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Future of TNBC Research and Treatment

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    Posted: Sep 22 2015 at 8:15pm
Future of TNBC Research and Treatment: A Movement Toward Precision Medicine 

While TNBC is a heterogeneous group of breast cancers there is increasing effort to subdivide it into more homogenous groups that may help in more accurate prognosis and response to therapy.

 

Le Du et al propose that five molecular subtypes of TNBC have a high potential to drive clinical trials. These include the basal-like, mesenchymal-like, the immune-associated, androgen receptor overexpression in the luminal/apocrine group, and HER2-enriched.80

 

Because of genetic instability of the tumors, the cancer can have molecular changes throughout the course of the disease. Therefore, it is not known if molecular classification at the time of diagnosis will continue to be predictive of response after treatment as the tumor evolves. Less invasive methods, such as analysis of circulating tumor DNA or circulating tumor cells, may be an accurate method of monitoring clinical response to treatment and personalizing the treatment as the disease progresses. As more research continues into the molecular subtypes of TNBC, there is the potential to uncover additional biomarkers (FIGURE 5).80

 

Figure 5. Triple-Negative Breast Cancer classifications.

Figure 5. Triple-Negative Breast Cancer classifications.


An additional target under research in the treatment of TNBC is the notch signaling pathway, which is involved in self-renewal, angiogenesis, proliferation, and apoptosis. TNBC xenograft models with NOTCH1 rearrangements were found to be sensitive to gamma-secretase inhibitors.81

PF-03084014 is a selective gamma-secretase inhibitor that is thought to have antitumor activity by blocking activation of notch receptors.82 A phase II, open-label biomarker study of PF- 030804014 is under way for nonmetastatic chemoresistant TNBC (NCT02338531).83

There is evidence that the JAK2/STAT3 pathway disruption may be a potential target in TNBC. Janus kinases (JAKs) are another group of tyrosine kinases involved in cell survival and growth. In basal-like breast cancer, JAK/STAT3 was found to be active and inhibition led to decreased growth in the xenograft models.81

Ruxolitinib, an IL-6/JAK/STAT inhibitor, is being studied in a phase I trial for recurrent breast cancer, with a phase II portion specifically for preoperative inflammatory TNBC (NCT02041429).84

Trop-2 is overexpressed in some epithelial cancers and involved in cell-to-cell adhesion. The US Food and Drug Administration (FDA) gave a fast track designation to IMMU-132 (isactuzumab govitecan) for progressive metastatic TNBC.81 An open-label, phase II study that is not yet recruiting will look at IMMU-132 and carboplatin in patients with TNBC (NCT02161679).85

Innate immunosurveillance has the ability to identify cancerous cells and destroy them. However, cancer cells characteristically have the ability to evade the immune system. New evidence points to cytotoxic T-lymphocyte antigen (CTLA) inhibitors and programed cell death-1 inhibitors (PD-1) as potential targeted immunotherapies. Furthermore, the PD-1 ligand, PD-L1, is expressed in about 20% of TNBC and confers a poorer prognosis.86 Nanda et al presented an abstract for pembrolizumab (MK-3475), a selective humanized monoclonal antibody that blocks PD-1, in the treatment of advanced TNBC. They found that pembrolizumab was tolerated and effective in heavily pretreated TNBC and thus opens the door for immune checkpoint inhibition in TNBC.87

New research into the association of CD44(+)/CD24(-) and TNBC found this relationship may play a role in the aggressive nature of TNBC. Therefore, CD44(+)/CD24(-) may be another future targeted therapy in the TNBC population.88

Finally, new research into insulin-like growth factor may provide even more options for targeted therapy. For example, insulin-like growth factor-2 mRNA binding protein 3 (IMP3) is expressed in TNBC, and its function is not completely understood. Evidence now points to IMP3 being involved in breast tumor initiation and more aggressive diease.89 Likewise, insulin-like growth factor binding protein-3 (IGFBP-3) is highly expressed in TNBC and may function as a tumor promotor. The mechanism involves interaction with EGFR and growth-stimulatory signaling. Furthermore, the interaction of IGFBP-3 and EGFR may be asscoiated with TNBC chemoresistance. In-depth understanding of this relationship is another potential target for TNBC treatment.90




http://www.targetedonc.com/publications/evolving-paradigms/2015/triple-negative-breast-cancer/future-of-tnbc-research-and-treatment-a-movement-toward-precision-medicine

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 22 2015 at 8:18pm
The treatment of TNBC continues to be a challenge for physicians because of its limited treatment options, the dearth of approved targeted therapies, high mortality, and poor prognosis. Patients and physicians are limited to chemotherapy that targets DNA repair complexes, p53, and cell proliferation by using anthracyclinebased, platinum-based, and taxane-based treatment regimens.1 However, research into targeted therapies for TNBC is robust. Further understanding of gene expression in breast cancer has led to classifications in TNBC that may help guide research into targeted therapies.16 The ultimate goal is to develop personalized, targeted treatments for TNBC. However, this requires a deep understanding of the interaction of the immune system, oncogenic pathways, and the microenvironments of the tumor.80 Understanding the etiology and ultimately prevention of TNBC requires further research using population-based studies.5 

New research and the potential for targeted, personalized treatment in TNBC allow room for some optimism. However, because TNBC represents a subset of breast cancer, this requires collaboration in trials and research in order to address TNBC on a large scale.91 - 

See more at: http://www.targetedonc.com/publications/evolving-paradigms/2015/triple-negative-breast-cancer/evolving-paradigms-in-triple-negative-breast-cancer-conclusion#sthash.UbsQscOh.dpuf
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)
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Post Options Post Options   Thanks (0) Thanks(0)   Quote mainsailset Quote  Post ReplyReply Direct Link To This Post Posted: Sep 23 2015 at 5:41pm
Thanks for bringing this home Donna. As I read it I'm reminded of my opinion before I was dx'd, which was, hey if they can send a man to the moon surely they can cure cancer. Since then I have continued to be amazed and humbled by the complex nature of this thing called Tneg and how tenacious the researchers are who are hellbent on unlocking its secrets.
dx 7/08 TN 14x6.5x5.5 cm tumor

3 Lymph nodes involved, Taxol/Sunitab+AC, 5/09 dbl masectomy, path 2mm tumor removed, lymphs all clear, RAD 32 finished 9/11/09. 9/28 CT clear 10/18/10 CT clear
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Post Options Post Options   Thanks (0) Thanks(0)   Quote 123Donna Quote  Post ReplyReply Direct Link To This Post Posted: Apr 27 2016 at 10:34am
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: May 20 2016 at 6:39pm
Mouse study: Triple-therapy cocktail shrinks triple-negative breast tumors

In a new study using mice and lab-grown human cells, a scientific team led by Johns Hopkins Kimmel Cancer Center researchers show how a triple-drug cocktail can shrink triple-negative breast cancers by killing off cancer cells and halting new tumor growth.

The combination treatment, described in a paper published in the April 1 issue of Cancer Research, is composed of thechemotherapy drug doxorubicin; all-trans retinoic acid, or ATRA, which can cause a tumor to lose its self-renewing cells; and entinostat, which makes cancer cells more sensitive to retinoic acid treatment.

Led by Saraswati Sukumar, Ph.D., the Barbara B. Rubenstein Professor of Oncology at the Johns Hopkins Kimmel Cancer Center, the scientific team reports that EAD therapy - named for each of its component drugs - "significantly" reduced the size of triple-negative breast cancer tumors in mice and the number of lab-grown spheres of metastatic breast cancer cells harvested from patients and grown in the laboratory.

Specifically, Sukumar and her colleagues tested several pairings of drugs before determining that the EAD combination was the most potent against triple-negative tumors. For instance, doxorubicin alone was able to reduce the formation of tumor spheres grown in the laboratory by 32 percent, while entinostat alone or ATRA alone could reduce them only by 18 percent. However, the combination EAD therapy reduced the formation of spheres by 90 percent.

To read the entire article:
http://www.medicalnewstoday.com/releases/310450.php


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 04 2016 at 12:59am
Finally, targeted therapies for 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 Catcat Quote  Post ReplyReply Direct Link To This Post Posted: Jun 04 2016 at 3:15am
This sounds good! How long does it usually take for fase 1 or 2 trials to become a common used and aproved treatment?
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Post Options Post Options   Thanks (0) Thanks(0)   Quote mainsailset Quote  Post ReplyReply Direct Link To This Post Posted: Jun 04 2016 at 10:39am
It's a long process, not uncommon to see 10 years of trials. But there is a fast track opportunity in play, particularly when a disease like Tneg has so few options for patients. A fast track would be less than half the normal.
dx 7/08 TN 14x6.5x5.5 cm tumor

3 Lymph nodes involved, Taxol/Sunitab+AC, 5/09 dbl masectomy, path 2mm tumor removed, lymphs all clear, RAD 32 finished 9/11/09. 9/28 CT clear 10/18/10 CT clear
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Post Options Post Options   Thanks (0) Thanks(0)   Quote 123Donna Quote  Post ReplyReply Direct Link To This Post Posted: Jun 14 2016 at 7:58am
University of Colorado Cancer Center researcher Jennifer Diamond, MD, is an investigator on three clinical trials of targeted therapies against triple-negative breast cancer (TNBC), two of which were presented at the American Society for Clinical Oncology (ASCO) Annual Meeting 2016 and one of which was presented just prior to the meeting. Each therapy uses a distinct strategy influenced by the immune system and all three have real potential to extend the lives of women whose cancers have progressed after previous treatments. . . 

. . .The first study, presented before ASCO, reports the phase I/II clinical trial of the drug IMMU-132, which was recently granted “breakthrough” status by the FDA, meant to speed the approval of the most promising new drugs. IMMU-132 is an “antibody-drug conjugate” meaning that it is, in fact, two distinct pieces linked together. In this case, the drug is a molecule related to the chemotherapy irinotecan. And the antibody is a molecule that binds to the protein Trop2, which is overexpressed in about 80 percent of all TNBC.

“The strategy is to use this Trop2 antibody to help the chemotherapy find and target the disease,” Diamond says.

The approach is similar to the mechanics of the immune system in which an antibody recognizes the surface proteins of a bacterium or virus and then directs a T cell to target invaders. (Only, in the case of this antibody-drug conjugate, irinotecan replaces the T cell as the agent responsible for killing unwanted cells.)

Sixty TNBC patients treated with IMMU-132 had an average of five prior rounds of therapy, meaning that their heavily pretreated cancers had proven especially resistant to therapy. In this notoriously difficult group, the overall response rate was 33% and the median duration of response was nearly 11 months. Six months later, 48 percent of patients’ tumors remained stable or better, with one complete response, meaning that after treatment, this woman’s aggressive breast cancer became undetectable.

The second study reports the results of a phase 1b study of the drug vantictumab in combination with the chemotherapy drug paclitaxel. In the trial of IMMU-132, an antibody sought cell-surface proteins specific to TNBC, bringing with it the payload of chemotherapy. In the trial of vantictumab, an antibody again seeks cell-surface proteins, namely the proteins of the “frizzled” receptor. But instead of bringing a poison to kill TNBC cells marked with frizzled receptors, vantictumab simply attaches to these receptors, plugging their ability to catch other molecules, and thus muting signals that these frizzled receptors could otherwise have transmitted inside the cell. These signals are the problem – frizzled receptors are an essential link in the Wnt signaling pathway, which transmits growth and survival signals to breast cancer stem cells. Vantictumab silences frizzled receptors, which interrupts messages through the Wnt signaling pathway, which results in TNBC stem cells not receiving instructions to grow, survive and replicate.

Of 21 patients treated on this phase 1b trial of vantictumab, 33 percent achieved at least a partial response.  Additionally, they have developed a test that seems to predict which patients will receive benefit from adding vantictumab.  This could lead to even better results in patients selected with that test in the future.

The third study reports the results of atezolizumab in combination with the chemotherapy nab-paclitaxel in patients with metastatic TNBC. Atezolizumab is a classical immunotherapy, one in a class of drugs known as PD-L1 inhibitors that counteract a tumor’s ability to hide itself from the immune system. Basically, T cells have PD1 receptors that, when activated, turn off a T cell’s cell-killing activity. Many tumors express PD-L1, which is the “ligand” that activates PD1, thus deactivating the T cell. Atezolizumab blocks the ability of PD1 receptors to bind PD-L1, thus leaving T cells able to target tumor tissue.

The combination of atezolizumab with chemotherapy has an interesting (if still somewhat scientifically controversial) symbiosis. Chemotherapy kills cancer cells. When a cancer cell dies, it releases tumor-specific antigens into the body – as if the body had been suddenly assaulted by a glut of bacteria or viruses, the immune system ramps up its production of antibodies that recognize these antigens, mustering T cells specifically enabled to target the perceived invasion. Now if PD-L1 is inhibited and tumors are unable to hide from these T cells, the hope is that it will result in the death of tumor tissue far beyond the effect of chemotherapy or immunotherapy alone. (Diamond points out that similar has been seen with targeted radiation: when an irradiated tumor releases antigens, the immune system may “ramp up” against these antigens and more effectively target far-away tumors, shrinking tumors that haven’t experienced direct treatment but which are marked by the same antigen.) There appears to be an especially synergistic relationship between atezolizumab and nab-paclitaxel, supporting this treatment.

In this study of 24 patients, 42 percent responded to treatment, with the majority of responders achieving stable disease.

“Many cancers are slow-growing and so when you see stable disease in trials of these cancers, you don’t know if it’s due to the treatment or to the fact that the cancer was going through a more dormant period. That’s not the case with triple negative breast cancer. This is a fast-growing disease and so seeing prolonged periods of stability is a very positive result,” Diamond says. The combination of atezolizumab and nab-paclitaxel is currently being tested in a Phase III clinical trial in triple-negative breast cancer.

In total, these three trials represent the transition of TNBC targeted therapies from years of work in the laboratory to promising results in the clinic. IMMU-132 is the closest to approval, but vantictumab and atezolizumab may also prove helpful. These three trials also demonstrate the clinical usefulness of strategies targeting cancer along the spectrum of immunotherapy, from the spot-on immunotherapy IMMU-132 that recruits T cells against tumor tissue, to approaches that are influenced by the mechanics of the immune system but do not directly coopt its resources to fight cancer cells.




Edited by 123Donna - Jun 14 2016 at 8:01am
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 15 2016 at 6:55pm
Researchers identify promising new compound for targeting triple-negative breast cancer

Researchers at the University of Michigan have identified a promising new compound for targeting one of the most aggressive types of breast cancer.

The compound, currently called UM-164, goes after a kinase known to play a role in the growth and spread of triple-negative breast cancer. UM-164 blocks the kinase c-Src and inhibits another pathway, p38, involved in this subtype. The researchers also found that the compound had very few side effects in mice.

To read the entire article:
http://www.news-medical.net/news/20160609/Researchers-identify-promising-new-compound-for-targeting-triple-negative-breast-cancer.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 (0) Thanks(0)   Quote 123Donna Quote  Post ReplyReply Direct Link To This Post Posted: Feb 05 2018 at 11:39am

Study find specific protein that plays a role in breast cancer spread.  Proposal for improving treatments for invasive breast cancer

Dr Mielgo said: "Our findings provide the rationale for further developing the combination of paclitaxel with IGF blockers for the treatment of invasive breast cancer.

https://www.news-medical.net/news/20180125/Study-finds-specific-protein-that-plays-role-in-breast-cancer-metastasis.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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