Infuse Inhibits Cancer? | Orthopedics This Week
Biologics

Infuse Inhibits Cancer?

Can 467, 916 spine fusion patients be wrong? Eugene Carragee, M.D., thinks so. Especially when a study powered by half a million patients didn’t agree with his analysis of the 463 patient AMPLIFY8 study. Dr. Carragee’s disappointment was in full view.


Paul Anderson, M.D.
We begin our report with the presentation given at the recent North American Spine Society (NASS) meeting by Paul Anderson, M.D., Professor of Orthopedic Surgery at the University of Wisconsin. On the morning of October 24, he presented a retrospective study of 467, 916 Medicare patients who’d had a spine fusion between 2005 and 2009.

Approximately a quarter of those patients (110, 808) received BMP-2 and the remainder (357, 108) did not.

At 467, 000 patients, Dr. Andersons’s study was the largest yet attempted to find a link between the use of BMP-2 and cancer.

As Dr. Anderson noted in his opening discussion, BMPs are powerful biologic agents which can induce bone formation. And there is an intuitive appeal to the argument that such bone inducing biologics could play a role in tumor formation.

But 463 patients in the AMPLIFY study just can’t provide statistically significant data about BMP-2 and cancer. In Dr. Anderson’s words, “The absolute risk of cancer promotion from BMP-2 may be small but could be significant at the population level. Small risks are difficult to detect in Phase 3 controlled trials. The effects on cancer risk may only be measurable using large sample sizes.”

Nearly half a million Medicare patients between 2005 and 2009 is a large sample size.

No Corporate Funding

In addition to Dr. Anderson, Jason Savage M.D. and Mick Kelly, a University of Wisconsin medical student, also worked on the study and the University of Wisconsin Medical School’s IRB (institutional review board) panel provided oversight.

Medtronic, Inc., the supplier of Infuse, had no financial or other role in this study. As far as we know, the company was not even aware of it. Anderson and his colleagues did not receive corporate support of any kind for this study.

Between 2005 and 2009, 467, 916 Medicare patients had spinal fusions and BMP-2 was used in 110, 808 of those patients. The remainder, 357, 108 patients, did not receive BMP-2.

The average follow up was 2.85 years in the BMP-2 cohort and 2.94 years in the control cohort. The patient demographics were similar in the BMP-2 and control group. Females were 62.5% of the BMP-2 cohort compared to 58.4% of the control group. Both groups had similar age distributions. Most of the patients in the study were under 65 years of age.

Study Findings

Here’s what this study of 467, 916 spine fusion patients found:

  • Of the patients who were treated with BMP-2, under six percent (5.9%) or 6, 557 developed a cancer2 during the study period.
  • Of the patients who were NOT treated with BMP-2, more than six percent (6.5%) or 23, 232 developed a cancer2 within the study period.
  • For each 100, 000 patients the incidence per year exposure of cancer was less in the BMP-2 group (2, 076 per 100, 000) than in the non-BMP-2 group (2, 212 per 100, 000).
  • The relative risk (RR) of developing cancer in the BMP-2 group compared to the control group was 0.938 (95% Confidence Intervals (CI): 0.913, 0.964). This was statistically significant (P=5.32E-06).
  • The BMP-2 group had a 6.2% reduced risk of cancer than in the control group.
  • The relative risk of developing cancer in males exposed to BMP-2 vs. control was 0.98 (CI: 0.94-1.02), which was not statistically significant.
  • The relative risk in females was 0.93 (CI: 0.90-0.97).
  • “We calculated relative risk of new neoplasms of 19 of 24 most common SEER cancer types. Patients exposed to BMP-2 had a relative risk less than one (indicating lower risk than control)—in 18 of the 19 neoplasms.” — Dr. Paul Anderson, et al.
  • “We found that exposure to BMP not only was not associated with increased cancer but that the opposite was true with a relative risk reduction in the BMP group of 6.2%.” – Dr. Paul Anderson, et al.
  • “Although this association was present, we cannot identify any biologic explanation for this effect. Further investigations are warranted.” – Dr. Paul Anderson, et al.

Present at Dr. Anderson’s talk at NASS was Dr. Eugene Carragee, Chief of Spinal Surgery at the Stanford University School of Medicine and managing editor of NASS’s peer review journal, The Spine Journal.


Eugene Carragee, M.D.
Dr. Carragee has written extensively regarding BMP-2 and cancer saying in previous podium presentation at NASS and elsewhere that BMP-2 may fuel existing cancers (see the November 5 article in the Milwaukee Journal Sentinel written by John Fauber). Specifically Dr. Carragee cited the 463 patient AMPLIFY study (239 patients with BMP-2 and 224 without) to support his opinions.

Carragee Reacts

Dr. Carragee’s reaction to Dr. Anderson’s data? He called it irresponsible.

Dr. Andersons’s response? I see your 463 patient study with my 467, 916 patient study.

And then raise you with decades of oncological research.

Dr. Anderson had the winning hand.

Bone Morphogenic Growth Factors and Cancer

Dr. Marshall Urist, who first described bone morphogenetic proteins (BMPs) in the mid-1960s, started his inquiry into BMPs as a result of a commission from the U.S. Atomic Energy Commission to research strontium 90, tetracycline, and the treatment of osteogenic sarcoma—cancer.

He was deeply aware of BMP and cancer yet he believed that BMP would transform orthopedics for the better. “The availability of the protein [BMP], " Dr. Urist told the Los Angeles Times in 1987 as his "bone glue" was undergoing testing by the Food and Drug Administration, "will make it possible to repair large bone defects caused by old infection, injuries, removal of tumors and congenital deformities in children and adults."

The FDA eventually approved BMP for bone growth in the spine and fractures. So while orthopedists went to work using BMP for tough cases, oncologists continued to research BMP’s links with cancer.

In fact, at the original FDA Panel when Infuse was first evaluated for commercial use in spine surgery, cancer was discussed in detail and the data at the time suggested that in most cases BMP-2 actually slowed cell growth. As the body of oncological research shows, this makes biologic sense since BMP-2 is a morphogen. Morphogens promote cell differentiation. Differentiation is a mutually exclusive from cell division.  Cancer is about pathological cell division.

Of course, Dr. Carragee’s arguments have been that BMP-2 could be leaking off the collagen sponge carrier and thereby have the opportunity to promote cancer—anywhere in the body since it could, in theory, travel throughout the body.  But, as was discussed at the original FDA Panel, most of the Infuse in the collagen carrier eluted in the first 5 days and rapidly cleared the blood in hours.  It was very hard to make a case that there was a high enough Infuse dose at the surgery site much less at the site of any nascent tumor somewhere downstream to even in theory contribute to tumor promotion.

Hundreds of peer reviewed studies of BMP and tumors were published. As a body of work they taught that BMPs play a role in both tumor formation AND inhibition.

Top Ten Findings From 50 Years of Oncological BMP Research

“BMPs are a double-edged sword in tumor biology: they function both as tumor promoters and tumor suppressors depending on the type of cell or tissue and the BMP dosage in the micro-environment. Additionally, we found no clear-cut pro- or anti-carcinogenic BMP’s in the oncogenic process, although some BMPs appear more often on the side of tumor promotion than others and vice-versa.”2

BMPs can act as growth and proliferation inhibitors. In different cancer environments, BMP-2 and -5 can inhibit proliferation, and modulate steroidogenesis of human adrenocortical tumor cells in vitro through a BMP dependent pathway. 2


BMP2-CEA expressing positive cells drive differentiation of mesenchymal stem cells to bone lineages.3

BMP-2 decreases the proliferation of MCF-7 breast cancer cells suggesting a crucial role of BMP-2 in repressing the activity of growth inhibitory pathway such as TGF-β. 4

In gastric cancer, BMP-2 act as growth inhibitor in a dose dependent manner by cell cycle arrest in the G1-phase mediated by p21/WAF1/CIP1, and enhances the pepsinogen II gene a differentiation marker of glandular cells of stomach, suggesting role in gastric cancer cell modulation. 5

It is common in advanced phases of prostate cancer to find BMPs associated with bone metastasis. BMP-2 produced by tumor cells is involved in heterotopic ossification in metastatic lesions from several types of cancerous cells such as urothelial bladder carcinoma. 2

BMPs are known to be associated with angiogenesis, particularly during embryogenesis . However, BMPs and their role in the process of angiogenesis in cancer remain to be determined. 6

Tumors adopt angiogenesis as a survival mechanism. Tumors secrete growth factors to induce blood vessel formation. Angiogenesis normally becomes quiescent during adulthood except for healing and some pathological conditions, including cancer. Onset of angiogenesis can occur at any stage of tumor progression but depends on the tumor type and micro environment. Angiogenesis is orchestrated by a diverse set of activators and inhibitors—which include the BMP family of proteins.7

BMPs behave differently at different doses, cell types, and cellular environments. This affects cellular attributes such as cell movement, adhesion, invasiveness, epithelial to mesenchymal transformation (EMT) and mesenchymal to epithelial transformation (MET).2

In complex oncogenic processes such as angiogenesis or metastasis, the role of individual BMPs may be direct or indirect. Further in vitro and in vivo studies are required to determine a mechanism in a specific type of cell, tissue or cancer. More study is needed to determine the combined effects of multiple BMPs on normal or cancer tissue, as the synergistic effects on cells may be different compared to individual effects. Such experiments would provide support (or lack thereof) for using BMPs in cancer therapy as an inhibitor. 2

Where to Now?

Dr. Paul Anderson’s study was the first large scale review of patients who’d received BMP-2 for bone formation. It shows that patients who’ve been administered BMP-2 to grow bone for spine fusion have a reduced risk of cancer. This is consistent with much existing oncological research. Furthermore, Dr. Anderson’s study, when examined within the context of existing and long standing oncological research, illustrates clearly that forming ANY conclusions from a 463 patient study is premature.

Dr. Carragee, who is the editor of The Spine Journal, stands in contrast to Dr. Anderson who approached this subject with thoughtfulness, objectivity and detail. As one would expect from a scientist.

Obviously more study is required. The good news is that the oncological community has laid an impressive foundation of BMP research. The other good news is that Dr. Paul Anderson and his team decided to actually look at 467, 000 patients and see if a link between BMP and cancer might be teased out of the data. Their work and this study is clearly a step in the right direction.

Finally.

References:
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1 24 cancer types as defined by theNational Cancer Institute’s Surveillance Epidemiology and End Results (SEER). Brain and other nervous system, breast, cervix uteri, colorectal, corpus uteri, esophagus, Hodgkin Lymphoma, Kaposi’s Sarcoma, kidney and renal pelvis, larynx, leukemia, liver and bile duct, lung and bronchus, melanoma, myeloma, non-Hodgkin lymphoma, oral cavity and pharynx, ovary, pancreas, prostate, stomach, testis, thyroid, and urinary bladder.

2 (Ashok Singh and Rebecca J. Morris, The Yin and Yang of Bone Morphogenic Proteins in Cancer, Cytokine Growth Factor Rev. 2010 Aug;21(4):299-313. Epub 2010 Aug 4.)

3 (Fong S, Chan MK, Fong A, Bowers WJ, Kelly KJ. Viral vector-induced expression of bone morphogenetic protein 2 produces inhibition of tumor growth and bone differentiation of stem cells. Cancer Gene Ther. 2010;17(2):80–5)

4 (Arnold SF, Tims E, McGrath BE. Identification of bone morphogenetic proteins and their receptors in human breast cancer cell lines: importance of BMP2. Cytokine. 1999;11(12):1031–7.)

5 (Wen XZ, Miyake S, Akiyama Y, Yuasa Y. BMP-2 modulates the proliferation and differentiation of normal and cancerous gastric cells. Biochem Biophys Res Commun. 2004;316(1):100–6.)

6 (Langenfeld EM, Langenfeld J. Bone morphogenetic protein-2 stimulates angiogenesis in developing tumors. Mol Cancer Res. 2004;2(3):141–9.) and (Valdimarsdottir G, Goumans MJ, Rosendahl A, Brugman M, Itoh S, Lebrin F, et al. Stimulation of Id1 expression by bone morphogenetic protein is sufficient and necessary for bone morphogenetic protein-induced activation of endothelial cells. Circulation. 2002;106(17):2263–70.) and ( Raida M, Clement JH, Leek RD, Ameri K, Bicknell R, Niederwieser D, et al. Bone morphogenetic protein 2 (BMP-2) and induction of tumor angiogenesis. J Cancer Res Clin Oncol. 2005;131(11):741–50.)

7 (Bergers G, Benjamin LE. Tumorigenesis and the angiogenic switch. Nat Rev Cancer. 2003;3(6):401–10.)

8 Administration FDA Panel, Executive Summary for P050036 Medtronic's AMPLIFY rhBMP-2 Matrix. Food and Drug Administration, 2010.

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