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Diverse Genetic Alterations Discovered In TNBC

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123Donna View Drop Down
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    Posted: Dec 12 2012 at 8:34am

Diverse Genetic Alterations Discovered In Triple-Negative Breast Cancers

Most triple-negative breast cancer patients who were treated with chemotherapy to shrink the tumor prior to surgery still had multiple genetic mutations in their tumor cells, according to a study by Vanderbilt-Ingram Cancer Center (VICC) investigators. 

Finding multiple mutations instead of just one primary mutation that can be targeted for therapy sheds more light on the challenges of treating triple-negative breast cancer. 

The study, led by Justin Balko, Pharm.D., Ph.D., and research faculty in the laboratory of Carlos Arteaga, M.D., director of the Breast Cancer Program at VICC, was presented at the 2012 CTRC-AACR San Antonio Breast Cancer Symposium. 

Approximately 15 percent of breast cancer patients in the U.S. have triple-negative cancer - a form of the disease that disproportionately affects young African-American women. Triple-negative breast cancer has traditionally been more difficult to treat than other forms of the disease. 

"The standard of care for many patients with triple-negative breast cancer is to administer chemotherapy before surgery to shrink the tumor," Balko said. "Unfortunately, about 70 percent of patients still have some residual disease at the time of surgery, despite treatment." 

Balko and colleagues profiled residual tumor tissue from 114 patients with triple-negative breast cancer who had received chemotherapy prior to surgery. Triple-negative breast cancer cells do not have estrogen receptors, progesterone receptors, or large amounts of the HER2/neu protein. 

The investigators were able to evaluate DNA from 81 tumors and used deep sequencing to examine 182 oncogenes and tumor suppressors that are known to be altered in human cancers. Instead of finding similar genes affected among the patients, they found a diverse set of genes were altered. 

"We already knew that triple-negative breast cancer is driven by a diverse group of genetic alterations," Balko said. "So, in one way, we fell further down this rabbit hole, but we also found some things that could be promising therapeutically, such as frequent MYC, MCL1 and JAK2 amplifications as well as mutations in the PI3K pathway." 

The additional genetic alterations found in the study may provide targets for new therapies. 

Balko said the next step is to confirm the findings in a larger patient group, and if the findings are replicated, broad molecular approaches will be needed to help develop personalized therapies for triple-negative breast cancer. It also will be necessary to explore the therapeutic sensitivity of breast cancers harboring these lesions in the laboratory to know how to treat patients who have these alterations. 
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 debB Quote  Post ReplyReply Direct Link To This Post Posted: Dec 12 2012 at 1:19pm
The Cisplatin/PARP trial that several of us have been on is going to be doing sequencing on residual tumor as well. It will be very interesting to see what kind of results they show. I will ask next week if they have started doing it yet and when they may be looking at results being more public.

It is a start...
Dx 4/29/11, 46 yrs old, 3.9 cm tumor, Stg 2 Grade 3 chemo 4 rounds DD AC, 12 weekly taxol, finish. Lumpectomy, 2mm residual tumor. 37 rounds rads completed. Cisplatin/PARP trial
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Post Options Post Options   Thanks (0) Thanks(0)   Quote debB Quote  Post ReplyReply Direct Link To This Post Posted: Dec 21 2012 at 10:44pm
Hi All,

I had a very exciting conversation with the oncologist today! I mentioned above that with the Cisplatin/PARP trial that they are planning to do genome sequencing. I asked today where they were in the process. I was told that they just got the equipment and at the first of the year they would get trained on running the machine, get it calibrated, etc. After that, they will begin running the sequencing. He said at first, they will only be able to do 1-2 a day but will later be doing probably 15-20 a day. They will then be comparing the sequencing of the tumors looking for commonalities. I did not ask and really have no idea what kind of timeframe we are talking about for comparing the genome sequencing but the study only has in the neighborhood of 115 people enrolled right now.

Now, the ultimately cool part...once they have done the genome sequencing on the primary tumors of all the individuals in the study, the are going to analyze our blood samples. They will be looking at the molecular level of the blood for mutations matching the tumor. In other words, they will be looking for circulating tumor cells, micromets looking for a home. We did not get into the specifics of what would happen if they DO find circulating tumor cells. He did tell me they will notify me if they do find cells. I imagine what to do in that case is getting into unchartered territory. In an ideal world, I would say targeted treatment would be in order, but we also know that with falling into a very gray area that insurance may not see it that way. Given the relative short period of time in which TNBC recurs, he feels that it is likely that it stays circulating in the blood as opposed to going dormant.

He also did say that with the sequencing, we may sometimes not like the answers that we get. When I asked in what way, he said that we may find mutations for which we do not yet have treatment available. But, the analyses should also lead us to new targeted pathways.

I did not ask about comparing results with the above study, but given that this trial is all TN or BRCA variations, I would think it could be likely. I don't know how much some of this info gets shared/compared. TNBC really needs an ultimate case manager to coordinate all the science!! All in all, he does feel like we will be moving forward pretty quickly on TNBC, all in relative terms, of course. It sounds great in theory, now we have to see how it plays out in reality. I will keep you posted as I find out more.

Deb
Dx 4/29/11, 46 yrs old, 3.9 cm tumor, Stg 2 Grade 3 chemo 4 rounds DD AC, 12 weekly taxol, finish. Lumpectomy, 2mm residual tumor. 37 rounds rads completed. Cisplatin/PARP trial
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Post Options Post Options   Thanks (1) Thanks(1)   Quote 123Donna Quote  Post ReplyReply Direct Link To This Post Posted: Oct 06 2017 at 2:32pm

Gene targets for triple negative breast cancers resistant to chemotherapy found

Researchers have finally found the genetic targets that could be used for treatment and development of new drugs in patients who are resistant to chemotherapy. These patients who are resistant to chemotherapy are most likely to have triple negative breast cancer which is the most aggressive form of breast cancer. The study appeared in the latest issue of the journal Cell Metabolism.

Researcher Dr. Carlos Arteaga, Director of the Harold C. Simmons Comprehensive Cancer Center and his colleagues have found that these chemotherapy resistant forms of breast cancers have increased activity of two genes, MCL1 and MYC. It is found that the activity of these two genes is responsible for development of chemotherapy resistance. This new study has shown that the increased activity of these two genes increase the mitochondrial oxidative phosphorylation. This action leads to the growth of chemotherapy-resistant cancer stem cells that makes the cancer resistant to chemotherapy and non responsive to treatment.

Dr. Arteaga, Professor of Internal Medicine at UT Southwestern Medical Center, explained that it is relatively easy to detect the alterations of these two genes using the tumor gene tests that are being used these days. Further this study could pave the way for development of drug targets that could inhibit MCL1 or MYC, or both. These drugs or their combinations can be tried in clinical trials to check if they can reduce the risk of development of chemotherapy resistance among patients with this most aggressive form of breast cancer he added. He said that the drugs that could inhibit MCL1 or MYC genes are already being developed. These drugs probably would be needed to be administered along with standard chemotherapies. He speculated that that these combinations would then slow or even prevent the onset or development of chemotherapy resistance. This would greatly benefit the thousands of women with this type of aggressive breast cancer.

The research took place at the Vanderbilt-Ingram Cancer Center. It received funding and support from Cure Foundation, the Breast Cancer Research Foundation, a National Institutes of Health Breast Cancer SPORE grant and Vanderbilt-Ingram Cancer Center Support Grant.
https://www.news-medical.net/news/20171004/Gene-targets-for-triple-negative-breast-cancers-resistant-to-chemotherapy-found.aspx

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 (1) Thanks(1)   Quote Kellyless Quote  Post ReplyReply Direct Link To This Post Posted: Oct 08 2017 at 7:51pm
This Dr. Arteaga just became the director of my cancer center, UT Southwestern in Dallas 💝 The whole cancer facility, not just the breast cancer department. I was so happy to read that news, and now see this study. Thank you for posting!
IDC, 2.2 cm, Stage IIb,lumpectomy 1/30/09 ACx4,Tx4 36 rads
6/1/17 Local recurrence same breast, same spot 1.8cm Carb.4x every 3 wks, Taxol 12x once wk. Dbl Mast. PCR!! Reconstruction fail, NED!
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