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nosurrender

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Reply with quote  #1 
I found this study very interesting- particularly if the Celebrex can also help with the pain from AIs, it would be a win win situation:

Reduced risk of bone metastases in breast cancer patients treated with Cox-2 inhibitors.

Category:

Breast Cancer--Local-Regional and Adjuvant Therapy




Abstract No:

526

Citation:

J Clin Oncol 26: 2008 (May 20 suppl; abstr 526)

Author(s):

W. J. Tester, M. Valsecchi, S. Pomerantz, R. Jaslow

Abstract:

Background: Approximately 40-70% of women diagnosed with breast cancer will develop bone metastases. The level of cyclooxygenase-2 (Cox-2) is overexpressed in human bone metastases and correlates with the occurrence of bone metastases in animal models. We hypothesize that the use of Cox-2 inhibitors in early phases of breast cancer could protect against the development of bone metastases. Methods: The medical charts of all patients treated for stage II and III breast cancer between 1999-2005 were reviewed. Patients were subsequently subdivided into those who took Cox-2 inhibitors (celecoxib, rofecoxib or valdecoxib) for at least 6 months following the diagnosis of breast cancer and those who did not. The diagnosis of bone metastases required conclusive radiologic imaging. Fisher's exact test and a multivariate logistic regression were used to analyze the data. Results: A total of 692 patients were included in this analysis. The patients' mean age was 59 and the mean follow up was 3.9 years. Eleven percent (74/644) of patients who did not take Cox-2 inhibitors developed bone metastasis compared to two percent (1/48) of those who did (Fisher's exact test p = 0.05). Significant predictors for developing bone metastases using a multivariate logistic regression model were: 3 or more positive nodes (p<0.001; Odds Ratio = 3.19, 95% CI = 1.79 - 5.70), stage IIb-IIIc (p = 0.001; OR = 4.61, 95% CI = 2.19-9.72) and use of Cox-2 inhibitors (p = 0.025; OR = 0.10, 95% CI = 0.013-0.75). Adjusting for TNM stage, of the 327 patients in stages IIb-IIIc, 21.5% (63/293) had bone metastasis in the non-Cox-2 group vs. 3% (1/34) in the Cox-2 group (p = 0.006). In this high-risk group of patients, the calculated odds ratio for development of bone metastases associated with the use of Cox-2 inhibitors was 0.10 (95% CI = 0.014-0.78). There was no significant difference between the groups in the number of patients that received adjuvant radiotherapy, chemotherapy, or hormone therapy. Conclusions: This retrospective study suggests that the use of Cox-2 inhibitors can reduce the risk of bone metastases in patients with stage II and III breast cancer. Prospective randomized trials of adjuvant Cox-2 inhibitors in patients with high-risk breast cancer are needed to validate this conclusion.




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Karen1956

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Reply with quote  #2 

Gina - very interesting article.  It seems like such a challenge to stay one step ahead of things.  My onc mentioned Zometa (I think thats it) if the Actonel and 2000/mg a day of Calcium did not help my BMD.  I went from borderline osteopenic to borderline osterporosis after one year on AI's.  You posted an article somewhere that Zometa also helped prevent bone mets (or am I imagining this).  I am so glad that you provide us with such valuable information.  I see my onc the end of the month and thinking about sharing this info with him.  Hugs, Karen

AlaskaDeb

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Reply with quote  #3 
I was on Celebrex after my initial Dx because of earlier studies that showed this.  I was on it over 2 years.  I still ended up with bone mets, BUT it is only in my marrow, not in the hard part of my bones.  I wonder if the Celebrex had any effect?.....
 
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CommandoBarbie

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Reply with quote  #4 
This is really interesting to me as Celebrex is heavily prescribed for those of us with RA. When I was first dx with RA almost 10 years ago, I assumed that I would take it as well. However, I was prescribed Voltaren instead. My Rheumy doesnt seem to be a big fan of Celebrex and while Voltaren is not a Cox 2 inhibitor, but when dealing just with RA, it offers similar joint pain relief with fewer side effects.

I see him next week and if I get the chance, I will ask him his take on this and if he's seen any studies. Granted, he's not an Onc, but it will be interesting to find out if he's seen this or any related studies.


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nosurrender

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Reply with quote  #5 
Karen, I actually wrote one of the articles on Zometa possibly preventing bone mets. I interviewed one of the top docs working on it. The only thing is what schedule do you go on? Once a month? Six Months? or once a year? That is what we need to find out.

Carynn, I didn't know we could get Voltaren in the US. Does it really help?

Deb, that is really a fascinating question- did the Celebrex protect the hard part of your bones? I am interested in hearing what your doc says.

Hope you are feeling ok!




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CommandoBarbie

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Reply with quote  #6 
Yup G - I've been on Voltaren (it's the generic for Diclofenac) for about 8 years now; and when used in concert with DMARDs and TNF blockers, it does help me quite noticeably. Unfortunately, my disease is bad enough that it takes all 3 together to see a real difference. But 8 years out, I have very minimal deformities and most days hold my own.

I was real interested when I heard that it was now available in the US in topical form. I asked my Rhuemy about it and he said that unfortunately, topicals wont provide much relief for RA joint pain.

Probably more info than you were interested in but since most DMARDs are low dose chemo drugs; I just find the whole RA/ Cancer tx aspect pretty interesting. 


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nosurrender

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Reply with quote  #7 
Carynn, thank you for telling me about this medicine.
My aunt has terrible RA. She even has it in her eyes. I am not sure how that works but apparently it can strike there.
Voltaren, I wonder if that would help for other things as well?
I am so very glad you haven't progressed too far with it.
It seems to be such a very hard disease to live with.

Love,
g


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CommandoBarbie

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Reply with quote  #8 
G - I am truly sorry to hear that your Aunt has RA. In some ways I've struggled more with it than I do with bc. Yes, hard to believe but RA can affect the eyes. My disease is classified as moderate to severe. I pretty much have it in every joint throughout my body.  But, I have a great, albeit strange, Rhuematologist  who has worked hard with me to find the right cocktail.

Frankly, this is why I whine so much when I have to go off my meds. I go from functioning almost normally (although slower than others), to needing a cane to walk. My Dr. got me a handicapped parking placard but I refuse to use it unless I'm having a really bad flare. I was really taken aback when I saw the paperwork said "permanent disability."

Is your Aunt on a TNF drug? (Enbrel, Humira, Remicade) They have helped tremendously to slow my progression. If she cant take any of them, yes Voltaren or Celebrex could help with the swelling.

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Reply with quote  #9 
Hi  This is interesting study but I was diagnosed a few months after being on Celebrex so wonder if it  maybe helped  keep my microcalifications quiet . Interesting. i also took Voltarin, Viox and am now on Naprosyn for arthriitis.
edge

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Reply with quote  #10 

Gina, Karen, CommandoBarbie, Mrsb:

Bone Metastasis 101
First, cyclooxygenase-2 (COX-2) is preferentially expressed in breast cancer cells compared to normal breast tissue, and more specifically is overexpressed in human bone metastases, correlating with the occurrence of bone metastases in animal models. Indeed, Zhigang Li at Baylor has shown that Increased COX2 expression enhances tumor-induced osteoclastic lesions in breast cancer bone metastasis. COX-2 itself is the enzyme involved in of prostaglandin synthesis, and prostaglandin (highly pro-inflammatory) production by human breast cancer cells positively correlates with the occurrence of bone metastases and has been implicated in cell growth, tumor invasiveness, apoptosis, angiogenesis and distant metastases (including non-bone metastases), this via the COX-2 metabolite known as prostaglandin E2, or PGE2 which stimulates osteoclastic bone resorption.

The normal process of bone remodeling involves osteoclastic bone resorption followed by osteoblastic (new) bone formation. Given that the first part of this process, osteoclastic bone resorption, is well-established as a central process in bone metastasis pathogenesis, that is, in the development and progression of bone metastases, therefore COX-2 is established as playing a contributive role in the bone metastasis of breast cancer, and of many other cancers (87% of the surgical specimens of bone metastases of cancer patients express COX-2). And note that by stimulating osteoclastic bone resorption, COX-2 also therefore plays a critical role in the promotion of osteolytic bone metastases. This is so because the process of osteoclastic bone resorption releases TGF-ß (transforming growth factor-beta) from the bone matrix; TGF-ß is a growth factor - a multifunctional protein peptide - that regulates the activity of osteoblasts and osteoclasts. The release of TGF-ß leads directly to elevated COX-2 expression which then leads to elevated PGE2 production, and in turn PGE2 production in breast cancer cells induces this tumor cells to colonize the bone (technically, via up-regulation of receptor activator of NF-kB ligand, called RANKL). Simplifying to show the essentials of this process:

TGF-ß ----> COX-2 ----> PGE2 -----> colonization of the bone by tumor cells

and this is viciously cyclic, as tumor cell bone colonization itself stimulates TGF-ß and hence restarts the whole process, feeding on itself.

COX-2 Inhibitors to the Rescue
The goal of COX-2 inhibitory therapy using COX-2 inhibitors such as celecoxib (Celebrex) and NSAIDs is to disrupt this pathogenic loop at the COX-2 phase in order to avoid PGE2 production and hence tumor cell bone colonization, and as powerfully observed recently by Toru Hirage's team at Osaka University, COX-2 expression regulated by bone-derived TGF-ß in breast cancer cells plays an important role in osteolytic bone metastasis, and so COX-2 inhibitors in part can reduce such osteolytic bone metastases, and they also exhibit direct inhibition of cell growth and induction of apoptosis in breast cancer cells.

What the Evidence Says
Clinical support of these observations is substantial. One of the most recent positive results are those just reported at ASCO 2008 by William Tester with the National Naval Medical Center who explored in a retrospective study (cited above by Gina) of 692 patients with early breast cancer the use of COX-2 inhibitors to protect against the development of bone metastases, finding that although 11% of patients not taking COX-2 inhibitors developed bone metastasis, only 2% of those taking COX-2 inhibitors did, suggesting that the use of COX-2 inhibitors can reduce the risk of bone metastases in patients with stage II and III breast cancer.

In addition, [Luc Yves Dirix with the GVAGroup / Medical Institute St. Augustinus in Belgium recently explored in a randomized phase II study the synergistic effect of celecoxib (Celebrex) on the efficacy and tolerability of exemestane (Aromasin) in a cohort of postmenopausal women with advanced breast cancer that progressed on tamoxifen, using a combination of exemestane (Aromasin) plus celecoxib (at 400 mg twice daily), finding a trend toward a longer duration of clinical benefit in the combination arm than in the exemestane (Aromasin) only arm, with the median duration of clinical benefit being two-fold longer in patients in the combination arm, and with no appreciable change to the tolerability profile of exemestane, and with no relevant clinical or pharmacologic adverse interactions between celecoxib (Celebrex) and exemestane (Aromasin). The tolerability findings are confrmative also of those from Louis Chow at University of Hong Kong in a undertaken sub-study of the CAAN trial which found that patients receiving combination of steroidal aromatase inhibitor exemestane (Aromasin) and pre-surgery COX-2 inhibitory therapy might actually have improved QoL in general (likely via the beneficial effects of COX-2 inhibition on the adverse musculoskeletal effects of AI therapy).

Way Out on that Frontier Edge
An extraordinarily gifted and innovative researcher at OSU (Ohio State University), Shu-Chuan Weng, has used a celecoxib (Celebrex)-derived PI3K/Akt signaling pathway inhibitor - an experimental Celebrex analog called, quite appropriately, OSU-03012 (from Cayman Chemical) after its birthplace - to sensitize estrogen receptor–negative (ER-) breast cancer cells to, amazingly, tamoxifen, trading insightfully on a little known fact, that tamoxifen under certain circumstances exhibits ER-independent antitumor activities (I have myself on a small number of occasions advised, successfully, a trial of tamoxifen in otherwise terminal, wholly unresponsive last-stage ER-negative disease, including triple negative breast cancer). This auspices that inhibition of PI3K/Akt signaling by COX-2-derived intervention may extend tamoxifen, and possibly also other endocrine therapy, to a broader population of breast cancer patients beyond just endocrine-responsive, and possibly to the challenging triple negative class.

And I should note in this connection that other research stemming out of the ever-innovative OSU research teams, in association with Wake Forest University, MD Anderson and others is beginning to suggest similar potential benefit in other cancers such as lymphomas, lung cancer and certain brain cancers (gliomas), and closer to home, research from Jill Kucab at the British Columbia Research Institute for Children's and Women's Health has recently found that two Celebrex analogs (both developed at OSU, OSU-03012 and OSU-O3013) were able to powerfully disrupt PI3K/Akt signaling which is commonly activated in breast tumors and they were also cytotoxic to HER2-overexpressing tumor cells.

It's development like these that represent the far frontier of the cutting edge, the kind I always follow and encourage closely.

Some Intersections at the Frontier Edge
First, there is a subtle and complex inflammatory pathogenic component to both cancer and to autoimmune inflammatory diseases like rheumatoid arthritis (RA), as witness by the fact that methotrexate (MTX, branded as Rheumatrex, Trexall) is currently a highly preferred DMARD (disease-modifying antirheumatic drug) for RA, and is of course the same agent as the "M" component of the infamous CMF chemotherapy regimen, being a powerful cytotoxic AND genotoxic (DNA-damaging) agent of value across the breast cancer spectrum, including estrogen receptor-negative BC such as triple negative disease, and although it is often noted that methotrexate is about as efficacious as many other DMARDs and other biological agents used in RA, I note here that methotrexate uniquely has an advantage over other anti-RA agents for cancer populations, as it is dual-mode: it is both an anti-RA intervention and at the same time an established cytotoxic and genotoxic anticancer agent.

Secondly, many CAM (complimentary and alternative medicine) interventions are also COX-2 inhibitory and anti-inflammatory, and effective in RA, including the ultra-powerful natural COX-2 inhibitory curcuminoids (derived from curcumin / Turmeric) and their near-cousins, the gingerols (from Ginger), and the EGCG components of green tea, and as I have already extensively documented the antitumor benefit of all these CAM agents, even specifically for breast cancer, then they too are dual-mode, being both anti-RA and antitumor.

Furthermore, I should note that another CAM intervention I have long advocated and advised as protective against the development of brain metastasis, boswellic acids derived from boswellia (from Frankencense, related to guggulsterone (Guggul),), is also powerfully anti-RA, as demonstrated by Smita Sontakke's team who compared in their randomized, prospective, open-label trial that BSE (Boswellia serrata extract, standardized on boswellic acids) in the treatment of knee osteoarthritis (OA) against the COX-2 inhibitor valdecoxib (Bextra, no longer available in the States but continuing to be used in India and elsewhere) and found that BSE (Boswellia serrata extract, standardized on boswellic acids) improved at a statistically significant level pain, stiffness, and difficulty of performing daily activities with two months of therapy, and this even lasted one month after stopping the BSE intervention, concluding that although BSE showed a slower onset of action than Bextra, the effect persisted even after therapy termination in contrast to Bextra with a faster onset which however waned quite rapidly after treatment termination, and indeed except for the slower onset of action, BSE was superior to Bextra in terms of safety, efficacy and duration of action, an impressive finding for an agent with no significant adverse effects to date.

I will conclude with a third and final intersection. Many cytokines, including tumour necrosis factor-a (TNF-a) are involved in free radical formation, in part via increasing the activity of NOS (nitric oxide synthase) which may mediate some of the deleterious effects of cytokines on bone resorption, and is suppressed by COX-2 inhibitors, methotrexate , the CAM interventions I documented briefly above, as well as n-3 polyunsaturated fatty acids (PUFAs), especially gamma linolenic acid (GLA) in omega-3 fish oils (especially the EPA component), and also the oleic acid component of olive oil. Hence these CAM agents are of significant benefit as anti-RA interventions and may also be of potential benefit as anti-bone metastatic agents.

In this connection, I find again a cutting edge result stemming from the research of Bernat Galarraga with the Institute of Cardiovascular Research, Vascular and Inflammatory Diseases Research Unit at Ninewells Hospital (UK) who in a just published dual-center, double-blind placebo-controlled randomized study addressed the problem of dose-dependant gastrointestinal and cardiovascular side-effects which sometimes limit the use of NSAIDs and COX-2 inhibitors in the treatment of RA. Their ingenious goal was to determine whether they could leverage an essential fatty acids (EFAs)-rich oil supplement (rich in omega-3 fish oil EPA and DHA) to help reduce daily COX-2 or NSAID requirements of patients with RA. They used an oral supplement providing 2.2 grams a day of EPA and DHA provided through cod liver oil supplementation in the form of 10 grams of Seven Seas Marine Oil 1 (SSMO1) which is a clinical grade of high-potency EFA-rich cod liver oil, and although this is a specialized formulation sold in the UK, equivalent preparations that will provide 2.2 grams of EPA and DHA will serve comparably (the Seven Seas product provides 150 mg of EPA and 70 mg of DHA in each capsule, so 10 capsules daily were required). What this methodologically robust study demonstrated is that this EFA-rich cod liver oil supplement allowed RA patients to reduce their daily NSAID requirement (mainly diclofenac (Voltaren), naproxen (Naprosyn, Alleve) and ibuprofen (Advil)) by more than a third, that is, by over 30%, thus reducing adverse events significantly and indeed the reduction of NSAID intake was not only achieved without worsening of disease activity, but there was a significant improvement in the pain benefit of the NSAID-sparing + EFA oil regimen. This is a landmark finding, allowing improved RA control plus enhanced pain relief, all with a significant reduction in adverse events. And I would easily hypothesize that the addition of further powerful anti-inflammatory CAM intervention as from curcuminoids, gingerols, boswellic acids, EGCG and/or oleic acid rich olive oils would add further anti-RA (and antitumor) benefit while reducing further all NSAID-related adverse events, and concurrently benefiting bone health and anti-bone-metastatic benefit.

That's the kind of lesson we learn on the frontier edge.


Constantine Kaniklidis
Breast Cancer Watch
edge@evidencewatch.com

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