Results of neoadjuvant trials of metformin

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jenrio
jenrio Member Posts: 558
edited June 2014 in Clinical Trials, Research News, Podcasts, and Study Results

 http://www.ncbi.nlm.nih.gov/pubmed/22564993

Basically, if you have normal blood sugar, has low tumor grade to start with, normal BMI, don't drink alcohol, then Metformin may not help you may even hurt your chances.    However, if you are the opposite of above in even one way, metformin may be good.   But more clinical trial is needed.  

Notice how fast this study came out with results (just 1 year recruiting patients and out pops the paper).   Neoadjuvant trials is the way to go.   with trials like this and ispy-2, development cycles for new drugs could be shortened even to 5 years from 15 years (the current time length between lab to clinic).    With this kind of turnaround time, it's quite possible we could have BC cure in 10 years.   

"The trend to an increased proliferation in women without insulin resistance, albeit nonsignificant, suggests a complex biologic effect of metformin in women without metabolic alterations. Animal studies
have shown that metformin may have tumor suppressive effects where a metabolic phenotype of high caloric intake, metabolic syndrome,and diabetes exists, but no effect or even a growth promoting effect
under normal energy intake.16,46 In humans, metformin has shown differential effects according to grade of obesity and glucose intoler-
ance, exercise, diet, alcohol use, and lipid levels, supporting the notion of a drug that regulates metabolic homeostasis depending on energy
balance."

This results differ from another presurgical trial from Scotland

http://www.tara.tcd.ie/jspui/bitstream/2262/61127/1/PEER_stage2_10.1007%2Fs10549-011-1612-1.pdf

Could be explained by methodology or patient population difference.

I'm not writing off metformin. On the contrary, I like metformin. And other biguanides and variation to metformin and 100 other interesting new drugs should be tested too. Cheap and quick pre-operative studies like this (costing a few million at most, 1 year of researcher time, 1 month patient commitment) are the only way to extensively test many promising drug candidate quickly and cheaply. Even if metformin fails to validate, there will be other drugs that would cure BC.  

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  • jenrio
    jenrio Member Posts: 558
    edited June 2012

    This results differ from another presurgical trial from Scotland

    http://www.tara.tcd.ie/jspui/bitstream/2262/61127/1/PEER_stage2_10.1007%2Fs10549-011-1612-1.pdf

    Could be explained by methodology or patient population differnece 

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  • Husband11
    Husband11 Member Posts: 2,264
    edited June 2012

    To clarify, this was a 4 week long trial in which presurgical tumour samples in 100 patients receiving metformin were compared to 100 patients on placebo and after 4 weeks the tumour was biopsied and examined for a tumour marker called Ki-67.  High Ki-67 levels are associated with more aggresive tumours.  It is not the results of a long term clinical trial that compares rates of recurrance.  I wouldn't draw any firm conclusion from this.

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  • jenrio
    jenrio Member Posts: 558
    edited June 2012

    You are right.   No firm conclusion but a strong hint that the longer term trials need to be designed with checks on patient's metabolism status.   Imagine waiting 5 years, recruiting 3000 patients, spending a billion dollars only to find that they did not do the right blood serum test (or do it fasting) at the beginning of trial and results turn out statistically insignificant.     Everyone loses.

    Another way this kind of trial is useful is that it could accelerate drugs which clearly shows significant effect.   Tumor growth is exponential.  so even 10% reduction of ki-67 over 1 month (assuming statistical significance) is nothing to sneeze at.    But the 10% increase in ki-67 in certain population is a little concerning (assuming statistical significance).   In this case, both increase and decrease in ki-67 are not statistically significant.    But if statistical significant benefit is reached, then FDA would allow acceleration  of drugs based on this kind of quickie trials.    THAT would be wonderful.

    Read the scottish study too.   Very different results.   consistency in testing ki-67 and deep sequencing is very important in this kind of studies. 

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  • Husband11
    Husband11 Member Posts: 2,264
    edited June 2012

    I think this type of trial would be a fast way to screen for a magic bullet (complete clinical response), but it might also pass over drugs that might be of benefit (slower acting or anti-metastasizing for instance).  It also relies on the assumption that the tumour marker being measured will always be a valid indicator of success.

     Thanks for posting the article.  Its certainly though provoking, but I wouldn't write off metformin just yet.

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  • jenrio
    jenrio Member Posts: 558
    edited June 2012

    I agree with you.   obviously pre-operative trials with *statistically insignificant* data are not going to yield *definite conclusions*.   But it got some interesting data quickly (1 year vs 5 years), cheaply (a 700 patient adjuvant trial costs about about 100M, this one probably costs a few million dollars max).

    Again, you need to read the Scottish study on metformin.   Also a pre-operative study with different conclusion about metformin.   It uses deeper genetic analysis on the biopsy samples.    

    I'm not writing off metformin.   On the contrary, I like metformin.   And other biguanides and variation to metformin should be tested too.   Pre-operative studies like this are the only way to extensively test many promising drug candidate quickly and cheaply.   Even if metformin fails to validate, there will be other drugs that would cure BC.  

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