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123Donna View Drop Down
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Post Options Post Options   Thanks (0) Thanks(0)   Quote 123Donna Quote  Post ReplyReply Direct Link To This Post Posted: Apr 30 2014 at 9:07pm
 Phospho-kinase profile of triple negative breast cancer and androgen receptor signaling


"The androgen receptor (AR) plays a central role in the oncogenesis of different tumors, as is the case in prostate cancer. In triple negative breast cancer (TNBC) a gene expression classification has described different subgroups including a luminal androgen subtype.


The AR can be controlled by several mechanisms like the activation of membrane tyrosine kinases and downstream signaling pathways. However little is known in TNBC about how the AR is modulated by these mechanisms and the potential therapeutic strategists to inhibit its expression. 

Methods: We used human samples to evaluate the expression of AR by western-blot and phospho-proteomic kinase arrays that recognize membrane tyrosine kinase receptors and downstream mediators.

Western-blots in human cell lines were carried out to analyze the expression and activation of individual proteins. Drugs against these kinases in different conditions were used to measure the expression of the androgen receptor."

PCR experiments were performed to assess changes in the AR gene after therapeutic modulation of these pathways. 

Results: AR is present in a subset of TNBC and its expression correlates with activated membrane receptor kinases-EGFR and PDGFRbeta in human samples and cell lines. Inhibition of the PI3K/mTOR pathway in TNBC cell lines decreased notably the expression of the AR.

Concomitant administration of the anti-androgen bicalutamide with the EGFR, PDGFRbeta and Erk1/2 inhibitors, decreased the amount of AR compared to each agent given alone, and had an additive anti-proliferative effect. Administration of dihydrotestosterone augmented the expression of AR that was not modified by the inhibition of the PI3K/mTOR or Erk1/2 pathways.

AR expression was posttranscriptionally regulated by PI3K or Erk1/2 inhibition. 

Conclusion: Our results describe the expression of the AR in TNBC as a druggable target and further suggest the combination of bicalutamide with inhibitors of EGFR, PDGFRbeta or Erk1/2 for future development.


Edited by 123Donna - Apr 30 2014 at 9:08pm
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: Jun 23 2014 at 9:50pm
Anti-androgen therapy for triple-negative breast cancer may benefit lower-androgen tumors

Triple-negative breast cancers do not benefit from the targeted therapies that have greatly improved the survival of patients with other subtypes of breast cancer. But recent work shows that while these cancers lack estrogen receptors, progesterone receptors, and aren't driven by the gene HER2, up to a third of these tumors express the androgen receptor – clinical trials are underway to inhibit the androgen receptor in these tumors in much the same way that the drug Tamoxifen inhibits estrogen receptor in estrogen-receptor-positive breast cancers. A new University of Colorado Cancer Center study being presented today at the Endocrine Society Annual Meeting shows that even triple negative breast cancers expressing very low levels of androgen receptor may benefit from this therapy.

"This line of work is starting to change our thinking about who and when – the timing and patient selection for anti-androgen receptor therapy in triple-negative breast cancer," says Valerie Barton, the study's first author and PhD candidate in the lab of CU Cancer Center investigator Jennifer Richer, PhD.

Triple negative breast cancers were recently divided into further subtypes including a subtype with high androgen receptor expression (Lehmann, JCI 2011). However, other subtypes also express the androgen receptor. How would these different subtypes respond to anti-androgen receptor therapy? To find out, Barton and colleagues treated cell lines with the drug enzalutamide and with shRNAs designed to knock down androgen receptor levels. Interestingly, the drug enzalutamide is in wide use for prostate cancer, which tends to be driven by and dependent on androgen receptor.

Results showed that not only does anti-androgen receptor therapy reduce the ability of androgen-receptor-expressing triple-negative breast cancers to proliferate, migrate and invade, but for these cells, androgen receptor seems essential to survival. When Barton and colleagues blocked androgen receptor in these cells, the cells died.

But it was not only the high androgen-receptor-expressing cells that were affected.

"The study showed that androgen receptor has important roles in other subtypes of triple negative breast cancer as well," Barton says.

Across multiple triple-negative breast cancer subtypes, inhibiting the androgen receptor greatly increased apoptosis (programmed cell death), inhibited growth and increased necrosis by 60 percent in animal models.

"We're still early in the study of androgen receptor in breast cancer and already scientists are divvying up the disease to say, for example, that only the high AR expressing subtype should be treated with anti-androgen receptor therapies," Barton says. "But what we show is that even triple negative breast cancers with lower androgen receptor expression critically depend on the androgen receptor and may benefit from anti-androgen receptor therapy. Our results suggest that anti-androgen receptor therapy may benefit a larger percentage of triple negative breast cancers than previously thought."

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: Feb 25 2015 at 8:17am
Even low-androgen triple-negative breast cancer responds to anti-androgen therapy

A University of Colorado Cancer Center study published today in the journal Molecular Cancer Therapeutics shows that only about 1 percent of triple-negative breast cancer cells in a tumor must be "androgen-receptor-positive" to show benefit from anti-androgen therapies. There are no FDA-approved targeted therapies for triple-negative breast cancer. Clinical trials currently underway are showing promising preliminary results of anti-androgen-receptor therapies against triple-negative breast cancers expressing a higher percentage of androgen-receptor-positive cells.

"What we're showing is that the threshold for benefit from anti-androgen-receptor therapies in triple-negative breast cancer may be far lower than we previously thought. This is an extremely optimistic finding for many people who have been without options for targeted cancer therapy," says Valerie Barton, the study's first author and PhD candidate in the lab of CU Cancer Center investigator Jennifer Richer, PhD. . . . .

. . . . ."We're getting closer to being able to call some triple-negative breast cancers, androgen-receptor-positive breast cancers. And we may have to start referring to the remaining triple-negative breast cancers that are completely without androgen receptors as quadruple-negative breast cancers," Barton says.

The current study treated triple-negative breast cancer cells with the anti-androgen-receptor drug Enzalutamide, currently FDA approved for use as an anti-androgen against prostate cancer. It has been previously shown that Enzalutamide is active against "luminal" triple-negative breast cancer cells that tend to have abundant androgen receptors. Barton and colleagues tested Enzalutamide against non-luminaltriple-negative breast cancer cell lines that have far fewer androgen receptors.

"Even in these cells and in mouse models of tumors with low percentage of androgen receptor positive breast cancer cells, we observed that Enzalutamide was significantly effective at reducing proliferation, growth, migration and invasion of cancer cells," Barton says.

"Our results suggest that anti-androgen receptor therapy may benefit a larger percentage of triple negative breast cancers than previously thought," Barton says.

http://medicalxpress.com/news/2015-02-low-androgen-triple-negative-breast-cancer-anti-androgen.html






Edited by 123Donna - Feb 25 2015 at 6:30pm
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 positive_attitude Quote  Post ReplyReply Direct Link To This Post Posted: Feb 25 2015 at 10:52am
Donna,

Thanks for posting this study. It is really wonderful. Caris report currently uses >=10% staining to define AR positive. Changing it to one percent will make a lot more people in our community AR positive, who could potentially benefit from the anti-AR therapy.

Rebecca
DX IDC TNBC May, 2014, 4.7cm, 5.8cm on Taxol. Taxol 4 weeks, AC 6. double mastectomy OCT 2014. 1.8cm residual in breast and 3mm a lymph node. BRCA-. 11/17 Abraxane,5FU.11/20, rads, 1/19 FUMEPx2
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Post Options Post Options   Thanks (0) Thanks(0)   Quote 123Donna Quote  Post ReplyReply Direct Link To This Post Posted: Feb 25 2015 at 6:29pm
Rebecca,

I found the 1% very interesting and may open up targeted therapy for those TNBCers that wouldn't have qualified before.  Not sure I like their suggestion of quadruple negative?

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 anndooleyallison Quote  Post ReplyReply Direct Link To This Post Posted: Feb 26 2015 at 9:49pm
Do most oncologists test for androgen receptor status?
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Post Options Post Options   Thanks (0) Thanks(0)   Quote 123Donna Quote  Post ReplyReply Direct Link To This Post Posted: Feb 26 2015 at 10:37pm
Anndooleyallison,

When I was diagnosed, it was not a routine test.  It would be interesting to see if anyone newly diagnosed was tested for the androgen receptor.  

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 positive_attitude Quote  Post ReplyReply Direct Link To This Post Posted: Feb 27 2015 at 9:01am
I do not think it is a routine test. My oncologist ordered Caris report for me and androgen is one of the biomarkers that were tested.
DX IDC TNBC May, 2014, 4.7cm, 5.8cm on Taxol. Taxol 4 weeks, AC 6. double mastectomy OCT 2014. 1.8cm residual in breast and 3mm a lymph node. BRCA-. 11/17 Abraxane,5FU.11/20, rads, 1/19 FUMEPx2
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Post Options Post Options   Thanks (0) Thanks(0)   Quote anndooleyallison Quote  Post ReplyReply Direct Link To This Post Posted: Feb 27 2015 at 6:55pm
Thank you. My daughter was recently diagnosed with a lung met. Neither MD Anderson or the local oncologist ordered testing. Her original tumor was ER/PR positive. The met was triple negative.
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Post Options Post Options   Thanks (0) Thanks(0)   Quote SagePatientAdvocates Quote  Post ReplyReply Direct Link To This Post Posted: Feb 27 2015 at 11:13pm
Dear Ann,

would suggest you go back to onc and ask if AR+ testing is appropriate.

Also I heard recently from a source I trust that...

the global enza trial is closed to accrual...but that Vanderbilt may have a trial for women who are low AR+.

Please do not take my word for anything but rather have your oncologist check to see if this or any other trial is recommended.

warmly,

Steve
I am a BRCA1+ grandson, son and father of women affected by breast/oc-my daughter inherited mutation from me, and at 36, was dx 2004 TNBC I am a volunteer patient advocate with SAGE Patient Advocates
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Post Options Post Options   Thanks (0) Thanks(0)   Quote anndooleyallison Quote  Post ReplyReply Direct Link To This Post Posted: Feb 28 2015 at 1:17am
Steve-Thank you so much. My daughter was diagnosed er/pr/positive at age 30 and 26 weeks pregnant. Started chemo after mastectomy, then radiation. Two months after radiation ended(Feb. 2014)- the lung nodule showed up. It was watched for a year and it was big enough to biopsy in January at MD Anderson where she received treatment. Path came back as cancer with inderminant source of either breast or lung. We came back to Illinois and she had VATS surgery to remove nodule. This path report said most likely not lung and that it looked consistent with he first breast cancer by appearance. It is now triple negative. Several drs. and surgeons have mentioned that it acts more like a lung cancer, but doesn't show markers for that. She started halaven 2 weeks ago, and had a clear pet san except for the lung nodule. No evidence of disease is what they called it. She has two preschoolers who need her and she wants to do all that she can. Steve -if you have any ideas or thoughts, please tell us about anything else we should be doing. Thanks so much.
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Post Options Post Options   Thanks (0) Thanks(0)   Quote nancyannee Quote  Post ReplyReply Direct Link To This Post Posted: Feb 28 2015 at 2:00am
I am newly diagnosed and can tell you the oncologists in my area DO NOT routinely test for AR status and when I asked my doctor, he only shook his head saying the standard does not call for it. I told him that TNBC was not standard to begin with and it seemed to me that identifying the sub-group would be key for a successful treatment.  He was surprised that I knew of this information and told me not to worry because that testing would/could be done in the event of a recurrence. Ugh! very upsetting because I want to wipe this out the first go round completely!!

Ann, my thoughts and prayers are with you and your family as y'all fight cancer. Believe in the impossible and it shall be possible. Your daughter sounds like a remarkable woman and Mother, she is lucky to have a Mom that cares for her so much.  I know with your help and her strength, she will overcome much.WinkFaith and Courage can get you through the toughest times.

peace

nancyHeart




Dx 09/14 IDC-TNBC
ST-3a,T2M2M0,3.8cm,BRCA-
10/14 bil/mast, 6 of 13 Nodes+
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Post Options Post Options   Thanks (0) Thanks(0)   Quote anndooleyallison Quote  Post ReplyReply Direct Link To This Post Posted: Feb 28 2015 at 10:31am
Thank you Nancy. It feels like everything we bring up about new research is dismissed in our local medical community. We may need to go elsewhere for the test. I appreciate your kind words.
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Post Options Post Options   Thanks (0) Thanks(0)   Quote 123Donna Quote  Post ReplyReply Direct Link To This Post Posted: Feb 28 2015 at 10:58am
Anndooleyallison,

It seems to be a test that is used more in the recurrent/metastatic setting than routine testing for newly diagnosed TNBC patient.  I hope the article about it being helpful for anyone over 1% positive might change the practices of oncologists and lead to routine testing.  Are you close to St. Louis?  Maybe consider seeking another opinion from Siteman Cancer Center.

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 anndooleyallison Quote  Post ReplyReply Direct Link To This Post Posted: Feb 28 2015 at 11:08am
Thanks Donna. My daughter is metastatic with the lung nodule. We are 3 hours away from St. Louis. Do you know of a Dr.at Siteman who does androgen testing and specializes in TNBC? Her primary was er/pr receptive, so we are trying to be as knowledgeable as we can with this change in receptivity.
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Post Options Post Options   Thanks (0) Thanks(0)   Quote 123Donna Quote  Post ReplyReply Direct Link To This Post Posted: Feb 28 2015 at 11:44am
Anndooleyallison,

For a second opinion, I'd highly recommend Dr. Cynthia Ma at Siteman.  She's head of breast oncology and specializes in metastatic bc.  She's very involved in research and clinical trials.



Donna


Edited by 123Donna - Mar 02 2015 at 7:49pm
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 anndooleyallison Quote  Post ReplyReply Direct Link To This Post Posted: Feb 28 2015 at 11:58am
Thanks so much.
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Post Options Post Options   Thanks (0) Thanks(0)   Quote DJacobs45 Quote  Post ReplyReply Direct Link To This Post Posted: Mar 02 2015 at 6:40am
I have TNBC and highly suspect I am AR+.  I appreciate your recommendation for Dr. Cynthia Ma at Siteman.  What is the best way to go about contacting her and requesting the test?
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Post Options Post Options   Thanks (0) Thanks(0)   Quote 123Donna Quote  Post ReplyReply Direct Link To This Post Posted: Mar 02 2015 at 7:39am
DJacobs45,

Have you asked your current oncologist for the androgen test?  If pathology can perform the test you'll know your androgen level.  To get an appointment from Dr. Ma, click on the first link listed above.  There is a telephone number to request an appointment.

If you are considering a second opinion, there are recommendations from members of this forum.  



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 tripleneg-mom Quote  Post ReplyReply Direct Link To This Post Posted: Mar 02 2015 at 4:02pm
I just did a blood draw last week for a lab test that somehow or another checks for circulating tumor cells and also androgen receptors.  Don't have the results yet.  Sounds very interesting!
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