Precancers 5: Regulatory justification of precancer as a surrogate marker for cancer

Precancers are the lesions from which cancers develop. Precancers can be easily treated, and when we eliminate precancers, we eliminate the cancers that would have developed from the precancers. This is the message in Precancer: The Beginning and the End of Cancer.

In the prior blog post, I discussed how precancers can be used as surrogate markers for cancers, in carcinogen assays. The example used was the increase in MGUS (the multiple myeloma precancer) in occupational exposure to pesticides. An increase in MGUS after human exposure is an indicator that pesticides can cause multiple myeloma.

Because precancers occur earlier than cancers, the use of precancers as surrogate markers for cancers, in animal studies and in human epidemiologic studies, can save enormous time and money in carcinogen assays.

Is there regulatory justification to use surrogate markers (instead of the ultimate disease end-point) in assays that test the effectiveness of interventions (to decrease the incidence of disease or to treat disease).

The Food and Drug Modernization Act of 1997 specifically allows and encourages the use of surrogate markers and end-points in drug evaluations (from the Act):

"(b) APPROVAL OF APPLICATION FOR A FAST TRACK PRODUCT.-
(1) IN GENERAL.-The Secretary may approve an application for approval of a fast track product under section 505(c) or section 351 of the Public Health Service Act upon a determination that the product has an effect on a clinical endpoint or on a surrogate endpoint that is reasonably likely to predict clinical benefit.
.
.
.
(d) AWARENESS EFFORTS.-The Secretary shall-
.
.
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(2) establish a program to encourage the development
of surrogate endpoints that are reasonably likely to predict
clinical benefit for serious or life-threatening conditions for
which there exist significant unmet medical needs."

An early use of a surrogate marker for disease response was the use of MRI evaluation of brain images for betaseron effectiveness as a treatment of multiple sclerosis. Wherease previous FDA requirements would have expected a clinical trial showing that betaseron produced a clinical treatment response, the Modernization Act permitted the use of MRI brain scans (showing improvement in MS lesions) to serve as a surrogate end-point for clinical data. The drug was approved largely on the basis of surrogate end-points.

Similarly, precancers might serve as surrogate end-points for cancers. A drug that increases the number of precancerous lesions would be expected to increase the number of cancers. Likewise, a drug that decreases precancerous lesions would be expected to reduce the incidence of cancers.

-© 2009 Jules J. Berman

related words: precancers, precancer, pre-cancerous condition, precancerous condition, preneoplastic lesions, preneoplasia, ien, intra-epithelial neoplasia, intraepithelial neoplasia, intra-epithelial neoplasm, intraepithelial neoplasm, in situ carcinoma, carcinoma in situ, cis, dcis, din, pin, panin, cin, dysplasia, adenoma, preneoplastic, pre-cancer, pre-cancerous, precancerous, early cancer, cancer prevention, cancer detection, common disease, orphan disease, orphan drugs, genetics of disease, disease genetics, rules of disease biology, rare disease, pathology

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In June, 2014, my book, entitled Rare Diseases and Orphan Drugs: Keys to Understanding and Treating the Common Diseases was published by Elsevier. The book builds the argument that our best chance of curing the common diseases will come from studying and curing the rare diseases.

I urge you to read more about my book. There's a generous preview of the book at the Google Books site.

Precancers 4: Agents that cause precancers are carcinogens

Precancers are the lesions from which cancers develop. Precancers can be easily treated, and when we eliminate precancers, we eliminate the cancers that would have developed from the precancers. This is the message in Precancer: The Beginning and the End of Cancer.

Because cancers emerge from precancers, agents that cause cancer will also cause precancers. Because precancers occur earlier than cancers, we can use observed population increases in specific types of precancers, as an early and sensitive signal indicating that we are being exposed to a carcinogen.

In yesterday's blog, we discussed MGUS (Monoclonal Gammopathy of Undetermined Significance), the precancer for multiple myeloma. There has been speculation that human exposure to pesticides increases the rate of occurrence of multiple myeloma.

If this were the case, we would also expect that human exposure to pesticides would increase the rate of occurrence of MGUS.

In a paper published in June, by Landren et al., the authors showed that men occupationally exposed to pesticides (pesticide applicators) had double the rate of occurrence of MGUS than men in the general population.

Landgren O, Kyle RA, Hoppin JA, Beane Freeman LE, Cerhan JR, Katzmann JA, Rajkumar SV, Alavanja MC. Pesticide exposure and risk of monoclonal gammopathy of undetermined
significance in the Agricultural Health Study. Blood. 2009 Jun 18;113(25):6386-6391.

The effect was stronger with some pesticides (highest increase of MGUS, 5.6-fold, in men exposed to dieldrin) than others.

The increase in MGUS (the precancer for multiple myeloma) among men exposed to pesticides strengthens the hypothesis that pesticides cause multiple myeloma.

This paper provides an example of how epidemiologic data on precancers can be used to warn us when we are being exposed to environmental carcinogens.

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In June, 2014, my book, entitled Rare Diseases and Orphan Drugs: Keys to Understanding and Treating the Common Diseases was published by Elsevier. The book builds the argument that our best chance of curing the common diseases will come from studying and curing the rare diseases.

I urge you to read more about my book. There's a generous preview of the book at the Google Books site. If you like the book, please request your librarian to purchase a copy of this book for your library or reading room.
-© 2009 Jules J. Berman, Ph.D., M.D.
tags: common disease, orphan disease, orphan drugs, rare disease, subsets of disease, disease genetics, genetics of complex disease, genetics of common diseases, precancers, precancer, pre-cancerous condition, precancerous condition, preneoplastic lesions, preneoplasia, ien, intra-epithelial neoplasia, intraepithelial neoplasia, intra-epithelial neoplasm, intraepithelial neoplasm, in situ carcinoma, carcinoma in situ, cis, dcis, din, pin, panin, cin, dysplasia, adenoma, preneoplastic, pre-cancer, pre-cancerous, precancerous, early cancer, cancer prevention, cancer detection

Precancers 3: All Myeloma Preceded by MGUS

Precancers are the lesions from which cancers develop. Precancers can be easily treated, and when we eliminate precancers, we eliminate the cancers that would have developed from the precancers. This is the message in Precancer: The Beginning and the End of Cancer.

One of the most important questions in precancer research is whether all cancers arise from precancers, or whether some cancers can arise ab initio (from the beginning) as fully malignant clones, without first passing through a precancer phase.

There are many different types of cancer, and most cancers of humans have a putative precancer precursor. Multiple myeloma, and its precursor, MGUS (monoclonal gammopathy of undetermined significance) are discussed in some detail in my recently published book, Precancer: The Beginning and the End of Cancer. Briefly, multiple myeloma is a cancer of plasma cells. Plasma cells are the specialized blood cells that produce gamma globulin antobody molecules. Cancerous plasma cells produce a monoclonal spike of gamma globulins that can be detected by looking at samples of blood. MGUS, the precursor of multiple myeloma, produces a similar monoclonal spike in gamma globulins, but it is not associated with clinically detectable masses of cancer cells.

In a recent paper by Langren et al, the authors answered a simple, fundamental question in tumor biology: Are all cases of myeloma preceded by MGUS?

The paper was published in the journal Blood.

Landgren O, Kyle RA, Pfeiffer RM, et al. Monoclonal gammopathy of undetermined significance (MGUS) consistently precedes multiple myeloma: a prospective study. Blood 113:5412-5417, 2009.

The paper is available as an open access document at:

http://bloodjournal.hematologylibrary.org/cgi/content/full/113/22/5412

The authors used data and serum samples from enrollees in the large PLCO (prostate lung colon and ovary) trial currently underway through the National Cancer Institute. They looked specifically at enrollees in the trial who developed multiple myeloma during the trial. All enrollees in the PLCO trial have blood drawn during the multi-year trial. When they looked at prior blood samples for newly diagnosed cases of multiple myeloma, they found MGUS in every instance. Therefore, at least for the 71 examined cases in their study, MGUS always preceded the myeloma.

It is extremely important to have studies (such as this study for multiple myeloma) that indicate that precancer is an obligatory step in carcinogenesis. If only a portion of cancers developed from precancers, we would never be able to eradicate all cancers [by treating their precancers]. On the other hand, if every case of cancer is preceded by a precancer, then we can be certain that if we successfully treat all of the precancers, then no cancers will follow.

-© 2009 Jules J. Berman

tags: precancers, precancer, pre-cancerous condition, precancerous condition, preneoplastic lesions, preneoplasia, ien, intra-epithelial neoplasia, intraepithelial neoplasia, intra-epithelial neoplasm, intraepithelial neoplasm, in situ carcinoma, carcinoma in situ, cis, dcis, din, pin, panin, cin, dysplasia, adenoma, preneoplastic, pre-cancer, pre-cancerous, precancerous, rare disease, orphan disease, orphan drugs, complex disease, disease genetics, genetics of disease, common disease, pathology of disease

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In June, 2014, my book, entitled Rare Diseases and Orphan Drugs: Keys to Understanding and Treating the Common Diseases was published by Elsevier. The book builds the argument that our best chance of curing the common diseases will come from studying and curing the rare diseases.

I urge you to read more about my book. There's a generous preview of the book at the Google Books site.

PRECANCERS: 2 Inducing regression in precancers

Precancers are the lesions from which cancers develop. Precancers can be easily treated, and when we eliminate precancers, we eliminate the cancers that would have developed from the precancers. This is the message of my new book, Precancer: The Beginning and the End of Cancer. In today's blog, I thought I'd provide one example, from the recent cancer research literature, of precancer treatment.

Colon cancer is one of the most common cancers of humans, accounting for about 50,000 deaths in the U.S. in 2009 (data from U.S. National Cancer Institute at:

http://www.cancer.gov/cancerinfo/types/colon-and-rectal

Almost all colon cancers arise from colon precancers, called colonic adenomas.

If we could eliminate colon adenomas, we could eliminate virtually all deaths from colon cancer. This is the premise behind colonoscopy (excise the adenomas and avoid the cancers).

A team of scientists from MIT, Mass Genl, Harvard and several other institutions have published a recent article in PNAS (Proceedings of the National Academy of Sciences), on the successful treatment of colon precancers, in a mouse model system.

The article is:

Elias Gounaris, Susan E. Erdman, Clifford Restaino, et al. Mast cells are an essential hematopoietic component for polyp development Proc Natl Acad Sci U S A. 2007 December 11; 104(50): 19977-19982.

The full-text article is available as an open access document:

http://www.pnas.org/content/104/50/19977.full.pdf+html

The investigators noticed that the stroma (the supporting connective tissue) in colon adenomas is infiltrated with mast cells (a blood cell involved in the inflammatory process). When the investigators reduced the mast cell population (in the tumor stroma) in precancerous mouse colon adenomas, many of the adenomas quickly regressed. In a related study, chimeric mice with a genetic deficiency of mast cell formation developed fewer colon adenomas than wild-type mice.

Precancers, unlike cancers, often regress spontaneously. It seems self-evident that it would be easier to treat a lesion that is unstable, and prone to die on its own, than to treat a lesion that has grown into a large, invasive mass, that has dissemminated throughout the body. This paper is one example of how easy it is to modify the growth of precancers and to induce a high rate of precancer regression.

Because treatment was aimed at the non-neoplastic cells in the stroma of the precancer, it is likely that the same treatment that was successful against colon adenomas may be successful against any precancer for which there is a population of mast cells that contribute to precancer progression. The authors discussed the observation that mast cells are found in a variety of human cancers, and, in a note attached to their paper, cited recent work indicating that mast cells have an important role in the development of pancreatic cancer and prostatic cancer.

It is important to begin treatment while neoplasms are stil in their precancer stage. AFTER an invasive cancer has emerged from a precancer, agents that target a sensitive step in precancer development will probably NOT be curative.

When we have candidate precancer treatments (and we do), we should start testing them in human clinical trials. When we learn how to eradicate precancers, we will have learned how to conquer cancer.

More on precancers in next post.

-© 2009 Jules J. Berman

related words: precancers, preneoplastic lesions, preneoplasia, ien, intra-epithelial neoplasia, intraepithelial neoplasia, intra-epithelial neoplasm, intraepithelial neoplasm, in situ carcinoma, carcinoma in situ, cis, dcis, din, pin, panin, cin, dysplasia, adenoma, preneoplastic, pre-cancer, pre-cancerous, precancerous

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Science is not a collection of facts. Science is what facts teach us; what we can learn about our universe, and ourselves, by deductive thinking. From observations of the night sky, made without the aid of telescopes, we can deduce that the universe is expanding, that the universe is not infinitely old, and why black holes exist. Without resorting to experimentation or mathematical analysis, we can deduce that gravity is a curvature in space-time, that the particles that compose light have no mass, that there is a theoretical limit to the number of different elements in the universe, and that the earth is billions of years old. Likewise, simple observations on animals tell us much about the migration of continents, the evolutionary relationships among classes of animals, why the nuclei of cells contain our genetic material, why certain animals are long-lived, why the gestation period of humans is 9 months, and why some diseases are rare and other diseases are common. In “Armchair Science”, the reader is confronted with 129 scientific mysteries, in cosmology, particle physics, chemistry, biology, and medicine. Beginning with simple observations, step-by-step analyses guide the reader toward solutions that are sometimes startling, and always entertaining. “Armchair Science” is written for general readers who are curious about science, and who want to sharpen their deductive skills.

Precancers: 1

After a long stretch of blog inactivity, I am starting to post again. I apologize for the absence, but I've been deeply absorbed writing several books. Now that the writing phase is finished, I hope to use the blog to post short essays on topics covered in those books.

Readers of this blog are familiar with my interest in precancers. Precancer: The Beginning and the End of Cancer, was just published (August 11, 2009) by Jones & Bartlett Publishers, Inc., and is now available at Amazon. It was written with the help of Dr. G. William Moore. Here's the publisher's blurb:

"Nearly every type of cancer passes through a precancer phase, during which it cannot metastasize or invade other tissues. While medicine is not always successful in treating or curing advanced stages of cancers, recent advances in our understanding of carcinogenesis have helped us to develop strategies to prevent, diagnose, and treat many cancers at the precancer stage. Research in this field is escalating rapidly as the evidence increasingly shows that the number of annual cancer deaths could be drastically reduced through the effective treatment and cure of precancer lesions. This book begins by explaining why it has been so difficult to cure cancers, followed by a review of precancer biology, with descriptions of the most common precancer lesions. The final chapters provide practical socio-political and medical goals for precancer treatment, including discussions of the economics and politics of treating precancers."

I've been interested in the precancers for over thirty-six years, and I think it's a shame that the precancers have not gotten more attention from cancer researchers and from the public. My impression is that many cancer researchers fail to distinguish between "precancers" and "early cancers". Precancers are very different from early cancers. One of the most important properties of precancers is their tendency to regress [spontaneously, or with simple treatments]. The book clarifies the biological properties that distinguish precancers from other early [and late] cancers, and describes how we can stop cancers from developing by treating precancers.

More on precancers in next post.

Jules Berman

related words: precancers, preneoplastic lesions, preneoplasia, ien, intra-epithelial neoplasia, intraepithelial neoplasia, intra-epithelial neoplasm, intraepithelial neoplasm, in situ carcinoma, carcinoma in situ, cis, dcis, din, pin, panin, cin, dysplasia, adenoma, preneoplastic, pre-cancer, pre-cancerous, precancerous

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Science is not a collection of facts. Science is what facts teach us; what we can learn about our universe, and ourselves, by deductive thinking. From observations of the night sky, made without the aid of telescopes, we can deduce that the universe is expanding, that the universe is not infinitely old, and why black holes exist. Without resorting to experimentation or mathematical analysis, we can deduce that gravity is a curvature in space-time, that the particles that compose light have no mass, that there is a theoretical limit to the number of different elements in the universe, and that the earth is billions of years old. Likewise, simple observations on animals tell us much about the migration of continents, the evolutionary relationships among classes of animals, why the nuclei of cells contain our genetic material, why certain animals are long-lived, why the gestation period of humans is 9 months, and why some diseases are rare and other diseases are common. In “Armchair Science”, the reader is confronted with 129 scientific mysteries, in cosmology, particle physics, chemistry, biology, and medicine. Beginning with simple observations, step-by-step analyses guide the reader toward solutions that are sometimes startling, and always entertaining. “Armchair Science” is written for general readers who are curious about science, and who want to sharpen their deductive skills.