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Asking questions on metformin trial

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    Posted: Sep 26 2011 at 11:27pm
To all the wonderful people who post and/or read the forums,

I need to make a decision by this Thursday morning whether to participate in the metformin vs
placebo clinical trial.   NCT 01101438.
(Short time to make decision due to a secretary declining to make a tentative appointment when
initially asked. Then, MD's schedule got booked up.)

Basically for me it comes down to 2 questions:
1. Which decision will give me greater peace of mind.
               Do study tolerating question of possible side effects/possible negative effect on cancer.
                        ( I am NED at present )
               Do not do study tolerating question that I did not pass up a future new treatment plan
                         component for TNBC.
2.   How to evaluate the one negative study that showed metformin increased cancer growth in animals
               with cell line MDA-MB-435.   ( Articles seem to question if MDA-MB-435 is a breast or melanoma
               cell line. ) ( Appears cell line more likely breast....still waiting an answer on this.)
                          Make decision with the info from the majority of studies so far.    (Do study)
                          Be concerned that any cancer cells might grow if one negative study is correct.
                                  (Don't do study)

The one negative study: by Kathryn Phoenix, Frank Vumbaca, Kevin Claffey.
Therapeutic Metformin/AMPK activation...........
        http://www.ncbi.nlm.nih.gov/pmc/articles/PM2606917
Negative study also referenced in:
Evaluation of metformin in early breast cancer: a modification....
Pamela J. Goodwin .......
       http://www.breastcancerrestreat (2011) 126:215-220

Realize I need to make my decision.
Asking for any thoughts or ideas or other things one might consider in this situation.
Asking how one might decrease the possible diarrhea side effect of metformin which some people
     get (reportedly, the diarrhea resolves)

Thanks

Grateful for today..........Judy
Clinical stage:     TNBC.    T2N1.   chemo (ACT). right mastectomy with axillary node dissection. Rads.
Pathology stage: TNBC.    ypT1cN1a
                     
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Post Options Post Options   Thanks (0) Thanks(0)   Quote 123Donna Quote  Post ReplyReply Direct Link To This Post Posted: Sep 27 2011 at 1:32am
Judy,

Metformin induces unique biological and molecular responses in triple negative breast cancer cells.

Abstract

Triple negative (TN) breast cancer is more frequent in women who are obese or have type II diabetes, as well as young women of color. These cancers do not express receptors for the steroid hormones estrogen or progesterone, or the type II receptor tyrosine kinase (RTK) Her-2 but do have upregulation of basal cytokeratins and the epidermal growth factor receptor (EGFR). These data suggest that aberrations of glucose and fatty acid metabolism, signaling through EGFR and genetic factors may promote the development of TN cancers. The anti-type II diabetes drug metformin has been associated with a decreased incidence of breast cancer, although the specific molecular subtypes that may be reduced by metformin have not been reported. Our data indicates that metformin has unique anti-TN breast cancer effects both in vitro and in vivo. It inhibits cell proliferation (with partial S phase arrest), colony formation and induces apoptosis via activation of the intrinsic and extrinsic signaling pathways only in TN breast cancer cell lines. At the molecular level, metformin increases P-AMPK, reduces P-EGFR, EGFR, P-MAPK, P-Src, cyclin D1 and cyclin E (but not cyclin A or B, p27 or p21), and induces PARP cleavage in a dose- and time-dependent manner. These data are in stark contrast to our previously published biological and molecular effects of metformin on luminal A and B, or Her-2 type breast cancer cells. Nude mice bearing tumor xenografts of the TN line MDA-MB-231, treated with metformin, show significant reductions in tumor growth (p = 0.0066) and cell proliferation (p = 0.0021) as compared to untreated controls. Metformin pre-treatment, before injection of MDA-MB-231 cells, results in a significant decrease in tumor outgrowth and incidence. Given the unique anti-cancer activity of metformin against TN disease, both in vitro and in vivo, it should be explored as a therapeutic agent against this aggressive form of breast cancer.

http://www.ncbi.nlm.nih.gov/pubmed/19440038


DX IDC TNBC 6/09 age 49, Stage 1,Grade 3, 1.5cm,0/5Nodes,KI-67 48%,BRCA-,6/09bi-mx, recon, T/C X4(9/09)
11/10 Recur IM node, Gem,Carb,Iniparib 12/10,MRI NED 2/11,IMRT Radsx40,CT NED11/13,MRI NED3/15

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Post Options Post Options   Thanks (0) Thanks(0)   Quote 123Donna Quote  Post ReplyReply Direct Link To This Post Posted: Sep 27 2011 at 1:53am
Also another study

Metformin: A Therapeutic Opportunity in Breast Cancer

  1. Ana M. Gonzalez-Angulo1,2 and
  2. Funda Meric-Bernstam3
http://clincancerres.aacrjournals.org/content/16/6/1695.long

Quote from the article:
"Furthermore, in estrogen receptor-negative cell lines, orthotopic MDA-MB-435 xenograft models, metformin treatment lead to increased tumor growth, increased cancer cell viability, and angiogenesis (49). In contrast, in a more recent report, investigators found that nude mice bearing tumor xenografts of the triple receptor negative cell line MDA-MB-231 show significant reductions in tumor growth and cell proliferation when treated with metformin, as compared with controls (50)."

Judy,

I agree with you when I look at some of these studies it looks promising, but there are some results where treatment lead to increased tumor growth.  Is the MDA-MB-435 cell line within the TN sub-types?  Or is the MDA-MB-231 cell line more in resemblance of TN?  Anytime we see results contrary to our purpose of participating in a clinical trial it give us doubts about proceeding.  Can you ask your onc about these studies?  Your decision will have to boil down to do you think the positives of the study outweigh the negatives.  I'd ask for a better explanation of the studies where it showed increased tumor growth.

Please let us know what you decide.

Donna

 


DX IDC TNBC 6/09 age 49, Stage 1,Grade 3, 1.5cm,0/5Nodes,KI-67 48%,BRCA-,6/09bi-mx, recon, T/C X4(9/09)
11/10 Recur IM node, Gem,Carb,Iniparib 12/10,MRI NED 2/11,IMRT Radsx40,CT NED11/13,MRI NED3/15

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Post Options Post Options   Thanks (0) Thanks(0)   Quote 123Donna Quote  Post ReplyReply Direct Link To This Post Posted: Sep 27 2011 at 1:57am
Some other abstracts on metformin and triple negative breast cancer:

http://www.ncbi.nlm.nih.gov/pubmed?term=metformin and triple negative breast cancer


DX IDC TNBC 6/09 age 49, Stage 1,Grade 3, 1.5cm,0/5Nodes,KI-67 48%,BRCA-,6/09bi-mx, recon, T/C X4(9/09)
11/10 Recur IM node, Gem,Carb,Iniparib 12/10,MRI NED 2/11,IMRT Radsx40,CT NED11/13,MRI NED3/15

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Post Options Post Options   Thanks (0) Thanks(0)   Quote TNinTN Quote  Post ReplyReply Direct Link To This Post Posted: Sep 27 2011 at 7:09am
Judy - thanks for the good questions.
 
Donna - thanks for the research.
 
Susan is on the Metformin trial. We did not have any discussions with our oncologist about which tumor line Susan had, or even if that was known at the time we started the trial, so I will be inquiring about this and will let you know what I find out. As for side effects, Susan has not experienced any. Of course we don't know if she is getting metformin or placebo, but we were told when we started the trial, as well as by many friends who are taking metformin for diabetes, that there often are no side effects.
 
Martin


Edited by TNinTN - Sep 27 2011 at 7:10am
Wife age 53@dx TN IDC Stage IIA 7/10; BRCA1&2 Neg; BROCA Neg; LN Neg; taxol+cisplatin+/-RAD001x12(clinical trial); lumpectomy 12/10;ACx4; 33 Rads complete 4/11; NED 5/5/11
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Post Options Post Options   Thanks (0) Thanks(0)   Quote Grateful for today Quote  Post ReplyReply Direct Link To This Post Posted: Sep 27 2011 at 9:56am
Hi Donna and Martin,

THANK YOU very much for your great....and very quick responses.
Please post again if you think of ANYTHING else.

My style is to research and explore an important matter to the Nth degree before making a decision......
so I am needing to adapt my style to decide by Thursday.
(Made my final breast surgery decision one week prior to scheduled date. My surgeon was great......
said he'd book the mastectomy and I could change to lumpectomy if needed when I made decision and
be able to keep the scheduled date. (rather then waiting to book or book a lumpectomy then if need to change to mastectomy there would be timing issue and most likely need to re-schedule.)

Fortunately, aware of some of Donna's references. Appreciate ones I had not found. Think I had only seen the abstract of the article by Ana Gonazlez on Metformn: A Therapeutic Opportuniy in Breast Cancer.
Have already scanned the entire article and plan to read it slowly a few more times.

Did check with onc MD re: pathology. She stated TNBC subtypes are not given on/done by hospital pathology at this time.   I asked about other tumor markers (other than E/P/Her2) and again told not
done by hospital pathology.
Regarding Phoenix article with the cancer tumor growth using MDA-MB-435 line, onc MD said that is why
clinical trials are needed.
Did attempt asking about off-label metformin. Onc MD: not an option. Other MD seemed like would consider.....spoke with my oncologist.....end result: no off-label metformin from other MD. (I wanted to know once I decided on metformin if there would be an option to get off-label)

Posting on forum: have seen posts on "Using metformin" and "Metformin Trials". Initially posted some info on metformin trials with some questions. The questions seemed to get buried there......so I made this
new topic post.    Is that the way to use the forum (post a new topic when one has specific questions)?
Am seeing that sometimes replies are made only to the last question posted on a forum.....
and prior questions above latest post may not get more responses?

Thanks again.   Will let you know my final decision.

Grateful for today............Judy


Hi everyone,
Please share any other thoughts or things to consider on my initial post.
Thanks.             
Grateful for today.......Judy

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Post Options Post Options   Thanks (0) Thanks(0)   Quote 123Donna Quote  Post ReplyReply Direct Link To This Post Posted: Sep 27 2011 at 11:07am
Judy,

Researching and researching is a great thing and you're doing everything right and asking the questions that need to be asked.  It's the only way we can learn.  Thanks for sharing your information and knowledge with us.  I too am interested in metformin and will be asking these same questions to my onc this week.  Sharing knowledge and information will help us be better patients.

Donna
DX IDC TNBC 6/09 age 49, Stage 1,Grade 3, 1.5cm,0/5Nodes,KI-67 48%,BRCA-,6/09bi-mx, recon, T/C X4(9/09)
11/10 Recur IM node, Gem,Carb,Iniparib 12/10,MRI NED 2/11,IMRT Radsx40,CT NED11/13,MRI NED3/15

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Post Options Post Options   Thanks (0) Thanks(0)   Quote Grateful for today Quote  Post ReplyReply Direct Link To This Post Posted: Sep 27 2011 at 7:37pm
Hi,

Still deciding. Still getting info.
Still welcoming any other thoughts or things to consider re: above initial post.
Will eventually post any additional info I get.
Again, info/references above very much appreciated.

Grateful for today............Judy
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Post Options Post Options   Thanks (0) Thanks(0)   Quote 123Donna Quote  Post ReplyReply Direct Link To This Post Posted: Sep 27 2011 at 7:39pm
DX IDC TNBC 6/09 age 49, Stage 1,Grade 3, 1.5cm,0/5Nodes,KI-67 48%,BRCA-,6/09bi-mx, recon, T/C X4(9/09)
11/10 Recur IM node, Gem,Carb,Iniparib 12/10,MRI NED 2/11,IMRT Radsx40,CT NED11/13,MRI NED3/15

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Post Options Post Options   Thanks (0) Thanks(0)   Quote 123Donna Quote  Post ReplyReply Direct Link To This Post Posted: Sep 28 2011 at 8:46am
DX IDC TNBC 6/09 age 49, Stage 1,Grade 3, 1.5cm,0/5Nodes,KI-67 48%,BRCA-,6/09bi-mx, recon, T/C X4(9/09)
11/10 Recur IM node, Gem,Carb,Iniparib 12/10,MRI NED 2/11,IMRT Radsx40,CT NED11/13,MRI NED3/15

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Post Options Post Options   Thanks (0) Thanks(0)   Quote AlohaGirl Warrior Quote  Post ReplyReply Direct Link To This Post Posted: Oct 27 2011 at 12:51pm
Hi Judy:

Came across this post and was just wondering if you have decided to proceed with the Metformin trial.
I have opted to be in the Metformin (vs. placebo) trial after my chemo is done. Has anyone out there proceeded with this trial? If so, please let me know what your experience has been.

Thanks,
Aloha Girl Warrior
______________________________________________________________________________
Dx TNBC stage II, SLN bx x3 neg, 8/18/11, Mastectomy 9/1, age 40, currently on TAC x2/6, Metformin trial, Radiation to follow. BRCA testing pending
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Post Options Post Options   Thanks (0) Thanks(0)   Quote TNinTN Quote  Post ReplyReply Direct Link To This Post Posted: Oct 27 2011 at 6:53pm
Hi Aloha Girl Warrior,
 
My wife, Susan, has been on the Metformin trial since July. So far she has had NO side effects and my understanding from speaking with several friends on Metformin that this is typical.
 
Good luck with your treatment.
 
Martin
Wife age 53@dx TN IDC Stage IIA 7/10; BRCA1&2 Neg; BROCA Neg; LN Neg; taxol+cisplatin+/-RAD001x12(clinical trial); lumpectomy 12/10;ACx4; 33 Rads complete 4/11; NED 5/5/11
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Post Options Post Options   Thanks (0) Thanks(0)   Quote clwille708 Quote  Post ReplyReply Direct Link To This Post Posted: Oct 27 2011 at 7:51pm

Dx Aug/10,age 62, Lump & SNB Sept/10,1.7 cm, grade 3, Triple Neg, Nodes clear. Annual screening due to family history of Ovarian C. BRCA - Chemo DD AC -->Taxol 21 Rads done. Hugs -Linda
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Post Options Post Options   Thanks (0) Thanks(0)   Quote clwille708 Quote  Post ReplyReply Direct Link To This Post Posted: Oct 27 2011 at 7:55pm
Hi Aloha:  I went on the Metformin trial in June.  I was very disappointed because I had to stop.  I was on it for 4 weeks (and sure I was on  the Placebo) , but when I upped my dose, my IBS came back in full force...I had been able to control it for four years.  I struggled to stay with it, but in the end I had to quit.  Hope it works for you.  I am sure there is some merit in it.

Regards
Linda from Wasaga Beach
Dx Aug/10,age 62, Lump & SNB Sept/10,1.7 cm, grade 3, Triple Neg, Nodes clear. Annual screening due to family history of Ovarian C. BRCA - Chemo DD AC -->Taxol 21 Rads done. Hugs -Linda
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Post Options Post Options   Thanks (0) Thanks(0)   Quote Grateful for today Quote  Post ReplyReply Direct Link To This Post Posted: Oct 27 2011 at 11:57pm

FYI: There are 2 other TNBC Talks forums on metformin:
                          Metformin trial.             Using metformin.
        See other Metformin info on other metformin topic sites.

_____________________________________________________________________________________________

Hi Aloha Girl Warrior,

Have been meaning to post my decision about the metformin trial and info I found.
Found a lot of info and will post that info soon.

After MUCH reading/research/thought, for me, I decided not to do the metformin trial.
Realize for some others, with reading/research/thought, others will decide to do the
metformin study.


Grateful for today.............Judy




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Post Options Post Options   Thanks (0) Thanks(0)   Quote Grateful for today Quote  Post ReplyReply Direct Link To This Post Posted: Oct 31 2011 at 8:02pm
SUCCESS!    USA metformin clinical trial sites now posted on:

http://clinicaltrials.gov     ( breast cancer    metformin placebo)
NCT: 01101438    Phase III Trial of Metformin versus Placebo in Early-Stage Breast Cancer

There are about 196 clinical trial sites in USA.


With positive and caring thoughts for all,

Grateful for today............Judy

-----------------
FYI: There are at least 3 forum sites on metformin. Am posting this info on all three.
            Metformin Trials
            Using metformin.
            Asking questions on metformin trials.
            
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