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    Posted: Sep 20 2013 at 11:29am

New Targets for Triple-Negative Breast Cancer

By Christina I. Herold, MD1, Carey K. Anders, MD2 | September 15, 2013
1Beth Israel Deaconess Medical Center, Boston, Massachusetts, 2University of North Carolina at Chapel Hill, Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina

Introduction

Triple-negative breast cancer (TNBC) is a unique subset of breast cancer. It is characterized by the lack of the three most commonly targeted receptors in human breast cancer: the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2)/neu. Given the lack of traditional targets, the propensity of early-stage TNBC to metastasize to visceral sites, and the poor survival associated with advanced TNBC, this subset of breast cancer is appropriately the subject of tremendous preclinical and clinical study.[1,2] While TNBC has historically represented a unique group of breast cancer patients, recent studies have continued to dissect the molecular heterogeneity of TNBC into smaller, distinct subsets, including the basal-like and claudin-low subtypes, both of which have unique genetic characteristics and treatment responses.[3,4] Moreover, a second molecular classification system of TNBC, also based on gene expression profiling, has identified six TNBC subtypes, including two basal-like subtypes (BL1 and BL2), an immunomodulatory subtype, mesenchymal and mesenchymal stem cell–like subtypes, and a luminal androgen receptor subtype, again with different responses to treatment.[5,6] Finally, The Cancer Genome Atlas (TCGA) project, supervised by the National Cancer Institute and the National Human Genome Research Institute, has also provided tremendous insight into the molecular heterogeneity and driver mutations specific to breast cancer, including TNBC.[7] As we unravel the biologic complexity of TNBC and develop rationally designed clinical trials rooted in strong preclinical evidence, our ability to treat this disease should continue to improve (Table).


Conclusions and Future Directions

The landscape of TNBC treatment is changing rapidly. At present and based on guidelines set forth by the National Comprehensive Cancer Network, the mainstay of treatment for TNBC, in both the curative and metastatic settings, is traditional cytotoxic chemotherapy. Concurrent with unraveling the biologic underpinnings of TNBC at the preclinical level to identify “druggable” targets, we are charged as a medical community with continuing to develop novel clinical trials rooted in sound science and to expand our armamentarium of targeted therapies to treat this aggressive disease more effectively. Perhaps our greatest hurdle is the amount of time necessary to carefully translate promising preclinical findings to the bedside, with the ultimate goal being FDA approval of new drugs that yield both superior survival and quality of life outcomes for patients with TNBC. In the meantime, we can only continue to stress the importance of clinical trial participation to move the entire field forward and provide patients with TNBC access to promising therapies.

For the full article, please click on this link:




Edited by 123Donna - Sep 22 2013 at 2:01pm
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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Triple Negative Breast Cancer: From Bench to Clinic in 2013 (from the IBC Network)

A guest post by Dr Angela Alexander, a TRIUMPH translational postdoctoral fellow at  MD Anderson. Her laboratory work focuses on combinatorial treatment approaches to benefit IBC and TNBC patients.  Her full bio is at the end of this post and we are so grateful for her generous of time and experience to share this information with our reader.   Thank you Dr. Alexander! 

As a breast cancer researcher in a mainly TNBC-lab, I get asked sometimes about the latest in research regarding TNBC and what sorts of options are available for patients. In this post I thought I would go over what sorts of trials are available and accruing right now at MD Anderson and several other large centers across the country and what science they are based on.

First though, one of the most interesting recent laboratory advances came out of Jennifer Pietenpol’s lab at Vanderbilt, where Lehmann and colleagues performed gene expression analysis on a large number of TNBC tumors and identified 7 different subtypes of TNBC each with some potential targets and deregulated pathways predicting sensitivity to different drugs. There are 2 subtypes that are basal like, 2 mesenchymal subtypes, a luminal subtype that expresses the Androgen Receptor as well as an immunomodulatory subtype. To read the paper where these subtypes were described, see (1).

More recently, Naoto Ueno’s lab asked whether these subtypes have prognostic value i.e. if we could identify upfront which subtype an individual patient’s tumor most resembles, can we determine their likely clinical response to neoadjuvant chemotherapy. Of course I wouldn’t be writing about this if the answer wasn’t yes, and these results were quite intriguing (2).  Moving forward however, in order to translate these findings into routine practice a number of steps will be required, including prospectively validating the Ueno study, determining whether overall survival rates are also predicted by subtype, then hopefully going through the CLIA-certification process to convert the currently research-based microarray method into a robust analysis approach on live patient samples. Stay tuned for more on these subtypes over the coming years!

Back to the major theme of the post however – what options are available today for TNBC patients.  Read on for what are the most promising angles of clinical and translational research or visit the tl;dr version of this info (a table with drugs and links)

PARP inhibitors – alone and in combination

First up: PARP inhibitors – one of the hottest areas of research in TNBC. PARP inhibitors are drugs that inhibit repair of DNA damage (one of the ways that chemotherapy kills cancer cells). Initially when studied in unselected populations, the response rates were not that high…but as the preclinical work has demonstrated increased sensitivity in BRCA1/2 mutant cell lines/tumors and more selected trials done, the results have been more promising.  Since about 70% of BRCA1/2 mutant breast cancers are triple negative, many of these studies use TNBC status, as well as young age, as a reasonable rationale to screen for mutations which would allow trial participation.

There are quite a few of these drugs in trials, and so far we have learned that they have a great safety profile. In the following sections with links to trials, I will use the following abbreviations for sites that come up multiple times: MDA = MD Anderson, MSKCC = Memorial-Sloan Kettering, DFCI = Dana Farber Cancer Center, FHCC = University of Washington Fred Hutchinson Cancer Center, NIH = National Institutes of Health).

Regarding PARP inhibitors, there are at least 2 phase 1 trials of newer PARP inhibitors as single agents to examine safety and hopefully gain early hints of efficacy.

Single agent trials:

1) BMN 673, in solid tumors including breast cancer –http://clinicaltrials.gov/ct2/show/NCT01286987 (Open: MDA, TGen, UCLA, others….)

2) Rucaparib – http://www.clinicaltrials.gov/ct2/show/NCT01482715  (Open: DFCI)

Moving forward however, it is more likely that PARP inhibitors will need to be used in combination with other drugs to have meaningful activity. These studies will be based on pre-clinical evidence of synergy, such as using PARP inhibitors to potentiate DNA damage by cytotoxic chemotherapy or other targeted agents that work via similar pathways.  On my blog, last year I wrote about 2 very nice Cancer Discovery papers that designed one such combination – ie PI3K inhibitors with PARP inhibitors (3+4).  To read more, you can visit thatpost.

Combination PARP inhibitor trials:

 1) Here is the trial with Olaparib (PARP inhibitor) and BKM120 (PI3K inhibitor) –http://clinicaltrials.gov/ct2/show/NCT01623349 (Open: MDA, MSKCC, DFCI, others)

2) Another quite reasonable combination is a Veliparib/ABT-888 (PARP inhibitor) with –  http://clinicaltrials.gov/ct2/show/NCT01149083 (Open: 21 sites including MDA, MSKCC, DFCI…)

3) Other chemotherapy combinations include this study with Veliparib in combination with either temozolomide or carboplatin & paclitaxel –http://www.clinicaltrials.gov/ct2/show/NCT01506609 (Open: MDA, DCFI and 90 other centers worldwide!) or Veliparib + cisplatin + vinorelbine –http://www.clinicaltrials.gov/ct2/show/NCT01104259 (Open: FHCC)

4) In a setting of a loco-regional recurrence of TNBC or IBC in a location that is amenable to radiation (ie no  previous chest wall coverage), there is also a trial available using Veliparib as a radiosensitizer. Trial info -http://www.clinicaltrials.gov/ct2/show/NCT01477489 (Open: MDA, MSKCC, DFCI, Duke, Uni of Michigan)

The majority of the above trials (other than the radiation one) use BRCA1/2 mutation status as an inclusion criteria.  So if the PARP inhibitor studies are not options based on being BRCA1/2 wild-type (ie negative for any known mutations), there are a good number of other options as outlined in the next sections.

Cell cycle checkpoints

One of the other new therapeutic vulnerabilities in TNBC is deregulated cell cycle checkpoints. A couple of options currently exist based on preclinical data. The lab that I am pursuing my postdoctoral work has been working on one of these for several years.  We have found that the majority of TNBCs have a protein called cyclin E that is cleaved and mislocalized in the cytoplasm causing it to be oncogenic due to high activity of its binding protein CDK2, and that cell lines with high levels of cyclin E in the cytoplasm are exquisitely sensitive to drugs that inhibit CDK2 (5).   Specifically the trial we have open right now is a combination of the CDK inhibitor (Dinaciclib) with epirubicin.  The trial info is here –http://clinicaltrials.gov/ct2/show/NCT01624441 (Open: MDA).

You might’ve heard of the p53 gene, which is one of the most commonly mutated tumor suppressor genes in cancer, including TNBC. One of the consequences of p53 mutation is loss of cell cycle checkpoints that normally protect cells from too much DNA damage. In the past few years it has become clear that p53 mutant cells are sensitive to inhibitors of another cell cycle checkpoint protein called Wee1 (6). In addition Wee1 inhibitors synergize with chemotherapy in cells (7).  AstraZeneca recently licensed Merck’s Wee1 inhibitor called MK-1775 that works well in cell lines, and now is being studied in several phase 1 trials. TNBC patients might be eligible for this study of MK-1775http://clinicaltrials.gov/ct2/show/NCT01748825 (Open: NIH).

 

Targeting Growth Factor Signaling Pathways

a) PI3K-AKT-mTOR pathway:

Another potential targeted therapy option is targeting the PI3K/AKT pathway, since this pathway is frequently altered in breast cancer, and multiple growth factor survival signaling pathways converge on AKT and mTOR (see figure 1 for a simplified schematic of the proteins in the pathway and how they can be targeted).  In addition, there is a recent study that shows that in residual tumors in TNBC patients after standard anthracycline-taxane chemotherapy, several PI3K pathway proteins are activated and correlate with relapse-free survival, suggesting again this pathway is relevant therapeutically (8). However it is currently not known where along the pathway would be best to target, so there are drugs that target many components of the pathway and even dual kinase inhibitors such as (GDC-0980). There are a few biomarkers of pathway alterations that appear to predict response to this class of agents, so some of these trials select only these patients.

PI3Kpathway

Figure 1: PI3K pathway schematic showing proteins and potential targeting mechanisms

One trial is a phase 2 trial of Merck’s AKT inhibitor (MK-2206) for advanced breast cancer patients with PIK3CA or AKT mutation or PTEN alterations. The trial info is –http://www.clinicaltrials.gov/ct2/show/NCT01277757 (Open: MDA, DFCI, Vanderbilt, and 2 other centers).

Drugs that target PI3K (upstream of AKT) are further along in development and there are more of them.  Two PI3K inhibitor trials that are open to TNBC patients are:

1) BKM120 – http://www.clinicaltrials.gov/ct2/show/NCT01790932 (Open: DFCI)

2) GDC-0941 in combination with paclitaxel, with or without bevacizumab (an angiogenesis inhibitor) -http://www.clinicaltrials.gov/ct2/show/NCT00960960 (Open: DFCI)

b) Growth factor receptors: cMet and EGFR

The other new signaling target that is promising is cMet which is a growth factor receptor that is found to be overexpressed in 60% of TNBCs and highly active in about 35% (9).  There are a number of drugs being tested that target cMet including antibodies and small molecule inhibitors. In the interest of full-disclosure of an incidental discovery while searching for something else recently, I discovered that Roche have discontinued development of the cMet-targeting monoclonal antibody (MetMab) in the TNBC setting. Given no other specific news, one could speculate that the response rate was pretty low.

1) One open study is of a dual cMet-ALK inhibitor X-396, which you can read more about here – http://clinicaltrials.gov/ct2/show/NCT01625234 (Open: MDA, Vanderbilt and Sarah Cannon Research Institute)

2) Another oral cMet-inhibitor being studied is ARQ197. The trial specifically for metastatic TNBC patients is here – http://www.clinicaltrials.gov/ct2/show/NCT01542996  (Open: DFCI and Brigham and Women’s Hospital)

3) A third cMet inhibitor XL184 trial is even more interesting, since this molecule also inhibits VEGFR2 which plays a role in angiogenesis, and is found to be amplified in about a third of TNBCs and linked to poor prognosis.  Therefore this trial has potential to inhibit 2 important processes for TNBC cell survival.

Trial info – http://www.clinicaltrials.gov/ct2/show/NCT01738438 (Open: DFCI and related centers in Boston)

Targeting EGFR has been attempted for a while, but the jury is still out whether this target is going to pan out.  EGFR is known to be overexpressed in a large fraction of TNBCs, and the preclinical work has been quite exciting with regard to the ability to block cell migration and metastasis in mouse models, as well as block repair of DNA damage, leading to cell death.  However, moving these studies into the clinic has been somewhat challenging for a number of reasons. One is that the EGFR antibodies are quite toxic.  Secondly, although there are a few signals of (short-term) response, we have certainly not identified the specific patient population who does benefit from these agents.  This year a phase 2 study of the EGFR antibody Cetuxumab in combination with cisplatin in unselected metastatic TNBC patients was published by Jose Baselga and colleagues, which showed a doubling in objective response rate (from 10-20%) – but this was not a large enough difference to meet the trial’s pre-defined criteria (10).

An alternative approach to target this important pathway is via oral tyrosine kinase inhibitors which may have different activities and toxicities from the antibodies such as Cetuximab. To understand these further, a trial with Erlotinib is available, examining its use in a maintenance setting after treatment with nanoparticle-encapsulated Paclitaxel (known as Abraxane) and Bevacizumab (the anti-angiogenesis drug mentioned previously. An interesting concept. see here for details –http://www.clinicaltrials.gov/ct2/show/NCT00733408  (Open: FHCC and 15 other centers)

c) Miscellaneous other signaling inhibitors

Inflammation from the tumor microenvironment has been linked to tumor growth due to stromal and immune cells secreting factors that signal through cytokine receptors. One example of such a pathway that has been found to be important and potentially targetable is the interleukin and JAK-STAT pathway.  A few years ago, a nice paper came out showing that the IL6-JAK2-STAT3 pathway is enriched in stem-like cells in breast cancer (11).  Following up on this observation, at the recent ASCO Breast Cancer Symposium, Beth Overmoyer’s group also presented correlative data showing concomitant activated mTOR signaling in IBC patient samples, suggesting that in the future they will likely try to combine the JAK2 inhibitor with an mTOR inhibitor. Based on this preclinical data showing the importance of this pathway, a JAK2 inhibitor, Ruxolitinib is being investigated in a combination TNBC and IBC (any receptor status) trial. Eligible patients must undergo a research biopsy to test for a biomarker in the JAK-STAT3 pathway i.e. phosphorylated Stat3, which is seen in ~60% of IBC patients.  The trial info is here – http://www.clinicaltrials.gov/ct2/show/NCT01562873 (Open: DFCI and soon other center(s)).

Another growth pathway that has been associated with a large portion of TNBCs involves the protein Src, which is a protein that signals upstream of various pathways that control proliferation, migration, differentiation, angiogenesis etc (12). Consequently inhibitors of Src have been considered.  Clinically though, even the potent Src inhibitor Dasatinib as a single agent has not shown much activity in unselected patients (13), but since the preclinical work indicated synergy with standard chemotherapies such as taxanes, it is now being tested in combination with weekly paclitaxel in this broad MBC trial –http://clinicaltrials.gov/ct2/show/NCT00820170  (open at MSKCC)

d) Angiogenesis targeting

Angiogenesis inhibitors have been studied for several years now based on solid rationale, but their optimal role in breast cancer treatment is still unknown. Bevacizumab (Avastin) is probably the best studied drug that has shown similar statistically significant benefit in TNBC patients as other subtypes when combined with chemotherapy in the first-line metastatic setting. However the very large 2600-patient BEATRICE study which was performed in the adjuvant setting with chemotherapy demonstrated that TNBC patients did not derive any additional benefit from Bevacizumab than chemotherapy alone in reducing recurrence.

This cautioned enthusiasm for VEGF targeting (in selected patients) has led to development of further agents that also target angiogenesis.  One such agent is the VEGF receptor inhibitor Tivozanib, which has been developed furthest in RCC. It is now being studied in TNBC in a placebo-controlled combination study with paclitaxel – seehttp://www.clinicaltrials.gov/ct2/show/NCT01745367 (Open: DFCI and up to 46 other centers eventually, see list on the trial link)

Immunotherapy

Probably the newest area of interest in TNBC biology is harnessing the potential of the immune system in iradicating tumors.  Many cancers including TNBC actively evade detection and eradication by the immune system via expressing proteins such as PD-L1 on their surface which interact with receptors on T-cells telling them to “be quiet”.  In fact, the data presented at ASCO earlier this year in melanoma and lung cancer using

antibodies that block this interaction, were so promising that some oncology thought leaders are already calling these the Drug of the Year.

With respect to TNBC now, there is a phase 1b trial that is currently open using Merck’s PD-1 inhibitor MK-3475 that includes 3 patient cohorts, one of which is TNBC. The inclusion criteria are quite broad, so check it out –http://www.clinicaltrials.gov/ct2/show/NCT01848834 (Open: FHCC, Moffitt Cancer Center and other mystery sites in IL, MA, NC, PA, WA)

Another variation on immunotherapy is targeting a specific type of myeloid immune cell called macrophages. Elevated numbers of macrophages have been found in residual tumors from patients who did not achieve a pCR with neoadjuvant chemotherapy (14). Why is this? Could be for a number of reasons – including macrophage suppression of T-cells and cytokine secretion that promotes angiogenesis. Therefore targeting these cells has been proposed as a way to boost natural immunosurveillance.  There are 2 trials open now testing combinations of chemotherapy with immunotherapy:

1) Eribulin (a microtubule-targeting chemotherapy) with the ‘macrophage inhibitor’ PLX3397 (CSF-1 inhibitor) is currently underway in an all-comers metastatic breast cancer trial, seehttp://clinicaltrials.gov/show/NCT01596751 (Open: UCSF, future at Duke and VICC)

2) An even broader study for solid tumors including TNBC of PLX3397 with weekly paclitaxel is also available – http://www.clinicaltrials.gov/ct2/show/NCT01525602 (Open: UCSF, Ohio State)

Finally another metabolic mechanism of immunosuppression, via the IDO pathway is being targeted in metastatic breast cancer in combination with docetaxel. The IDO inhibitor being studied is  Indoximod (1-methyl-D-tryptophan) http://clinicaltrials.gov/show/NCT01191216(Open: Moffitt, Emory, and several other centers)

http://www.theibcnetwork.org/triple-negative-breast-cancer-bench-clinic-2013/



Edited by 123Donna - Sep 22 2013 at 1:39pm
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 (1) Thanks(1)   Quote 123Donna Quote  Post ReplyReply Direct Link To This Post Posted: Oct 31 2013 at 9:22pm
"His new project will study how two proteins – Numb and Set8 – interact in this reaction and look for compounds that could serve as the first targeted treatments for triple-negative breast cancer."

Innovation Grant targets breast cancer subset

They represent less than 15 per cent of women diagnosed with breast cancer. But for Dr. Shawn Li, continuing a search for solutions in this rarely diagnosed area of breast cancer has become his main mission.

Thanks to a $200,000 (over two years) Innovation Grant from the Canadian Cancer Society, the Western Biochemistry professor hopes to find ways to overcome chemotherapy resistance in women with triple-negative breast cancer, which women under the age of 40 and those of African or Asian ancestry are at higher risk for.

Li was one of 37 researchers across Canada to share in $7 million in Innovation Grants, supporting creative problem-solving in cancer research.

While the high survival rate for breast cancer – 88 per cent – is often celebrated, this success is due to progress in early detection and treatment therapies. With triple-negative breast cancer, current treatments and newer therapies are not effective. Triple-negative breast cancer earns its name because the cancer cells test negative for three things: estrogen receptors, progesterone receptors and HER2 overexpression.

“While, in general, survival rates for breast cancer are high, it’s important to focus on a breast cancer that is more difficult to treat and affects many young women,” Li said. “Because they miss all the common targets of breast cancer treatment, after attempting surgery, it leaves us with only chemotherapy, which is quite toxic and devastating for so many people. It kills good and bad cells, and cancer cells can often return because they develop a resistance to the chemotherapy.”

With this continued support of the Canadian Cancer Society, who has given Li’s research $2.4 million since 2001, Li will be studying the biochemical reaction that plays a critical role in the death of triple-negative breast cancer cells, and is also involved in chemotherapy resistance.

His new project will study how two proteins – Numb and Set8 – interact in this reaction and look for compounds that could serve as the first targeted treatments for triple-negative breast cancer.

Li’s previous work showed the Numb protein plays an important role in cancer cell death. However, the Set8 protein interferes with this process and leads to chemotherapy resistance. Li and his team will study the Set8 protein and how it interferes with cancer cell death and, more importantly, screen thousands of drugs to look for those that prevent Set8 from interfering with cancer cell death, which could lead to better outcomes for women with this hard-to-treat form of breast cancer.

“Research gives you the opportunity to do something new every day, to do something you’ve never done before,” Li said. “It’s like an adventure. You know you want to climb that mountain, but you don’t know how to get there. And don’t be surprised if a bear may jump out of the woods along the way. You need to be prepared for different surprises and make another turn. You get frustrated all the time, but you need a high resilience level to move ahead. You try to see as far ahead as possible, but you can’t get ahead of yourself. With each step you take, you may have to tweak a bit.”

http://communications.uwo.ca/western_news/stories/2013/October/innovation_grant_targets_breast_cancer_subset.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

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Post Options Post Options   Thanks (0) Thanks(0)   Quote centsan Quote  Post ReplyReply Direct Link To This Post Posted: Nov 01 2013 at 11:45pm
These are very interesting studies and clinical trails.  I have a new primary TNBC after 5 years survivor free of the first TNBC the cancer came back in the other breast.  This time I had a bilateral mastectomy but I do not know which chemo regiment is right for a new primary.  My first regiment was 6 rounds of TAC.  I have gotten three Oncologist opinion and all three says something different.
1. TAC again
2. TC again or CMF
2. Cloboplatin and Genzar (Genibidazine (?))
I'm trying to find answers.  My surgery was October 8 with only the sentinel lymph node as positive. * other lymph nodes were negative/
I have expanders for future reconstruction surgery and these are the worse thing that I every gotten.  I keep having muscle spasms.
 
Looking for answers
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Post Options Post Options   Thanks (0) Thanks(0)   Quote 123Donna Quote  Post ReplyReply Direct Link To This Post Posted: Nov 02 2013 at 11:57am
Centsan,

So sorry you have a new primary in your other breast.  That really sucks (sorry, my feeling about this stupid disease!).  Glad you sought 3 opinions, I did the same with my recurrence and felt better about my decisions.  But it makes things difficult when they give you 3 different opinions.  

I thought there was a lifetime "max/limit" with Adriamycin?  Cytoxan too?  With your 6 treatments 5 years ago, have you reached that limit?

When I had my recurrence, which was just 13 months after finishing chemo, my onc thought we should try something else as maybe my cancer wasn't responsive to the taxanes.  So we tried a clinical trial with Carboplatin and Gemzar (Gemicitabine) with Iniparib.  Carboplatin is a platinum chemo (so is Cisplatin) and seems to work well for some of triple negatives.  I think the difference in us is mine was a recurrence shortly after and yours is a new primary after 5 years.  

I agree with you about the expanders.  They were the most uncomfortable thing to have placed in your body!  My plastic surgeon gave me valium to help with the muscle spasms.  It really worked, especially at first and when I got "fills" in them.

It's always difficult trying to make these decisions, especially when we feel like it's a guessing game.  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 (1) Thanks(1)   Quote 123Donna Quote  Post ReplyReply Direct Link To This Post Posted: Aug 20 2014 at 9:42pm
Originally posted by 123Donna 123Donna wrote:

c) Miscellaneous other signaling inhibitors

Inflammation from the tumor microenvironment has been linked to tumor growth due to stromal and immune cells secreting factors that signal through cytokine receptors. One example of such a pathway that has been found to be important and potentially targetable is the interleukin and JAK-STAT pathway.  A few years ago, a nice paper came out showing that the IL6-JAK2-STAT3 pathway is enriched in stem-like cells in breast cancer (11).  Following up on this observation, at the recent ASCO Breast Cancer Symposium, Beth Overmoyer’s group also presented correlative data showing concomitant activated mTOR signaling in IBC patient samples, suggesting that in the future they will likely try to combine the JAK2 inhibitor with an mTOR inhibitor. Based on this preclinical data showing the importance of this pathway, a JAK2 inhibitor, Ruxolitinib is being investigated in a combination TNBC and IBC (any receptor status) trial. Eligible patients must undergo a research biopsy to test for a biomarker in the JAK-STAT3 pathway i.e. phosphorylated Stat3, which is seen in ~60% of IBC patients.  The trial info is here – http://www.clinicaltrials.gov/ct2/show/NCT01562873 (Open: DFCI and soon other center(s)).

Another growth pathway that has been associated with a large portion of TNBCs involves the protein Src, which is a protein that signals upstream of various pathways that control proliferation, migration, differentiation, angiogenesis etc (12). Consequently inhibitors of Src have been considered.  Clinically though, even the potent Src inhibitor Dasatinib as a single agent has not shown much activity in unselected patients (13), but since the preclinical work indicated synergy with standard chemotherapies such as taxanes, it is now being tested in combination with weekly paclitaxel in this broad MBC trial –http://clinicaltrials.gov/ct2/show/NCT00820170  (open at MSKCC)
http://www.theibcnetwork.org/triple-negative-breast-cancer-bench-clinic-2013/


Biomarker in aggressive breast cancer identified

Two Northwestern University scientists have identified a biomarker strongly associated with basal-like breast cancer, a highly aggressive carcinoma that is resistant to many types of chemotherapy. The biomarker, a protein called STAT3, provides a smart target for new therapeutics designed to treat this often deadly cancer.

To read the article
http://medicalxpress.com/news/2014-08-biomarker-aggressive-breast-cancer.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

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Post Options Post Options   Thanks (0) Thanks(0)   Quote 123Donna Quote  Post ReplyReply Direct Link To This Post Posted: Sep 23 2014 at 2:48pm
Clovis Oncology Announces First Patient Enrolled in Lucitanib Phase 2 Study in FGF-aberrant Advanced Breast Cancer

Announced that its Phase 2 study of lucitanib in patients with FGF-aberrant, advanced breast cancer has commenced and the first patient dosed at a U.S. study site. Lucitanib is the Company’s oral, potent inhibitor of the tyrosine kinase activity of fibroblast growth factor receptors 1 and 2 (FGFR1-2), vascular endothelial growth factor receptors 1 through 3 (VEGFR1-3) and platelet-derived growth factor receptors alpha and beta (PDGFR a-ß).
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 8malik Quote  Post ReplyReply Direct Link To This Post Posted: Sep 23 2014 at 7:02pm
Hi Donna,


Very interesting info on clinical trials.  I am in an immunaltherapy drug in Phase I.  I will have my 2nd Cat Scan after 4 sessions this thursday Sept. 25 in Portland.  It has been going very well.  Thanks again for the info.
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Post Options Post Options   Thanks (0) Thanks(0)   Quote 123Donna Quote  Post ReplyReply Direct Link To This Post Posted: Nov 20 2014 at 8:21pm
Researchers in the NCI-designated Dan L. Duncan Cancer Center at Baylor College of Medicine have been awarded an additional $9.9 million in grant funding from the Cancer Prevention and Research Institute of Texas

The newest wave of funding brings Baylor’s total funding from the state cancer program to more than $130 million.

Baylor received $5.9 million for three early translational research grants – the highest amount awarded to an institution in the state in that category -- and $4 million in grants to help recruit promising first-time, tenure-track faculty members.

The individual awards included:

Early Translational Research

  • Dr. Debananda Pati, professor of pediatrics – oncology at Baylor and a member of the Texas Children’s Cancer Center, for a $2 million grant project titled “Novel Separase Inhibitors to Treat Refractory Breast Cancer.”
  • Dr. David Tweardy, professor of medicine – infectious diseases, for a $1,999,569 grant project titled “Oral Stat3 Inhibitor as Targeted Treatment for Triple-negative Breast Cancer.”
  • Dr. Leonid Metelitsa, associate professor of pediatrics – oncology at Baylor and a member of the Texas Children’s Cancer Center, for a $1,928,220 grant project titled “NKT Cell Platform for Cancer Immunotherapy.”
  • http://www.bcm.edu/news/grants/baylor-awarded-9-million-in-cprit-funding
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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