Go To Main TNBC Website


  New Posts New Posts RSS Feed - Diverse Genetic Alterations Discovered In TNBC
  FAQ FAQ  Forum Search   Events   Register Register  Login Login

Diverse Genetic Alterations Discovered In TNBC

 Post Reply Post Reply
Author
123Donna View Drop Down
Senior Member
Senior Member
Avatar

Joined: Aug 24 2009
Location: St. Louis, MO
Status: Offline
Points: 12845
Post Options Post Options   Thanks (0) Thanks(0)   Quote 123Donna Quote  Post ReplyReply Direct Link To This Post Topic: Diverse Genetic Alterations Discovered In TNBC
    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

Back to Top
debB View Drop Down
Senior Member
Senior Member
Avatar

Joined: Sep 14 2011
Location: Central Illinoi
Status: Offline
Points: 692
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
Back to Top
debB View Drop Down
Senior Member
Senior Member
Avatar

Joined: Sep 14 2011
Location: Central Illinoi
Status: Offline
Points: 692
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
Back to Top
123Donna View Drop Down
Senior Member
Senior Member
Avatar

Joined: Aug 24 2009
Location: St. Louis, MO
Status: Offline
Points: 12845
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

Back to Top
Kellyless View Drop Down
Senior Member
Senior Member


Joined: Jun 18 2009
Location: Dallas, Texas
Status: Offline
Points: 937
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!
Back to Top
123Donna View Drop Down
Senior Member
Senior Member
Avatar

Joined: Aug 24 2009
Location: St. Louis, MO
Status: Offline
Points: 12845
Post Options Post Options   Thanks (0) Thanks(0)   Quote 123Donna Quote  Post ReplyReply Direct Link To This Post Posted: Feb 07 2018 at 9:36pm

Study uncovers therapeutic targets for aggressive triple-negative breast cancers

As part of a breast-cancer diagnosis, doctors analyze the tumor to determine which therapies might best attack the malignancy. But for patients whose cancer is triple-negative—that is, lacking receptors for estrogen, progesterone and Her2—the options for treatment dwindle. Triple-negative cancers, or TNBC, also tend to be more aggressive than other cancer subtypes.


While it is known that defects in mitochondria, the cells' energy generators, are associated with the initiation of breast cancers, it is currently unclear whether alterations in mitochondrial DNA or mitochondrial functioncontributes to TNBC metastasis or to their notorious resistance to chemotherapy.

New findings from a study led by researchers at the University of Pennsylvania have made inroads into a strategy to identify TNBC tumors at risk for metastasis, and eventually target these cancers with drugs. The work, which compared the metabolic profiles of different cancer sub-types, identified patterns associated with aggressive triple-negative breast cancers that point to the possibility for more accurate risk assessment and personalized treatment.

"Currently there is no molecular diagnostic to identify which TNBC patients might be poor responders to available chemotherapies," said Manti Guha, a research assistant professor in Penn's School of Veterinary Medicine. "By identifying unique mitochondrial defects and alterations in metabolic gene expression in the most aggressive subset of tumors, this study provides new molecular biomarkers that could identify the aggressive subset of TNBCs and more importantly offer these patients promising options for treatment."

"The role of mitochondria in disease has been largely overlooked in western medicine," added Douglas Wallace, director of the Center for Mitochondrial and Epigenomic Medicine at Children's Hospital of Philadelphia and a mentor and collaborator of Guha's who was not an author on the paper. "Manti's work is transformative for this particular cancer because by identifying what is different about the mitochondrial energy system in triple-negative breast cancer compared to other, less dangerous forms of breast cancer gives us a real window into how we might intervene."

"We have known for almost a century that, compared to normal cells, tumors have impaired mitochondrial functions and metabolic reprogramming," Guha said. "I was interested in identifying if there were differences in mitochondrial signatures among breast-tumor subtypes and if this variability in mitochondrial genome and functions among patient tumors can help identify cancer patients who are at an increased risk for metastasis."

The researchers made use of tissue samples from patients with different breast-cancer subtypes, defined cancer lines and previously collected genomic data representing 825 breast cancer patients. Screening for mitochondrial DNA copy numbers, they found that patients who had more advanced disease were more likely to have the lowest mtDNA copy numbers. They also found clear patterns in mtDNA copy numbers between breast-cancer subtypes, with triple-negative cancers having the most reduced copy numbers. Additional screening revealed an imbalance in a particular sequence of mtDNA that was prevalent in triple-negative tumors but not in other breast tumor subtypes.

"This particular mtDNA sequence imbalance is fairly unique and has not been reported in cancers," Guha said. "This could potentially be used to stratify patients into different risk categories."

Examining breast-cancer cell lines, they found differences in oxygen consumption between triple-negative and other cancer subtypes, indicating impaired cellular respiration and thus mitochondrial function in those cells.

In a broad screen of 84 genes related to metabolism, a process that mitochondria regulate, the researchers found clear patterns that characterized triple-negative tumors from other breast-tumor subtypes. These genes could serve as potential therapeutic targets for intervention, or as biomarkers to identify breast tumors that are more likely to metastasize, the researchers noted.

"We observed unique mitochondrial aberrations in TNBCs which can serve as a diagnostic marker of TNBC metastasis and be utilized to improved combined chemotherapeutic or individualized approaches," Guha said.

To build on these findings, Guha and colleagues are investigating whether FDA-approved therapies, or those currently in clinical trials, that target metabolic pathways could prove particularly effective against triple-negative breast cancer.


https://medicalxpress.com/news/2018-02-uncovers-therapeutic-aggressive-triple-negative-breast.html

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

Back to Top
 Post Reply Post Reply
  Share Topic   

Forum Jump Forum Permissions View Drop Down

Forum Software by Web Wiz Forums® version 11.05
Copyright ©2001-2016 Web Wiz Ltd.