

Neither of these tests - either the circulating tumor cell or the paraffin block method - is in common and “accepted” use by the medical profession, for reasons which escape me. Both can provide useful information when determining a rational approach to chemotherapeutic treatment of a known cancer.

Why are these tests not accepted by the medical oncology community?

An article in Fortune Magazine in 2004 describes the situation well. The author writes:

…virtually all these experts offered testimony that, when taken together, describes a dysfunctional “cancer culture”-a groupthink that pushes tens of thousands of physicians and scientists toward the goal of finding the tiniest improvements in treatment rather than genuine breakthroughs; that fosters isolated (and redundant) problem solving instead of cooperation; and rewards academic achievement and publication over all else.[8]

Tumors may start out as a single mutated cell with abnormal DNA. However, one of the hallmarks of cancer is its extreme genetic instability. By the time the original cell has divided a sufficient number of times to form a tumor, it has also mutated multiple times, so that the genetics of the resulting tumor are no longer identical to the genetics of the original cell. The larger tumors are made up of countless genetic cousins, many of which may have far different responses to chemotherapeutic agents than the original tumor cells.

And yet we persist doing clinical trials with chemotherapeutic agents, comparing one drug to another in a most heterogeneous population of people. We have no idea of the tumor genetics - patients with tumor type X are all lumped together - and we are looking at progression-free survival as an endpoint. That means how long does it take for the tumor to start growing again. We’re talking months, not years, before the tumor grows again. We seem to have pretty much given up the 5-year benchmark. Patients are lumped together in these trials without regard for their genetic make-up. So is it any wonder that our chemotherapeutic agents work so poorly, and that so many people die of cancer every year?

Most of the time it is not the original tumor that kills a victim - it is the fact that those tumors eventually metastasize, and begin to take over the body. Very little research is done on what causes tumors to metastasize.

So what will it take to win this war we have declared on cancer? Looking again at the Fortune article:

The cancer community must embrace a coordinated assault on this disease. Doctors and scientists now have enough knowledge to do what Sydney Farber hoped they might do 33 years ago: to work as an army, not as individuals fighting on their own. We can change the way cancer research is funded, putting emphasis on clinical response, and involving laboratory researchers with the physicians who are treating the patients.

We can look for good predictive biomarkers - thus increasing our ability to diagnose potential cancer long before it forms.

We can look at diet and lifestyle - for real, not just paying lip service. It’s not so difficult to change our diet, if the alternative is death by metastatic cancer. What messages are we giving our bodies through the foods we eat?

filopodiaCancer cells - at least those that metastasize - act almost like nerve cells or parasites. They send out a little exploring foot called a filopodium before they actually begin to move, or to settle down into a tissue. Filopodia are characteristic parts of growing nerve cells. So do cancer cells somehow have intelligence? Are they in some way related to our brain and nervous system? Does this explain why we develop tumors and metastases in some places but not in others? Do they somehow seek out those places where we are unhealthy? Where we have major metabolic disturbances?

If that is indeed the case, then we are well advised to be careful how and what we think... we encourage our brain cells to form new neural pathways when we are learning a new task. Is it possible that we might encourage cancer stem cells to do the same thing?

What’s more, cancer cells appear to be able to transform themselves into cancer stem cells , providing at least a partial explanation for why cancer can become so lethal, once it begins to metastasize and spread around the entire body. Cancer appears to be a two-way street - giving a possible explanation for the so-called “spontaneous” cures.

So if cancer cells can transform themselves back and forth, who is in control? Where are the brains of the outfit? In our efforts to control the spread of cancer, I think we forget to look at the driving forces behind the development of cancer in the first place.

Our next discussion will tackle some of those driving forces.


[1] http://csn.cancer.org/node/145883 downloaded 7/1/2012 [2] Brennan K, Garcia-Closas M, Flanagan JM et al. Intragenic ATM methylation in peripheral blood DNA as a biomarker of breast cancer risk. Cancer Res. 2012 May 1;72(9):2304-13. [3] Baggerly KA, Coombs KR. Deriving chemosensitivity from cell lines: Forensic bioinformatics and reproducible research in high-throughput biology. Annals of Applied Statistics 2009, Vol. 3, No. 4, 1309-1334. DOI: 10.1214/09-AOAS291. Downloaded 7/1/2012 from http://arxiv.org/abs/1010.1092 [4] Kolata G. How Bright Promise in Cancer Testing Fell Apart. New York Times 07-07-2011. [5] Whicher J T, Chambers R E et al. Acute phase response of serum amyloid A protein and C reactive protein to the common cold and influenza. J Clin Pathol. 1985 March; 38(3): 312-316. [6] Rational Therapeutics http://www.rational-t.com/cancer-testing/index.aspx [7] Weisenthal LM, Patel N, Rueff-Weisenthal C. Cell culture detection of microvascular cell death in clinical specimens of human neoplasms and peripheral blood. J Int Med 264;3:275-87 (Sept 2008). [8] The War on Cancer, downloaded 7/4/2012 from http://blog.aperio.com/articles/Fortune_Cancer.pdf [9] Shibue T, Brooks MW, Weinberg RA et al. The outgrowth of micrometastases is enabled by the formation of filopodium-like protrusions. Cancer Discovery, May 18, 2012; doi: 10.1158/2159-8290.CD-11-0239. [10] Chaffer CL, Brueckmann I, Weinberg RA et al. Normal and neoplastic nonstem cells can spontaneously convert to a stem-like state. Proc Natl Acad Sci U S A. 2011 May 10;108(19):7950-5.
What if there were a test for cancer that had therapeutic as well as predictive value?

The good news - there is such a test for breast cancer, measuring the genetic predisposition to development of cancer (and, by the way, also to chemical sensitivity, environmental illness, chronic inflammatory disease and poor detoxification capacity). The test measures methylation of DNA, specific sequences, and it uses peripheral blood to do it. No need to do surgery and get tissue biopsies. This test is done through a simple blood draw - like a blood biopsy - measuring the DNA of white cells which are in plentiful supply.[2]

The bad news - this test does not measure chemosensitivity, so it’s no good after you already have cancer. But it may have some predictive value, and might at least give you a heads-up that it’s time to change your diet and lifestyle.

The other bad news - the test will not be available at least until the year 2017. It has to be checked and double checked, with all the statistical analysis validated, to be sure that the correct conclusions are being drawn. At the moment, the American Society of Clinical Oncology recommends against doing such testing.

The really bad news - Tests of chemosensitivity come and go.

The infamous Duke University cancer biomarkers experiment came to a crashing close when two things happened: First, the statistics were found to be poorly done and inaccurate.[3] And second, the lead researcher was found to have falsified his credentials.[4] That was in 2010.

The bright side of that whole sad story is that the Institute of Medicine and the National Cancer Institute are finally looking at such genetic testing with a fresh eye.

Other tests may also have predictive value.

Inflammation is known to be a cause of cancer - or at the very least an early warning sign. There are biomarkers which can be measured in a standard laboratory which contribute to the development of cancer, and which are certainly early warning signs.[5]

At the Arizona Center for Advanced Medicine, we routinely measure c-reactive protein and other biomarkers of inflammation like sedimentation rate and fibrinogen levels, to determine a patient’s state of inflammation and risk of chronic illness.

Diabetes and insulin resistance are also predictive factors for development of cancer. We also routinely measure both fasting blood sugar and fasting insulin, so that we do not allow the patient with insulin resistance to develop full-blown diabetes before we begin to treat them preventively.

No chemosensitivity test using peripheral blood has yet come in to common use in the United States.

There are, however, some companies in the world which provide such a test. Of course it costs money to do the testing. Nevertheless, these tests do give some idea about rational choices of chemotherapy based on the individual’s tumor genetics rather than population results.

Two basic mechanisms of chemosensitivity testing are used: Type I are assays based on cell proliferation or DNA synthesis. Type II are based on cell death. Type I assays predict which agents the tumor should be sensitive to. Type II assays state which chemo agents actually killed the patient’s tumor cells in a petri dish.

We are aware of two laboratories which use peripheral blood to determine the likelihood, by circulating tumor cell genetics, of a cancer’s chemosensitivity or resistance. Both labs isolate peripheral tumor cells and grow them in cell culture before determining their genetic make-up and potential sensitivity to various commonly used chemotherapeutic drugs.

BioFocus Laboratory in Germany and the RGCC Laboratory in Greece both provide culture assays of circulating tumor cells (in peripheral blood), with assay of cell genetics which can provide a reason why these cells should or should not be sensitive to specific chemotherapy agents (Type I). Both companies can test the tumor cells against alternative as well as standard therapies. The biggest difference between the two companies is that the RGCC Laboratory also performs a viability assay (Type II) using specific drugs, to see if there is a correlation between the genetics and the performance of specific drugs against the cultured tumor cells.

Other laboratories use tumor tissue, either fresh from surgery or fixed in a paraffin bloc, to determine likelihood of chemosensitivity to various agents.[6,7] Caris Lifesciences, a private company in Phoenix, AZ, does a test they call “molecular” profiling, based on immunohistochemistry, FISH, RT-PCR, and molecular microarrays. Precision Therapeutics requires fresh tissue for their analysis. Both of these laboratories provide a type I analysis. Neither lab tests alternative treatments, only standard chemotherapy.

Neither of these tests - either the circulating tumor cell or the paraffin block method - is in common and “accepted” use by the medical profession, for reasons which escape me. Both can provide useful information when determining a rational approach to chemotherapeutic treatment of a known cancer.

Why are these tests not accepted by the medical oncology community?

An article in Fortune Magazine in 2004 describes the situation well. The author writes:

…virtually all these experts offered testimony that, when taken together, describes a dysfunctional “cancer culture”-a groupthink that pushes tens of thousands of physicians and scientists toward the goal of finding the tiniest improvements in treatment rather than genuine breakthroughs; that fosters isolated (and redundant) problem solving instead of cooperation; and rewards academic achievement and publication over all else.[8]

Tumors may start out as a single mutated cell with abnormal DNA. However, one of the hallmarks of cancer is its extreme genetic instability. By the time the original cell has divided a sufficient number of times to form a tumor, it has also mutated multiple times, so that the genetics of the resulting tumor are no longer identical to the genetics of the original cell. The larger tumors are made up of countless genetic cousins, many of which may have far different responses to chemotherapeutic agents than the original tumor cells.

And yet we persist doing clinical trials with chemotherapeutic agents, comparing one drug to another in a most heterogeneous population of people. We have no idea of the tumor genetics - patients with tumor type X are all lumped together - and we are looking at progression-free survival as an endpoint. That means how long does it take for the tumor to start growing again. We’re talking months, not years, before the tumor grows again. We seem to have pretty much given up the 5-year benchmark. Patients are lumped together in these trials without regard for their genetic make-up. So is it any wonder that our chemotherapeutic agents work so poorly, and that so many people die of cancer every year?

Most of the time it is not the original tumor that kills a victim - it is the fact that those tumors eventually metastasize, and begin to take over the body. Very little research is done on what causes tumors to metastasize.

So what will it take to win this war we have declared on cancer? Looking again at the Fortune article:

The cancer community must embrace a coordinated assault on this disease. Doctors and scientists now have enough knowledge to do what Sydney Farber hoped they might do 33 years ago: to work as an army, not as individuals fighting on their own. We can change the way cancer research is funded, putting emphasis on clinical response, and involving laboratory researchers with the physicians who are treating the patients.

We can look for good predictive biomarkers - thus increasing our ability to diagnose potential cancer long before it forms.

We can look at diet and lifestyle - for real, not just paying lip service. It’s not so difficult to change our diet, if the alternative is death by metastatic cancer. What messages are we giving our bodies through the foods we eat?

filopodiaCancer cells - at least those that metastasize - act almost like nerve cells or parasites. They send out a little exploring foot called a filopodium before they actually begin to move, or to settle down into a tissue. Filopodia are characteristic parts of growing nerve cells. So do cancer cells somehow have intelligence? Are they in some way related to our brain and nervous system? Does this explain why we develop tumors and metastases in some places but not in others? Do they somehow seek out those places where we are unhealthy? Where we have major metabolic disturbances?

If that is indeed the case, then we are well advised to be careful how and what we think... we encourage our brain cells to form new neural pathways when we are learning a new task. Is it possible that we might encourage cancer stem cells to do the same thing?

What’s more, cancer cells appear to be able to transform themselves into cancer stem cells , providing at least a partial explanation for why cancer can become so lethal, once it begins to metastasize and spread around the entire body. Cancer appears to be a two-way street - giving a possible explanation for the so-called “spontaneous” cures.

So if cancer cells can transform themselves back and forth, who is in control? Where are the brains of the outfit? In our efforts to control the spread of cancer, I think we forget to look at the driving forces behind the development of cancer in the first place.

Our next discussion will tackle some of those driving forces.


[1] http://csn.cancer.org/node/145883 downloaded 7/1/2012 [2] Brennan K, Garcia-Closas M, Flanagan JM et al. Intragenic ATM methylation in peripheral blood DNA as a biomarker of breast cancer risk. Cancer Res. 2012 May 1;72(9):2304-13. [3] Baggerly KA, Coombs KR. Deriving chemosensitivity from cell lines: Forensic bioinformatics and reproducible research in high-throughput biology. Annals of Applied Statistics 2009, Vol. 3, No. 4, 1309-1334. DOI: 10.1214/09-AOAS291. Downloaded 7/1/2012 from http://arxiv.org/abs/1010.1092 [4] Kolata G. How Bright Promise in Cancer Testing Fell Apart. New York Times 07-07-2011. [5] Whicher J T, Chambers R E et al. Acute phase response of serum amyloid A protein and C reactive protein to the common cold and influenza. J Clin Pathol. 1985 March; 38(3): 312-316. [6] Rational Therapeutics http://www.rational-t.com/cancer-testing/index.aspx [7] Weisenthal LM, Patel N, Rueff-Weisenthal C. Cell culture detection of microvascular cell death in clinical specimens of human neoplasms and peripheral blood. J Int Med 264;3:275-87 (Sept 2008). [8] The War on Cancer, downloaded 7/4/2012 from http://blog.aperio.com/articles/Fortune_Cancer.pdf [9] Shibue T, Brooks MW, Weinberg RA et al. The outgrowth of micrometastases is enabled by the formation of filopodium-like protrusions. Cancer Discovery, May 18, 2012; doi: 10.1158/2159-8290.CD-11-0239. [10] Chaffer CL, Brueckmann I, Weinberg RA et al. Normal and neoplastic nonstem cells can spontaneously convert to a stem-like state. Proc Natl Acad Sci U S A. 2011 May 10;108(19):7950-5.
What if there were a test for cancer that had therapeutic as well as predictive value?

The bad news - this test does not measure chemosensitivity, so it’s no good after you already have cancer. But it may have some predictive value, and might at least give you a heads-up that it’s time to change your diet and lifestyle.

The other bad news - the test will not be available at least until the year 2017. It has to be checked and double checked, with all the statistical analysis validated, to be sure that the correct conclusions are being drawn. At the moment, the American Society of Clinical Oncology recommends against doing such testing.

The really bad news - Tests of chemosensitivity come and go.

The infamous Duke University cancer biomarkers experiment came to a crashing close when two things happened: First, the statistics were found to be poorly done and inaccurate.[3] And second, the lead researcher was found to have falsified his credentials.[4] That was in 2010.

The bright side of that whole sad story is that the Institute of Medicine and the National Cancer Institute are finally looking at such genetic testing with a fresh eye.

Other tests may also have predictive value.

Inflammation is known to be a cause of cancer - or at the very least an early warning sign. There are biomarkers which can be measured in a standard laboratory which contribute to the development of cancer, and which are certainly early warning signs.[5]

At the Arizona Center for Advanced Medicine, we routinely measure c-reactive protein and other biomarkers of inflammation like sedimentation rate and fibrinogen levels, to determine a patient’s state of inflammation and risk of chronic illness.

Diabetes and insulin resistance are also predictive factors for development of cancer. We also routinely measure both fasting blood sugar and fasting insulin, so that we do not allow the patient with insulin resistance to develop full-blown diabetes before we begin to treat them preventively.

No chemosensitivity test using peripheral blood has yet come in to common use in the United States.

There are, however, some companies in the world which provide such a test. Of course it costs money to do the testing. Nevertheless, these tests do give some idea about rational choices of chemotherapy based on the individual’s tumor genetics rather than population results.

Two basic mechanisms of chemosensitivity testing are used: Type I are assays based on cell proliferation or DNA synthesis. Type II are based on cell death. Type I assays predict which agents the tumor should be sensitive to. Type II assays state which chemo agents actually killed the patient’s tumor cells in a petri dish.

We are aware of two laboratories which use peripheral blood to determine the likelihood, by circulating tumor cell genetics, of a cancer’s chemosensitivity or resistance. Both labs isolate peripheral tumor cells and grow them in cell culture before determining their genetic make-up and potential sensitivity to various commonly used chemotherapeutic drugs.

BioFocus Laboratory in Germany and the RGCC Laboratory in Greece both provide culture assays of circulating tumor cells (in peripheral blood), with assay of cell genetics which can provide a reason why these cells should or should not be sensitive to specific chemotherapy agents (Type I). Both companies can test the tumor cells against alternative as well as standard therapies. The biggest difference between the two companies is that the RGCC Laboratory also performs a viability assay (Type II) using specific drugs, to see if there is a correlation between the genetics and the performance of specific drugs against the cultured tumor cells.

Other laboratories use tumor tissue, either fresh from surgery or fixed in a paraffin bloc, to determine likelihood of chemosensitivity to various agents.[6,7] Caris Lifesciences, a private company in Phoenix, AZ, does a test they call “molecular” profiling, based on immunohistochemistry, FISH, RT-PCR, and molecular microarrays. Precision Therapeutics requires fresh tissue for their analysis. Both of these laboratories provide a type I analysis. Neither lab tests alternative treatments, only standard chemotherapy.

Neither of these tests - either the circulating tumor cell or the paraffin block method - is in common and “accepted” use by the medical profession, for reasons which escape me. Both can provide useful information when determining a rational approach to chemotherapeutic treatment of a known cancer.

Why are these tests not accepted by the medical oncology community?

An article in Fortune Magazine in 2004 describes the situation well. The author writes:

…virtually all these experts offered testimony that, when taken together, describes a dysfunctional “cancer culture”-a groupthink that pushes tens of thousands of physicians and scientists toward the goal of finding the tiniest improvements in treatment rather than genuine breakthroughs; that fosters isolated (and redundant) problem solving instead of cooperation; and rewards academic achievement and publication over all else.[8]

Tumors may start out as a single mutated cell with abnormal DNA. However, one of the hallmarks of cancer is its extreme genetic instability. By the time the original cell has divided a sufficient number of times to form a tumor, it has also mutated multiple times, so that the genetics of the resulting tumor are no longer identical to the genetics of the original cell. The larger tumors are made up of countless genetic cousins, many of which may have far different responses to chemotherapeutic agents than the original tumor cells.

And yet we persist doing clinical trials with chemotherapeutic agents, comparing one drug to another in a most heterogeneous population of people. We have no idea of the tumor genetics - patients with tumor type X are all lumped together - and we are looking at progression-free survival as an endpoint. That means how long does it take for the tumor to start growing again. We’re talking months, not years, before the tumor grows again. We seem to have pretty much given up the 5-year benchmark. Patients are lumped together in these trials without regard for their genetic make-up. So is it any wonder that our chemotherapeutic agents work so poorly, and that so many people die of cancer every year?

Most of the time it is not the original tumor that kills a victim - it is the fact that those tumors eventually metastasize, and begin to take over the body. Very little research is done on what causes tumors to metastasize.

So what will it take to win this war we have declared on cancer? Looking again at the Fortune article:

The cancer community must embrace a coordinated assault on this disease. Doctors and scientists now have enough knowledge to do what Sydney Farber hoped they might do 33 years ago: to work as an army, not as individuals fighting on their own. We can change the way cancer research is funded, putting emphasis on clinical response, and involving laboratory researchers with the physicians who are treating the patients.

We can look for good predictive biomarkers - thus increasing our ability to diagnose potential cancer long before it forms.

We can look at diet and lifestyle - for real, not just paying lip service. It’s not so difficult to change our diet, if the alternative is death by metastatic cancer. What messages are we giving our bodies through the foods we eat?

filopodiaCancer cells - at least those that metastasize - act almost like nerve cells or parasites. They send out a little exploring foot called a filopodium before they actually begin to move, or to settle down into a tissue. Filopodia are characteristic parts of growing nerve cells. So do cancer cells somehow have intelligence? Are they in some way related to our brain and nervous system? Does this explain why we develop tumors and metastases in some places but not in others? Do they somehow seek out those places where we are unhealthy? Where we have major metabolic disturbances?

If that is indeed the case, then we are well advised to be careful how and what we think... we encourage our brain cells to form new neural pathways when we are learning a new task. Is it possible that we might encourage cancer stem cells to do the same thing?

What’s more, cancer cells appear to be able to transform themselves into cancer stem cells , providing at least a partial explanation for why cancer can become so lethal, once it begins to metastasize and spread around the entire body. Cancer appears to be a two-way street - giving a possible explanation for the so-called “spontaneous” cures.

So if cancer cells can transform themselves back and forth, who is in control? Where are the brains of the outfit? In our efforts to control the spread of cancer, I think we forget to look at the driving forces behind the development of cancer in the first place.

Our next discussion will tackle some of those driving forces.


[1] http://csn.cancer.org/node/145883 downloaded 7/1/2012 [2] Brennan K, Garcia-Closas M, Flanagan JM et al. Intragenic ATM methylation in peripheral blood DNA as a biomarker of breast cancer risk. Cancer Res. 2012 May 1;72(9):2304-13. [3] Baggerly KA, Coombs KR. Deriving chemosensitivity from cell lines: Forensic bioinformatics and reproducible research in high-throughput biology. Annals of Applied Statistics 2009, Vol. 3, No. 4, 1309-1334. DOI: 10.1214/09-AOAS291. Downloaded 7/1/2012 from http://arxiv.org/abs/1010.1092 [4] Kolata G. How Bright Promise in Cancer Testing Fell Apart. New York Times 07-07-2011. [5] Whicher J T, Chambers R E et al. Acute phase response of serum amyloid A protein and C reactive protein to the common cold and influenza. J Clin Pathol. 1985 March; 38(3): 312-316. [6] Rational Therapeutics http://www.rational-t.com/cancer-testing/index.aspx [7] Weisenthal LM, Patel N, Rueff-Weisenthal C. Cell culture detection of microvascular cell death in clinical specimens of human neoplasms and peripheral blood. J Int Med 264;3:275-87 (Sept 2008). [8] The War on Cancer, downloaded 7/4/2012 from http://blog.aperio.com/articles/Fortune_Cancer.pdf [9] Shibue T, Brooks MW, Weinberg RA et al. The outgrowth of micrometastases is enabled by the formation of filopodium-like protrusions. Cancer Discovery, May 18, 2012; doi: 10.1158/2159-8290.CD-11-0239. [10] Chaffer CL, Brueckmann I, Weinberg RA et al. Normal and neoplastic nonstem cells can spontaneously convert to a stem-like state. Proc Natl Acad Sci U S A. 2011 May 10;108(19):7950-5.
What if there were a test for cancer that had therapeutic as well as predictive value?

At the Arizona Center for Advanced Medicine, we routinely measure c-reactive protein and other biomarkers of inflammation like sedimentation rate and fibrinogen levels, to determine a patient’s state of inflammation and risk of chronic illness.

Diabetes and insulin resistance are also predictive factors for development of cancer. We also routinely measure both fasting blood sugar and fasting insulin, so that we do not allow the patient with insulin resistance to develop full-blown diabetes before we begin to treat them preventively.

No chemosensitivity test using peripheral blood has yet come in to common use in the United States.

There are, however, some companies in the world which provide such a test. Of course it costs money to do the testing. Nevertheless, these tests do give some idea about rational choices of chemotherapy based on the individual’s tumor genetics rather than population results.

Two basic mechanisms of chemosensitivity testing are used: Type I are assays based on cell proliferation or DNA synthesis. Type II are based on cell death. Type I assays predict which agents the tumor should be sensitive to. Type II assays state which chemo agents actually killed the patient’s tumor cells in a petri dish.

We are aware of two laboratories which use peripheral blood to determine the likelihood, by circulating tumor cell genetics, of a cancer’s chemosensitivity or resistance. Both labs isolate peripheral tumor cells and grow them in cell culture before determining their genetic make-up and potential sensitivity to various commonly used chemotherapeutic drugs.

BioFocus Laboratory in Germany and the RGCC Laboratory in Greece both provide culture assays of circulating tumor cells (in peripheral blood), with assay of cell genetics which can provide a reason why these cells should or should not be sensitive to specific chemotherapy agents (Type I). Both companies can test the tumor cells against alternative as well as standard therapies. The biggest difference between the two companies is that the RGCC Laboratory also performs a viability assay (Type II) using specific drugs, to see if there is a correlation between the genetics and the performance of specific drugs against the cultured tumor cells.

Other laboratories use tumor tissue, either fresh from surgery or fixed in a paraffin bloc, to determine likelihood of chemosensitivity to various agents.[6,7] Caris Lifesciences, a private company in Phoenix, AZ, does a test they call “molecular” profiling, based on immunohistochemistry, FISH, RT-PCR, and molecular microarrays. Precision Therapeutics requires fresh tissue for their analysis. Both of these laboratories provide a type I analysis. Neither lab tests alternative treatments, only standard chemotherapy.

Neither of these tests - either the circulating tumor cell or the paraffin block method - is in common and “accepted” use by the medical profession, for reasons which escape me. Both can provide useful information when determining a rational approach to chemotherapeutic treatment of a known cancer.

Why are these tests not accepted by the medical oncology community?

An article in Fortune Magazine in 2004 describes the situation well. The author writes:

…virtually all these experts offered testimony that, when taken together, describes a dysfunctional “cancer culture”-a groupthink that pushes tens of thousands of physicians and scientists toward the goal of finding the tiniest improvements in treatment rather than genuine breakthroughs; that fosters isolated (and redundant) problem solving instead of cooperation; and rewards academic achievement and publication over all else.[8]

Tumors may start out as a single mutated cell with abnormal DNA. However, one of the hallmarks of cancer is its extreme genetic instability. By the time the original cell has divided a sufficient number of times to form a tumor, it has also mutated multiple times, so that the genetics of the resulting tumor are no longer identical to the genetics of the original cell. The larger tumors are made up of countless genetic cousins, many of which may have far different responses to chemotherapeutic agents than the original tumor cells.

And yet we persist doing clinical trials with chemotherapeutic agents, comparing one drug to another in a most heterogeneous population of people. We have no idea of the tumor genetics - patients with tumor type X are all lumped together - and we are looking at progression-free survival as an endpoint. That means how long does it take for the tumor to start growing again. We’re talking months, not years, before the tumor grows again. We seem to have pretty much given up the 5-year benchmark. Patients are lumped together in these trials without regard for their genetic make-up. So is it any wonder that our chemotherapeutic agents work so poorly, and that so many people die of cancer every year?

Most of the time it is not the original tumor that kills a victim - it is the fact that those tumors eventually metastasize, and begin to take over the body. Very little research is done on what causes tumors to metastasize.

So what will it take to win this war we have declared on cancer? Looking again at the Fortune article:

The cancer community must embrace a coordinated assault on this disease. Doctors and scientists now have enough knowledge to do what Sydney Farber hoped they might do 33 years ago: to work as an army, not as individuals fighting on their own. We can change the way cancer research is funded, putting emphasis on clinical response, and involving laboratory researchers with the physicians who are treating the patients.

We can look for good predictive biomarkers - thus increasing our ability to diagnose potential cancer long before it forms.

We can look at diet and lifestyle - for real, not just paying lip service. It’s not so difficult to change our diet, if the alternative is death by metastatic cancer. What messages are we giving our bodies through the foods we eat?

filopodiaCancer cells - at least those that metastasize - act almost like nerve cells or parasites. They send out a little exploring foot called a filopodium before they actually begin to move, or to settle down into a tissue. Filopodia are characteristic parts of growing nerve cells. So do cancer cells somehow have intelligence? Are they in some way related to our brain and nervous system? Does this explain why we develop tumors and metastases in some places but not in others? Do they somehow seek out those places where we are unhealthy? Where we have major metabolic disturbances?

If that is indeed the case, then we are well advised to be careful how and what we think... we encourage our brain cells to form new neural pathways when we are learning a new task. Is it possible that we might encourage cancer stem cells to do the same thing?

What’s more, cancer cells appear to be able to transform themselves into cancer stem cells , providing at least a partial explanation for why cancer can become so lethal, once it begins to metastasize and spread around the entire body. Cancer appears to be a two-way street - giving a possible explanation for the so-called “spontaneous” cures.

So if cancer cells can transform themselves back and forth, who is in control? Where are the brains of the outfit? In our efforts to control the spread of cancer, I think we forget to look at the driving forces behind the development of cancer in the first place.

Our next discussion will tackle some of those driving forces.


[1] http://csn.cancer.org/node/145883 downloaded 7/1/2012

Tumors may start out as a single mutated cell with abnormal DNA. However, one of the hallmarks of cancer is its extreme genetic instability. By the time the original cell has divided a sufficient number of times to form a tumor, it has also mutated multiple times, so that the genetics of the resulting tumor are no longer identical to the genetics of the original cell. The larger tumors are made up of countless genetic cousins, many of which may have far different responses to chemotherapeutic agents than the original tumor cells.

And yet we persist doing clinical trials with chemotherapeutic agents, comparing one drug to another in a most heterogeneous population of people. We have no idea of the tumor genetics - patients with tumor type X are all lumped together - and we are looking at progression-free survival as an endpoint. That means how long does it take for the tumor to start growing again. We’re talking months, not years, before the tumor grows again. We seem to have pretty much given up the 5-year benchmark. Patients are lumped together in these trials without regard for their genetic make-up. So is it any wonder that our chemotherapeutic agents work so poorly, and that so many people die of cancer every year?

Most of the time it is not the original tumor that kills a victim - it is the fact that those tumors eventually metastasize, and begin to take over the body. Very little research is done on what causes tumors to metastasize.

So what will it take to win this war we have declared on cancer? Looking again at the Fortune article:

The cancer community must embrace a coordinated assault on this disease. Doctors and scientists now have enough knowledge to do what Sydney Farber hoped they might do 33 years ago: to work as an army, not as individuals fighting on their own. We can change the way cancer research is funded, putting emphasis on clinical response, and involving laboratory researchers with the physicians who are treating the patients.

We can look for good predictive biomarkers - thus increasing our ability to diagnose potential cancer long before it forms.

We can look at diet and lifestyle - for real, not just paying lip service. It’s not so difficult to change our diet, if the alternative is death by metastatic cancer. What messages are we giving our bodies through the foods we eat?

filopodiaCancer cells - at least those that metastasize - act almost like nerve cells or parasites. They send out a little exploring foot called a filopodium before they actually begin to move, or to settle down into a tissue. Filopodia are characteristic parts of growing nerve cells. So do cancer cells somehow have intelligence? Are they in some way related to our brain and nervous system? Does this explain why we develop tumors and metastases in some places but not in others? Do they somehow seek out those places where we are unhealthy? Where we have major metabolic disturbances?

If that is indeed the case, then we are well advised to be careful how and what we think... we encourage our brain cells to form new neural pathways when we are learning a new task. Is it possible that we might encourage cancer stem cells to do the same thing?

What’s more, cancer cells appear to be able to transform themselves into cancer stem cells , providing at least a partial explanation for why cancer can become so lethal, once it begins to metastasize and spread around the entire body. Cancer appears to be a two-way street - giving a possible explanation for the so-called “spontaneous” cures.

So if cancer cells can transform themselves back and forth, who is in control? Where are the brains of the outfit? In our efforts to control the spread of cancer, I think we forget to look at the driving forces behind the development of cancer in the first place.

Our next discussion will tackle some of those driving forces.

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