Test Shown to Reduce Early Cancer Deaths is Now Available to Patients

gdpawel

Huntington Beach, CA - SignatureCLL announced that the first laboratory test ever shown in a clinical trial to improve one year survival rates in cancer is now available to patients with chronic lymphocytic leukemia (also called CLL).

The U.S. cancer physician who invented the test and the British scientist who used it to make discoveries in leukemia will offer the test under the trade name SignatuRx through their own, newly-formed laboratory company.

The company’s technology, in its generic form, was shown in a 777 patient randomized clinical trial to reduce early cancer deaths among relapsed CLL patients by identifying the most promising personalized chemotherapy treatment for each patient. In the study, CLL patients were more than twice as likely to die within the first year after an initial treatment relapse if their next chemotherapy drug selections were not guided by the test.

According to test developers, the ground-breaking aspect of this clinical trial is that it is the first time any test was shown in a randomized clinical trial to reduce cancer deaths over any time period. Usually, cancer tests are judged only on the basis of accuracy – how reliably they identify a certain biological condition. Prior to this study, no cancer test was ever asked to prove that its use actually made patients live longer. A randomized clinical trial is one in which two or more groups of patients are chosen at random to receive different types of treatment.

Principles of the SignatuRx test were conceived by Larry Weisenthal, M.D., Ph.D., a cancer physician and researcher, while he was working at the National Cancer Institute. In a prospective, randomized clinical trial that followed CLL patients for over 10 years, Andrew Bosanquet, Ph.D. and colleagues found that CLL patients who relapsed after initial chemotherapy treatment were 2.5 times more likely to die within the first year following relapse if their chemotherapy drugs were selected without test guidance. Results of the trial, officially designated LRF CLL4, were published in the journals Lancet and Leukemia.

Survival at one year was significantly better in the personalized chemotherapy arm of the study,” said Dr. Bosanquet. “The finding is of particular interest given that no other chemotherapy-only protocol has ever been shown to increase overall survival.”

In the SignatuRx test, patients’ own, living cancer cells are exposed to a wide range of different chemotherapy drugs to learn which chemotherapy drug or drug combination most effectively kills each patient’s cells. Chemotherapy is then personalized for each patient by focusing on effective drugs and avoiding ineffective drugs. This is a noteworthy break from what Dr. Weisenthal calls “one size fits all” chemotherapy, still used by most cancer physicians, in which drugs are chosen on some rational basis that does not involve directly testing candidate drugs in advance against each patient’s own cancer cells.

“The problem with that approach,” said Dr. Weisenthal, “is that many drugs are available for treatment of CLL but patient responses to the drugs are hit or miss. Some patients might be helped by one drug and other patients by another but no drug ever helps all patients equally. Without testing, there is no way to know in advance which drugs are best for which patients.”

Drs. Weisenthal and Bosanquet state that the SignatuRx personalized chemotherapy test can be ordered by physicians for their chronic lymphocytic leukemia patients from virtually anywhere in the world. Blood samples are sent to Dr. Weisenthal and Bosanquet’s California-based laboratory by overnight courier where the cancer cells are tested for susceptibility to treatment with up to 30 different chemotherapy drugs and drug combinations. Test reports are available in 7 to 10 days.

Detailed information about the clinical trial and about SignatureCLL is available on the company’s website: www.signaturecll.com

Chronic lymphocytic leukemia is the most common form of leukemia in adults. Approximately 120,000 people in the US are living with CLL and about 4,600 persons will die of the disease this year according to the American Cancer Society.

gdpawel

About this CLL clinical trial

To my knowledge, there hasn't been a clinical trial of any predictive test to show clinical benefit in a prospective randomized trial, in which patients are randomized to treatment on the basis of test results versus treatment without benefit of test results (the only exception to this is the British LRF-4 study, which showed improved one year survival for CLL patients treated on the basis of test results, compared to "physician's choice" therapy).

The LRF CLL4 trial is the first-ever prospective, randomized clinical cytometric profiling trial that involves the DISC assay. The study is focused entirely in CLL. It certainly does prove the principle of cytometric profiling in exactly the way nay-sayers have demanded. There will never be a randomized clinical trial in every cancer type and for every drug, so, at some point you have to ask yourself, given all of the other evidence that exists in support of cytometric profiling in so many other tumor types, is it reasonable to think that this clinical trial is an anomaly that applies only to CLL? Of course not!

Matutes E, Bosanquet AG, Wade R, et al, The use of individualized tumor response testing in treatment selection: second randomization results from the LRF CLL4 trial and the predictive value of the test at trial entry. Leukemia (2013) 27, 507–510; doi:10.1038/leu.2012.209

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3567236/

Bosanquet AG, Nygren P, and Weisenthal LM, Individualized tumor response testing in leukemia and lymphoma in Innovative Leukemia and Lymphoma, 2008.

http://www.crcnetbase.com/doi/abs/10.3109/9781420014082-3

gdpawel

gdpawel said:

About this CLL clinical trial

To my knowledge, there hasn't been a clinical trial of any predictive test to show clinical benefit in a prospective randomized trial, in which patients are randomized to treatment on the basis of test results versus treatment without benefit of test results (the only exception to this is the British LRF-4 study, which showed improved one year survival for CLL patients treated on the basis of test results, compared to "physician's choice" therapy).

The LRF CLL4 trial is the first-ever prospective, randomized clinical cytometric profiling trial that involves the DISC assay. The study is focused entirely in CLL. It certainly does prove the principle of cytometric profiling in exactly the way nay-sayers have demanded. There will never be a randomized clinical trial in every cancer type and for every drug, so, at some point you have to ask yourself, given all of the other evidence that exists in support of cytometric profiling in so many other tumor types, is it reasonable to think that this clinical trial is an anomaly that applies only to CLL? Of course not!

Matutes E, Bosanquet AG, Wade R, et al, The use of individualized tumor response testing in treatment selection: second randomization results from the LRF CLL4 trial and the predictive value of the test at trial entry. Leukemia (2013) 27, 507–510; doi:10.1038/leu.2012.209

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3567236/

Bosanquet AG, Nygren P, and Weisenthal LM, Individualized tumor response testing in leukemia and lymphoma in Innovative Leukemia and Lymphoma, 2008.

http://www.crcnetbase.com/doi/abs/10.3109/9781420014082-3

Dr. Weisenthal Replies to ASCO Post

Replies to comments regarding personalized cancer treatment, as published in the December 15, 2013 "ASCO Post" (American Society of Clinical Oncology publication).

By Larry Weisenthal, MD
December 15, 2013, Volume 4, Issue 20

Dr. Mason states that I implied that Dr. Telli supports the routine application of chemosensitivity assays. I have no knowledge regarding Dr. Telli’s views on this subject, nor did I in any way attempt to represent her views, much less imply that she was supportive of anything relating to chemosensitivity assays.

Dr. Mason also raises the issue of conflict of interest. I am an expert in chemosensitivity testing, with 35 years of largely full-time experience with the relevant technologies. Dr. Telli stated that her group was working on predictive markers to identify the best candidates for platinum treatment in breast cancer. I quoted our data presented at the 2009 Breast Cancer Symposium, which prospectively identified the best candidates for such treatment as being patients with triple-negative disease and a Bloom-Richardson score of 9/9. My laboratory provides neither marker studies for triple-negative disease nor Bloom-Richardson scoring.

Obvious vs Nonobvious Conflicts

Let’s imagine that I were a pathologist, who pointed out to Dr. Telli that there was prior work suggesting that the above routine pathology markers could be useful in identifying candidates for platinum treatment. Would this be a conflict of interest?

Dr. Mason seems to be implying that any expert/specialist who provides a service related to his/her comment should declare a conflict of interest. Thus, a radiotherapist commenting on a surgical study should declare a conflict of interest, a chemotherapist commenting on a radiotherapy study should declare a conflict of interest, and so forth.

In my case, it was obvious from my letter that I performed chemosensitivity testing, as I quoted my own work in this field! In a similar vein, pathologists, radiotherapists, and chemotherapists generally make note of their own specialties in their comments, as workers in a particular field typically have the most relevant knowledge base, and their conflicts of interest are likewise obvious. One generally makes a formal conflict of interest declaration when one’s conflict is not obvious, eg, most typically in disclosing a relationship to an entity not obviously related to one’s medical practice, such as a relationship with an outside pharmaceutical company. 

I am going to hazard a guess that Dr. Mason would state that the difference between an oncologist providing chemosensitivity testing and a pathologist providing estrogen receptor testing is that the former testing is considered to be “investigational/not recognized by ASCO,” whereas the latter is considered to be noninvestigational/recognized. But is this a fair distinction?

Double Standard?

To date, ASCO has provided two formal reviews of chemosensitivity testing.1,2 In both reviews, the sole criterion being assessed was “efficacy,” meaning the existing data relating to the question of whether the use of this testing improves clinical outcomes. In both reviews, no attempt was made to assess the considerable data documenting the accuracy of chemosensitivity testing, where test accuracy is the only criterion ever used to “validate” any predictive laboratory technology, specifically including the triple-negative tests (ie, for estrogen receptor, progesterone receptor, and HER2).

This double standard has had the effect of halting virtually all progress in the field of chemosensitivity testing since the late 1980s. Critics have labeled the technology “investigational” and have then failed to support the investigations they have demanded, as readily evidenced by the complete absence of NIH grant–supported publications in the American literature over the past 2 decades. The technologies are largely in the public domain and labor-intensive, and there has accordingly been no serious private sector money to compete with pharmaceutical company funding for clinical trials.

New Development

Just this year, however, there has been a new development. A large-scale (777-patient) prospective, randomized trial in chronic lymphocytic leukemia was published, supported by the British Leukemia Research Fund.3 I would ask fair reviewers to compare and contrast the quality and results of this trial with what is the self-proclaimed “best” trial ever performed to “validate” estrogen receptor testing4 (estrogen receptor negativity being the most powerful contributor to platinum sensitivity in patients with triple-negative disease in our 2009 study).5

Comparing the chemosensitivity test study with the estrogen receptor study, the former had a greater number of patients and stronger predictive correlations, and used real-world test conditions (real-time processing and prospective reporting, as opposed to post hoc batch-processing and retrospective reporting). Additionally, for the first time ever in all studies of predictive markers used for treatment selection in cancer, the chemosensitivity study showed an improved clinical outcome for patients randomly assigned to test-guided treatment selection vs non–test-guided treatment selection. (Patients in the empiric therapy arm had a 2.5-fold greater probability of being dead at 1 year, compared to the patients in the test-directed arm.)

Lost Opportunity

I view the lack of support and overt hostility to chemosensitivity testing as being the single greatest lost opportunity in clinical cancer research over the past 25 years.

As a postscript, there was a nonfunctioning link to our 2009 ASCO Breast Symposium presentation relating to platinum therapy in triple-negative breast cancer in my original comment, as published. Here is the correct link, presenting our abstract and most important data: 

http://meetinglibrary.asco.org/content/40486-70 

—Larry Weisenthal, MD
Huntington Beach, California

References

1. Schrag D, Garewal HS, Burstein HJ, et al: American Society of Clinical Oncology Technology Assessment: Chemotherapy sensitivity and resistance assays. J Clin Oncol 22:3631-3638, 2004.

2. Burstein HJ, Mangu PB, Somerfield MR, et al: American Society of Clinical Oncology clinical practice guideline update on the use of chemotherapy sensitivity and resistance assays. J Clin Oncol 29:3328-3330, 2011.

3. Matutes E, Bosanquet AG, Wade R, et al: The use of individualized tumor response testing in treatment selection: Second randomization results from the LRF CLL4 trial and the predictive value of the test at trial entry. Leukemia 27:507-510, 2013.

4. Elledge RM, Green S, Pugh R, et al: Estrogen receptor (ER) and progesterone receptor (PgR), by ligand-binding assay compared with ER, PgR and pS2, by immuno-histochemistry in predicting response to tamoxifen in metastatic breast cancer: A Southwest Oncology Group Study. Int J Cancer 89:111-117, 2000.

5. Weisenthal L: Activity of cisplatin in triple-negative breast cancer in comparison to other cancer types in fresh tumor cell culture assay using a cell death endpoint. 2009 Breast Cancer Symposium. Abstract 61. Presented October 8-10, 2009.

Disclaimer: This letter represents the views of the author and may not necessarily reflect the views of ASCO.

Citation: The ASCO Post. Dr. Weisenthal Replies. December 15, 2013, Volume 4, Issue 20

gdpawel

gdpawel said:

Dr. Weisenthal Replies to ASCO Post

Replies to comments regarding personalized cancer treatment, as published in the December 15, 2013 "ASCO Post" (American Society of Clinical Oncology publication).

By Larry Weisenthal, MD
December 15, 2013, Volume 4, Issue 20

Dr. Mason states that I implied that Dr. Telli supports the routine application of chemosensitivity assays. I have no knowledge regarding Dr. Telli’s views on this subject, nor did I in any way attempt to represent her views, much less imply that she was supportive of anything relating to chemosensitivity assays.

Dr. Mason also raises the issue of conflict of interest. I am an expert in chemosensitivity testing, with 35 years of largely full-time experience with the relevant technologies. Dr. Telli stated that her group was working on predictive markers to identify the best candidates for platinum treatment in breast cancer. I quoted our data presented at the 2009 Breast Cancer Symposium, which prospectively identified the best candidates for such treatment as being patients with triple-negative disease and a Bloom-Richardson score of 9/9. My laboratory provides neither marker studies for triple-negative disease nor Bloom-Richardson scoring.

Obvious vs Nonobvious Conflicts

Let’s imagine that I were a pathologist, who pointed out to Dr. Telli that there was prior work suggesting that the above routine pathology markers could be useful in identifying candidates for platinum treatment. Would this be a conflict of interest?

Dr. Mason seems to be implying that any expert/specialist who provides a service related to his/her comment should declare a conflict of interest. Thus, a radiotherapist commenting on a surgical study should declare a conflict of interest, a chemotherapist commenting on a radiotherapy study should declare a conflict of interest, and so forth.

In my case, it was obvious from my letter that I performed chemosensitivity testing, as I quoted my own work in this field! In a similar vein, pathologists, radiotherapists, and chemotherapists generally make note of their own specialties in their comments, as workers in a particular field typically have the most relevant knowledge base, and their conflicts of interest are likewise obvious. One generally makes a formal conflict of interest declaration when one’s conflict is not obvious, eg, most typically in disclosing a relationship to an entity not obviously related to one’s medical practice, such as a relationship with an outside pharmaceutical company. 

I am going to hazard a guess that Dr. Mason would state that the difference between an oncologist providing chemosensitivity testing and a pathologist providing estrogen receptor testing is that the former testing is considered to be “investigational/not recognized by ASCO,” whereas the latter is considered to be noninvestigational/recognized. But is this a fair distinction?

Double Standard?

To date, ASCO has provided two formal reviews of chemosensitivity testing.1,2 In both reviews, the sole criterion being assessed was “efficacy,” meaning the existing data relating to the question of whether the use of this testing improves clinical outcomes. In both reviews, no attempt was made to assess the considerable data documenting the accuracy of chemosensitivity testing, where test accuracy is the only criterion ever used to “validate” any predictive laboratory technology, specifically including the triple-negative tests (ie, for estrogen receptor, progesterone receptor, and HER2).

This double standard has had the effect of halting virtually all progress in the field of chemosensitivity testing since the late 1980s. Critics have labeled the technology “investigational” and have then failed to support the investigations they have demanded, as readily evidenced by the complete absence of NIH grant–supported publications in the American literature over the past 2 decades. The technologies are largely in the public domain and labor-intensive, and there has accordingly been no serious private sector money to compete with pharmaceutical company funding for clinical trials.

New Development

Just this year, however, there has been a new development. A large-scale (777-patient) prospective, randomized trial in chronic lymphocytic leukemia was published, supported by the British Leukemia Research Fund.3 I would ask fair reviewers to compare and contrast the quality and results of this trial with what is the self-proclaimed “best” trial ever performed to “validate” estrogen receptor testing4 (estrogen receptor negativity being the most powerful contributor to platinum sensitivity in patients with triple-negative disease in our 2009 study).5

Comparing the chemosensitivity test study with the estrogen receptor study, the former had a greater number of patients and stronger predictive correlations, and used real-world test conditions (real-time processing and prospective reporting, as opposed to post hoc batch-processing and retrospective reporting). Additionally, for the first time ever in all studies of predictive markers used for treatment selection in cancer, the chemosensitivity study showed an improved clinical outcome for patients randomly assigned to test-guided treatment selection vs non–test-guided treatment selection. (Patients in the empiric therapy arm had a 2.5-fold greater probability of being dead at 1 year, compared to the patients in the test-directed arm.)

Lost Opportunity

I view the lack of support and overt hostility to chemosensitivity testing as being the single greatest lost opportunity in clinical cancer research over the past 25 years.

As a postscript, there was a nonfunctioning link to our 2009 ASCO Breast Symposium presentation relating to platinum therapy in triple-negative breast cancer in my original comment, as published. Here is the correct link, presenting our abstract and most important data: 

http://meetinglibrary.asco.org/content/40486-70 

—Larry Weisenthal, MD
Huntington Beach, California

References

1. Schrag D, Garewal HS, Burstein HJ, et al: American Society of Clinical Oncology Technology Assessment: Chemotherapy sensitivity and resistance assays. J Clin Oncol 22:3631-3638, 2004.

2. Burstein HJ, Mangu PB, Somerfield MR, et al: American Society of Clinical Oncology clinical practice guideline update on the use of chemotherapy sensitivity and resistance assays. J Clin Oncol 29:3328-3330, 2011.

3. Matutes E, Bosanquet AG, Wade R, et al: The use of individualized tumor response testing in treatment selection: Second randomization results from the LRF CLL4 trial and the predictive value of the test at trial entry. Leukemia 27:507-510, 2013.

4. Elledge RM, Green S, Pugh R, et al: Estrogen receptor (ER) and progesterone receptor (PgR), by ligand-binding assay compared with ER, PgR and pS2, by immuno-histochemistry in predicting response to tamoxifen in metastatic breast cancer: A Southwest Oncology Group Study. Int J Cancer 89:111-117, 2000.

5. Weisenthal L: Activity of cisplatin in triple-negative breast cancer in comparison to other cancer types in fresh tumor cell culture assay using a cell death endpoint. 2009 Breast Cancer Symposium. Abstract 61. Presented October 8-10, 2009.

Disclaimer: This letter represents the views of the author and may not necessarily reflect the views of ASCO.

Citation: The ASCO Post. Dr. Weisenthal Replies. December 15, 2013, Volume 4, Issue 20

The Test of Time

50 years of uniformly positive studies support the accuracy and clinical utility of cytometric profiling in Chronic Lymphocytic Leukemia. 

Despite a wide diversity in study designs, personalized cytometric profiling in CLL has correlated positively and consistently with response, with progression-free survival, with overall survival, with the documented activity of individual chemotherapy agents, with the well-established body of clinical experience, and with the known molecular biology of CLL.

https://www.facebook.com/signaturecll