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    Posted: Sep 26 2019 at 11:38am

FDA: Novel Breast Ca Drugs Linked to Severe Lung Illness

Reports of ILD, pneumonitis in patients on CDK4/6 inhibitors

The FDA issued a warning Friday that CDK4/6 inhibitors for advanced breast cancer may cause rare but severe lung inflammation, and said fatalities had been reported.

Package warnings have been added to the three approved agents in the class -- palbociclib (Ibrance), ribociclib (Kisqali), and abemaciclib (Verzenio) -- and breast cancer patients taking these agents should be monitored for pulmonary symptoms indicative of either pneumonitis or interstitial lung disease (ILD).

"The overall benefit of CDK4/6 inhibitors is still greater than the risks when used as prescribed," the agency said in the statement announcing the move. But clinicians should suspend treatment in patients "who have new or worsening respiratory symptoms, and permanently discontinue treatment in patients with severe ILD and/or pneumonitis."

Data from completed and ongoing postmarketing trials involving CDK4/6 inhibitors were reviewed and revealed the connection, the FDA said, but factors to identify at-risk patients have not been found.

Signs and symptoms of ILD and pneumonitis can include "hypoxia, cough, dyspnea, or interstitial infiltrates on radiologic exams in patients in whom infectious, neoplastic, and other causes have been excluded."

CDK4/6 inhibitors are used in combination with hormone therapies for patients with advanced or metastatic hormone receptor-positive, HER2-negative breast cancer. The first of these agents, palbociclib, received FDA approval for women in 2015. This was followed by the 2017 approvals of ribociclib and abemaciclib. Most recently, palbociclib's indication was expanded to include men.

https://www.medpagetoday.com/hematologyoncology/breastcancer/82165



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 Kellyless Quote  Post ReplyReply Direct Link To This Post Posted: Aug 02 2019 at 1:09am
To get the full Keytruda immunotherapy effect it has to be taken that long. And that's the trial - if you're in a trial you really really really need to stay in it unless there's a health issue. If she'd dropped out her whole participation in the trial is worthless to the trial - it's ruined. Placebo or no, pCR or not - it's an important commitment. And pCR is in no way a YAY I'm cured forever for sure Thing, it's just better odds,  so not a reason to quit the treatment. I don't understand why they put such a brutal chemo regimen with it, it's a LOT, and Keytruda can be a lot more on top of it. She did it because of the mutation, she had a higher risk factor. But then she also did a diep flap reconstruction so tummy tuck! And to cap off a helluva lot of tough stuff she did the hysterectomy because BARD1 is also ovarian risk so dayum - it was a medical odyssey. 
I have another friend with Colon cancer mets to the lungs. He's doing Keytruda every 3 weeks or so and it's working. The first time he tried it he had a huge flare up of rheumatoid arthritis that he didn't know he had! So bad and painful he called an ambulance and spent time in hospital. He had to quit Keytruda and get that under control, but 3-4 months later went back in Keytruda and is doing ok with it. Immunotherapy is very promising, but it's not a chemo replacement and it's not an easy, small thing. 
I would LOVE to see a trial with the standard AC-T plus Keytruda trial. Is the Carboplatin necessary to get the pCR advantage? If it's not then YAY! Skip it, and do the A.C. First cuz it is easier that way. 
IDC, 2.2 cm, Stage IIb,lumpectomy 1/30/09 ACx4,Tx4 36 rads
6/1/16 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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Post Options Post Options   Thanks (0) Thanks(0)   Quote sophie Quote  Post ReplyReply Direct Link To This Post Posted: Aug 01 2019 at 11:19pm
Hi Kelly, thank you for your input on 522 trail... I am not sure I understand how to declare PCR after sugery is over and continue taking drugs ... is it the same after surgery taking taxol and  carboplatin and then declare PCr?


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Post Options Post Options   Thanks (0) Thanks(0)   Quote Kellyless Quote  Post ReplyReply Direct Link To This Post Posted: Aug 01 2019 at 11:07pm
I just googled, it's the same trial. They are reporting preliminary results show an increase in pCR, so the study will continue as is.
FYI - if you enter the study you may get a placebo. My friend had major Keytruda specific side effects so she knew she was getting it. If she'd figured out she was on a placebo she'd have bailed on those last 6-8 months of treatments so she could move the hell on to completing reconstruction. Because skin expanders are evil!!
https://www.pharmaceutical-business-review.com/news/keytruda-keynote-522-trial/ 

Keytruda plus chemotherapy meets co-primary endpoint in KEYNOTE-522 trial

Merck said that Keytruda in combination with chemotherapy has met one of the two primary endpoints of a phase 3 trial in triple-negative breast cancer (TNBC).

n the late-stage trial called KEYNOTE-522, Keytruda and chemotherapy combination achieved pathological complete response (pCR) following the neoadjuvant part of the neoadjuvant/adjuvant study regimen.

pCR is defined as an absence of all signs of cancer in tissue samples that are analysed after completion of neoadjuvant therapy and definitive surgery.

As per an interim analysis carried out by the independent data monitoring committee (DMC), Keytruda and chemotherapy combination delivered a statistically significant improvement in pCR rates, in comparison to chemotherapy alone, irrespective of PD-L1 status.

Merck said that based on the DMC’s recommendation, the KEYNOTE-522 trial will go on without changes to study the other dual-primary endpoint of event-free survival (EFS), as per its design.

Keytruda’s safety profile in the late-stage trial was on par with previously reported studies with no new safety signals observed.

Merck Research Laboratories president Roger Perlmutter said: “These findings from this innovatively designed trial with Keytruda mark the first time an anti-PD-1 therapy plus chemotherapy has demonstrated a statistically significant improvement in pathological complete response rate as a neoadjuvant, or pre-surgical, segment of treatment for triple-negative breast cancer.

“TNBC is an aggressive malignancy with a high rate of recurrence within the first five years of diagnosis. We are encouraged by these results and plan to discuss these data with health authorities and to present these findings at an upcoming medical congress.”

Keytruda, which has been approved in the US, European Union and in other countries for multiple indications, is an anti-PD-1 therapy that functions by enhancing the ability of the body’s immune system to help detect and fight tumour cells. The humanised monoclonal antibody prevents the interaction between PD-1 and its ligands, PD-L1 and PD-L2 to help in the activation of T lymphocytes that may impact tumour cells and healthy cells.

Earlier this month, the anti-PD-1 therapy in combination with Eisai’s Lenvima has been granted breakthrough therapy designation from the US Food and Drug Administration (FDA) for unresectable hepatocellular carcinoma (HCC).

IDC, 2.2 cm, Stage IIb,lumpectomy 1/30/09 ACx4,Tx4 36 rads
6/1/16 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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Post Options Post Options   Thanks (0) Thanks(0)   Quote Kellyless Quote  Post ReplyReply Direct Link To This Post Posted: Aug 01 2019 at 10:54pm
It's the Keytruda trial that's been going a while that my friend did I think. It's Taxol for 12 weeks with Carboplatin every 3 or 4, followed by the usual dose dense A.C. Every 2 weeks times 4, while doing doses of Keytruda every...few weeks the whole time. Then surgery of your choice 4-6 weeks after chemo ends, keep doing the Keytruda after surgery every few weeks for like...6-8 months? My friend got sick as a dog, but did get a pCR. She had a mastectomy because of a positive BARD gene mutation. It was a loooong year, but she's a year out from the whole thing and doing well. 
IDC, 2.2 cm, Stage IIb,lumpectomy 1/30/09 ACx4,Tx4 36 rads
6/1/16 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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Post Options Post Options   Thanks (0) Thanks(0)   Quote sophie Quote  Post ReplyReply Direct Link To This Post Posted: Aug 01 2019 at 5:18pm
Has anyone heard of keynote 522? Which just come out this week which is related to immunization therapy shall we get benefit ?
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Post Options Post Options   Thanks (0) Thanks(0)   Quote 123Donna Quote  Post ReplyReply Direct Link To This Post Posted: Jul 13 2019 at 12:18pm

Promising Combo for Triple-Negative Breast Cancer, but Only With a BRCA Mutation


Combination therapy with niraparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, and pembrolizumab had clinical activity in triple-negative breast cancer (TNBC), according to the results of the TOPACIO trial. However, that activity appeared limited to patients with BRCA-mutated tumors, a finding that aligns with PARP inhibitor activity seen to date. The two PARP inhibitors olaparib and talazoparib are currently approved for TNBC patients with BRCA mutations. Results of this study were published in JAMA Oncology.

OPACIO is an open-label, single-arm, multicenter, phase II clinical trial that included 55 women with advanced or metastatic TNBC from 34 sites across the United States, all of whom received niraparib in combination with pembrolizumab on day 1 of each 21-day cycle. Patients were eligible for the trial regardless of BRCA mutation status or programmed death ligand 1 (PD-L1) expression.

In terms of the safety profile, 32 patients (58%) had a grade 3 or higher treatment-related adverse event. The most common grade 3 or higher events were anemia (18%), thrombocytopenia (15%), and fatigue (7%). “These are typical class effects from PARP inhibitors,” said Yuan Yuan, MD, PhD, a medical oncologist specializing in breast cancer at City of Hope, during an interview with Cancer Network, who was not involved in the current study. “Totally not surprising,” she added.

As for immune-related adverse events, the most frequent any-grade events were adrenal insufficiency (2%), hyperglycemia (2%), hyperthyroidism (2%), hypothyroidism (7%), pneumonitis (2%), and polymyalgia rheumatica (2%). There were only 2 grade 3 immune-related adverse events, one of which was adrenal insufficiency and the other polymyalgia rheumatica. Yuan said the immune toxicities were “very consistent” with what’s been seen for pembrolizumab.

For the entire study population, the overall response rate (ORR) was 21% (10 of 47 evaluable patients), which included 5 confirmed complete responses and 5 confirmed partial responses. In addition, 13 patients had stable disease, yielding a disease control rate (DCR) of 49% (23 of 47 evaluable patients). Seven patients were still on treatment.

“I definitely think there is a signal for the combination,” said Yuan. That said, she cautioned, the study is a single-arm trial without a control. “There would need to be a confirmatory study comparing the PARP inhibitor plus immune checkpoint inhibitor vs single agent,” she said. She added that the response rate “appears” to be higher in the single-arm trial than the historical data using the PARP inhibitor alone.

For patients with BRCA mutations, the clinical activity was even more pronounced, with an ORR of 47% (7 of 15 evaluable patients), a DCR of 80% (12 of 15 evaluable patients), and a median progression-free survival (PFS) of 8.3 months (95% CI, 2.1 months–not estimable).

However, the opposite was true for patients without a BRCA mutation; the ORR dropped to 11% (3 of 27 evaluable patients), DCR to 33% (9 of 27 evaluable patients), and the median PFS to 2.1 months (95% CI, 1.4–2.5 months).

“There is a good scientific rationale to do this combination,” said Yuan. “But when you look at the patients without BRCA tumors, the overall response rate is a little bit disappointing.” She said the ORR for these patients—that is, 11%—is “almost comparable” with a single-agent immune checkpoint inhibitor.

https://www.cancernetwork.com/immuno-oncology/promising-combo-triple-negative-breast-cancer-only-brca-mutation

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: Dec 10 2018 at 7:50am

Two of these studies were highlighted at SABCS 2018:

The first is a scientifically complex study aimed at determining which patients will have the highest response rates to an immunotherapy agent known as atezolizumab, the same agent in the IMPASSION study. That trial showed patients with a marker called PD-L1 benefit from treatment with atezolizumab. This will help researchers both design future trials and personalize treatment for TNBC patients.

The second study is a phase I trial of CAR-T therapy for patients that have a specific targetable mutation, including TNBC patients. CAR-T is a technically complex form of treatment in which cells are removed from the patient, genetically re-engineered and then injected back into the patient where the goal is to stimulate an ongoing immune response to the tumor. It has been used in clinical trials with patients who have a range of leukemias, lymphomas, non small cell lung cancer and other tumors, but this is the first trial to include TNBC patients.

This is a phase I study with small numbers of patients and very early results. Only four TNBC patients were included in the data presented at SABCS, Three of them had responses to their treatment, but it is still far too soon to draw conclusions about the future of CAR-T therapy for TNBC.


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: Oct 29 2018 at 9:47pm

Atezolizumab and Nab-Paclitaxel in Advanced Triple-Negative Breast Cancer

Background

Unresectable locally advanced or metastatic triple-negative (hormone-receptor–negative and human epidermal growth factor receptor 2 [HER2]–negative) breast cancer is an aggressive disease with poor outcomes. Nanoparticle albumin-bound (nab)–paclitaxel may enhance the anticancer activity of atezolizumab.

Methods

In this phase 3 trial, we randomly assigned (in a 1:1 ratio) patients with untreated metastatic triple-negative breast cancer to receive atezolizumab plus nab-paclitaxel or placebo plus nab-paclitaxel; patients continued the intervention until disease progression or an unacceptable level of toxic effects occurred. Stratification factors were the receipt or nonreceipt of neoadjuvant or adjuvant taxane therapy, the presence or absence of liver metastases at baseline, and programmed death ligand 1 (PD-L1) expression at baseline (positive vs. negative). The two primary end points were progression-free survival (in the intention-to-treat population and PD-L1–positive subgroup) and overall survival (tested in the intention-to-treat population; if the finding was significant, then it would be tested in the PD-L1–positive subgroup).

Results

Each group included 451 patients (median follow-up, 12.9 months). In the intention-to-treat analysis, the median progression-free survival was 7.2 months with atezolizumab plus nab-paclitaxel, as compared with 5.5 months with placebo plus nab-paclitaxel (hazard ratio for progression or death, 0.80; 95% confidence interval [CI], 0.69 to 0.92; P=0.002); among patients with PD-L1–positive tumors, the median progression-free survival was 7.5 months and 5.0 months, respectively (hazard ratio, 0.62; 95% CI, 0.49 to 0.78; P<0.001). In the intention-to-treat analysis, the median overall survival was 21.3 months with atezolizumab plus nab-paclitaxel and 17.6 months with placebo plus nab-paclitaxel (hazard ratio for death, 0.84; 95% CI, 0.69 to 1.02; P=0.08); among patients with PD-L1–positive tumors, the median overall survival was 25.0 months and 15.5 months, respectively (hazard ratio, 0.62; 95% CI, 0.45 to 0.86). No new adverse effects were identified. Adverse events that led to the discontinuation of any agent occurred in 15.9% of the patients who received atezolizumab plus nab-paclitaxel and in 8.2% of those who received placebo plus nab-paclitaxel.

Conclusions

Atezolizumab plus nab-paclitaxel prolonged progression-free survival among patients with metastatic triple-negative breast cancer in both the intention-to-treat population and the PD-L1–positive subgroup. Adverse events were consistent with the known safety profiles of each agent. (Funded by F. Hoffmann–La Roche/Genentech; IMpassion130 ClinicalTrials.gov number, NCT02425891.)

https://www.nejm.org/doi/full/10.1056/NEJMoa1809615


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: Aug 27 2018 at 6:26pm

NCI Awards $2.3M Grant to Advance Possible Therapy for Triple-negative Breast Cancer


The National Cancer Institute has awarded a Fast Track Small Business Innovation Research grant to Agilvax to support development of the company’s lead immunotherapy candidate, AX09, for an aggressive and difficult-to-treat breast cancer.

The grant, worth about $2.3 million, will go toward preclinical trials, a toxicology study, and the establishment of good manufacturing practices. Ultimately, it aims to enable the submission of AX09’s investigational new drug application (IND) to the U.S. Food and Drug Administration to begin clinical testing.

The three most common types of receptors that fuel breast cancer growth are the estrogen, progesterone, and HER2. In some 20 percent of breast cancer patients, whose cancer is called triple-negative, these receptors are not present in the tumor.

In these patients, treatments like hormone therapy or those that target estrogen, progesterone, and HER-2 are ineffective. Triple-negative breast cancer (TNBC) also tends to be more aggressive.

AX09 is a virus-like-particle immunotherapy aiming to treat TNBC. It targets the stem cell protein xCT, found in a high percentage of breast cancers including TNBC.

“We are delighted to receive this grant award from the National Cancer Institute (NCI) to advance the development of AX09 in TNBC, which is one of the lead indications for this product,” Federica Pericle, PhD, president and chief executive officer of Agilvax, said in a news release. “The SBIR award is an important indication of the significant clinical and commercial opportunity of AX09. We are extremely grateful to the NCI and our investors as we execute our development of this novel immunotherapy.”

Expression of xCT is associated with poorer outcomes in patients, with xCT being linked to tumor growth and cancer spread. Animal studies in TNBC mouse model show that AX09 significantly decreases cancer metastases and the amount of breast cancer stem cells within tumor.

“There is a desperate need for targeted therapies and combinational approaches for patients with TNBC,” said George Peoples, MD, FACS, director of the Cancer Vaccine Development Program at the Metis Foundation, a nonprofit that supports research relevant to military personnel. “AX09 shows promise in preclinical studies to inhibit an exploitable target and its novel mechanism of action makes AX09 a potentially powerful combination therapy to achieve durable responses for breast cancer patients.”

http://breastcancer-news.com/2018/08/13/nci-awards-2-3-million-grant-to-advance-agilvaxs-lead-candidate-ax09-to-treat-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 123Donna Quote  Post ReplyReply Direct Link To This Post Posted: Jun 25 2018 at 7:06pm

Zejula-Keytruda Shows Promising Response Rates for Triple-negative Breast Cancer in Phase 1/2 Trial


A combination of Keytruda (pembrolizumab) and Zejula (niraparib) has shown promising and durable response rates in triple-negative breast cancer patients, regardless of their BRCA mutational status, Phase 1/2 trial data show.

The trial, called TOPACIO (NCT02657889), is assessing the combination in triple-negative breast cancer patients with advanced or metastatic disease and in women with ovarian cancer.

Results from the breast cancer group were recently presented at the 2018 American Society of Clinical Oncology Annual Meeting, in an oral presentation, titled “TOPACIO/Keynote-162: Niraparib + pembrolizumab in patients (pts) with metastatic triple-negative breast cancer (TNBC), a phase 2 trial.”

PARP enzymes act as DNA damage sensors, binding to the sites of DNA damage and contributing to their repair. Cancer cells that have defects in other DNA repair mechanisms — such as those with mutated BRCA tumor suppressor genes — rely on PARP to survive and proliferate.

Zejula, developed by TESARO, is a PARP inhibitor that leads to the accumulation of DNA damage and ultimately to the death of these cancer cells.

The medicine is already approved as a maintenance therapy for ovarian cancer patients, and has shown promise in breast cancer patients with mutations in the BRCA genes.

Keytruda, developed by Merck, has been shown to induce responses in 5-18% of triple-negative breast cancer patients, which led researchers to test a combination of both agents.

TOPACIO is a Phase 1/2 trial assessing if Keytruda and Zejula together can increase response rates in patients with advanced or metastatic triple-negative breast cancer (TNBC) and recurrent ovarian cancer.

As of April 2018, 46 of the TNBC patients were able to be assessed for an initial response. Among them, 15 had BRCA mutations, and five had genetic alterations in other DNA repair genes.

To date, three patients had complete responses, 10 had partial tumor reductions, and 10 had their disease stabilized with the treatment. This represents an overall response rate of 28% and a disease control rate of 50%.

As expected, patients with BRCA mutations had the best response rates, at 60%, followed by those with mutations in other DNA repair genes, at 55%, and those who were positive for the PD-L1 protein — a biomarker that predicts response to Keytruda — at 36%.

Overall, the 15 patients with BRCA mutations lived for a median of 8.3 months without their disease progressing, which is better than the three to five months seen with standard chemotherapy, or the rates seen with either agent alone.

The study is ongoing, with eight of the responders still receiving the combination, including five patients who experienced a beneficial clinical effect for approximately one year.

In general the treatment has been well-tolerated, with the most common serious events being anemia and reduced blood platelet levels.

http://breastcancer-news.com/2018/06/18/zejula-keytruda-promising-response-rates-phase-1-2-trial-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 123Donna Quote  Post ReplyReply Direct Link To This Post Posted: Mar 23 2018 at 1:05pm
More research needed, but looks promising.

Groundbreaking research has revealed a promising strategy to stop the recurrence of cancer, and it comes in the form of a biodegradable gel.

Created by scientists at the Dana-Farber Cancer Institute in Boston, MA, the gel was designed to deliver immunotherapy directly to the area from which a cancerous tumor has been surgically removed.

Upon testing the gel on mice during the surgical removal of breast cancer tumors, the scientists found that it not only helped to prevent tumor recurrence at the primary site, but that it also eliminated secondary tumors in the lungs. . . .

. . .'Encouraging' results

For their study, Goldberg and team tested the gel in mice that underwent the surgical removal of breast cancer tumors. The team made the decision to use the gel directly after tumor removal, rather than before.

"We reasoned," Goldberg explains, "that it would be easier to eliminate a small number of residual cancer cells by creating an immunostimulatory environment than it would be to treat an intact primary tumor, which has many means of evading an immune system attack."

Several months after surgery, the mice treated with the gel were much less likely to experience tumor regrowth, compared with rodents that received conventional immunotherapy delivery.

When the researchers injected breast cancer cells into the side opposite to where the original tumor was removed, the gel-treated rodents showed no signs of tumor formation.

Also, the study found that the gel eradicated secondary tumors in the lungs of the mice — that is, it eliminated lung tumors formed from breast cancer cells that had spread from the primary site.

The researchers also replicated their findings in mice with primary lung cancer and melanoma, which is a deadly form of skin cancer.

Based on their results, Goldberg and colleagues believe that their gel-based immunotherapy could be an effective treatment strategy against a number of different cancers.

"This approach has the potential to deliver immunotherapy in a manner that focuses the therapy at the site of interest during a critical time window," he says.

"We are extremely encouraged by the results of this study and hope that this technology will be adapted for patients for testing in clinical trials in the not-too-distant future."

Michael Goldberg, Ph.D.



https://www.medicalnewstoday.com/articles/321307.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: Feb 21 2018 at 6:37pm

Newly Identified Potential Therapeutic Approach Kills Triple-Negative Breast Cancer Cells in Pre-Clinical Study

Findings suggests potential new area of focus for checkpoint blockade immunotherapy


Triple-negative breast cancer (TNBC), a highly aggressive, relapse-prone cancer that accounts for one-fourth of all breast cancers, could be the focus of a new area of study for immune checkpoint blockade therapy.  A team of researchers at The University of Texas MD Anderson Cancer Center revealed that in TNBC a cell process called glycosylation is required for PD-L1/PD1 molecules to interact and identified exactly how and why glycosylation is so crucial. Findings from the study were published in the Feb. 12 issue of Cancer Cell.

Immune checkpoint blockade therapy relies on connections between PD-L1 and its sister molecule, PD1, found on T-cell surfaces, allowing cancer cells to go undetected by the immune system. Blocking PD-L1 and PD-1 interaction has been the basis for successful immunotherapies already in use in other cancers.

“Glycosylation is a process that attaches portions of sugar molecules called moieties to the protein providing it fuel to grow and spread,” said Mien-Chie Hung, Ph.D., chair of Molecular and Cellular Oncology. “Glycosylation of PD-L1 in tumor cells stabilizes PD-L1, but it is largely unknown whether sugar moiety by itself is required for binding to PD-1 to suppress anti-tumor immunity.”

Hung’s research group shed further light in this area through discovery of glycosylated PD-L1 (gPD-L1), and worked with STCube Pharmaceuticals, Inc. to develop anti-gPD-L1 antibodies that recognize this glycosylated form of PD-L1, killing tumor cells while not harming healthy ones.

To improve the therapeutic efficacy of anti-gPD-l1 antibody, the team linked a potent small molecule chemotherapy agent, called MMAE, to the anti-gPD-L1, creating a new antibody drug conjugate (ADC), called anti-gPD-L1-MMAE, which resulted in higher therapeutic efficacy in animal models. Hung believes the development of this glycosylated PD-L1 ADC (anti-gPD-L1-MMAE) may represent a new generation of immunotherapy that is more targeted with fewer adverse effects.

“We demonstrated that gPD-L1 is an excellent candidate for ADC as sugar moiety is critical for PD-L1’s detrimental role in TNBC,” said Hung. “Immune checkpoint blockade treatment options remains limited in TNBC, so identifying new immune checkpoint targets to improve upon current therapy is urgently needed.”

https://newswise.com/articles/newly-identified-potential-therapeutic-approach-kills-triple-negative-breast-cancer-cells-in-pre-clinical-study

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Post Options Post Options   Thanks (0) Thanks(0)   Quote 123Donna Quote  Post ReplyReply Direct Link To This Post Posted: Feb 15 2018 at 7:06pm

Triple-negative Breast Cancer Patients Who Responded to Immunotherapy Had Long-term Survival Benefit

Among patients with metastatic triple-negative breast cancer (TNBC) who were treated with the anti-PD-L1 cancer immunotherapy Tecentriq (atezolizumab), those who responded to the medicine lived significantly longer compared with those who did not respond, according to data from a small clinical study presented at the American Association of Cancer Research annual meeting.

About Tecentriq

Tecentriq is an agent that helps to restore the body’s immune system in fighting cancer. It creates its anti-cancer effects by blocking a specific protein that is used by cancer cells to escape an attack by the immune system, called PD-L1. Once PD-L1 is blocked, cells of the immune system are able to identify cancer cells as a threat, and initiate an attack to destroy the cancer. Tecentriq and other “checkpoint inhibitors” have been approved for the treatment of several cancers recently.

In the current clinical study evaluating Tecentriq in patients with TNBC, the most significant findings were the difference in the overall survival between patients who responded to Tecentriq and patients who did not respond, and the prolonged average duration of response; 21 months, which is substantially longer than what has been seen with other treatments. All responders were alive after one year and the one-year survival rate for nonresponders was only 38 percent.

Immune therapy with checkpoint inhibitors appears to be a promising treatment approach for individuals with TNBC whether used alone or in combination with other therapies.2,3

http://news.cancerconnect.com/triple-negative-breast-cancer-patients-responded-immunotherapy-long-term-survival-benefit/

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Post Options Post Options   Thanks (0) Thanks(0)   Quote 123Donna Quote  Post ReplyReply Direct Link To This Post Posted: Dec 21 2017 at 8:02am

According to new research out of the Case Comprehensive Cancer Center at Case Western Reserve University School of Medicine. In the Proceedings of the National Academy of Sciences, researchers showed triple-negative breast cancer cells are highly vulnerable to interferon-β-;a potent antimicrobial that also activates the immune system. The new study shows interferon-β impairs breast cancer cells' ability to migrate and form tumors. The study also suggests interferon-β treatment could improve outcomes for certain breast cancer patients.

"We demonstrate that interferon-β reverses some of the more aggressive features of triple-negative breast cancer, which are responsible for metastasis and therapy-failure," said Mary Doherty, first author and pathology graduate student at Case Western Reserve School of Medicine. "Moreover, we found that evidence of interferon-β in triple-negative breast cancer tumors correlates with improved patient survival following chemotherapy.

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Post Options Post Options   Thanks (0) Thanks(0)   Quote 123Donna Quote  Post ReplyReply Direct Link To This Post Posted: Oct 25 2017 at 11:14pm
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 1maJ Quote  Post ReplyReply Direct Link To This Post Posted: Sep 04 2017 at 10:22pm
Hi Donna, thanks for posting all this info on new research.  I came back to the forum to look for the latest on TNBC treatments, and this gives me hope and calms me down.  I am 2 years out from diagnosis, the time when most women have their recurrence, so I am finding myself to have a bit more anxiety than I would like.  Every little headache is a reminder that something could be brewing :(  But I am doing fine though, and enjoying life more than ever :)

Thanks!

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Post Options Post Options   Thanks (0) Thanks(0)   Quote mainsailset Quote  Post ReplyReply Direct Link To This Post Posted: Aug 31 2017 at 10:56am
Donna, I saw that report this morning and it's so interesting and a good reminder how now more than ever it's important for our medical teams to id all the characteristics of our particular tumor to determine what choices in treatment can be made. Amazing to me to see the researchers perplexed by the finding that the Claudin low tumors reacted the opposite of what they expected.
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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: Aug 31 2017 at 8:47am

Study sheds light on why some breast cancers have limited response to immunotherapy

UNC Lineberger Comprehensive Cancer Center researchers have identified a possible reason why some aggressive breast cancers are unresponsive to certain immunotherapy treatments, as well as a potential solution.

In the Journal of Clinical Investigation, researchers report on their study that explored a perplexing question: Why were drugs designed to unleash the immune system against cancer ineffective in a type of triple negative breast cancer with a heavy presence of immune cells? Their findings could lead to a strategy to improve immunotherapy responses in the "claudin-low" subtype of breast cancer.

"We were trying to figure out why a tumor made up, in some instances, of half immune cells doesn't respond to a treatment that should ramp up immune cells present in the tumor," said the study's senior author Jonathan Serody, MD, UNC Lineberger member and the Elizabeth Thomas Professor in the UNC School of Medicine. "I think it's important for us to try to start segregating out the types of tumors that don't respond to these treatments at a much granular genomic level, and try to figure out new mechanisms to enhance the response rate to immunotherapy."

The American Cancer Society estimates that approximately 12 percent of breast cancers are "triple negative," meaning they lack three cell surface receptors that are known to help drive the cancer. Triple negative breast cancer tumors typically grow faster and come back sooner than other breast cancer types. There are no targeted treatments for these cancers.

In a subset of triple negative breast cancers known as "claudin low," researchers found an elevated level of immune cells in and around the tumors. They believed this would help the body fight the cancer. However, the researchers found the opposite: "Checkpoint inhibitors," a type of immunotherapy that works by unlocking the immune system's brakes against cancer, were ineffective in this subtype.

They determined with gene expression analysis that, instead of being flooded with immune cells that attack cancer tumors, claudin-low tumors had a high concentration of regulatory T-cells - a type of immune cell that suppresses the body's defenses. Claudin-low tumors were releasing a chemical signal to attract these regulatory T-cells.

"This regulatory T-cell population is preventing the immune system from rejecting the cancer," said UNC Lineberger's Benjamin Vincent, MD, an assistant professor in the UNC School of Medicine. "We thought if we could get rid of those cells, we could help the immune system better fight the breast cancer cells."

In an effort to allow the immune-stimulating cancer treatments to work, the researchers tested an investigational approach to deplete the regulatory T-cells, and they combined the treatment with a checkpoint inhibitor in order to try to improve outcomes. This combination slowed tumor growth. They believe they have identified a key aspect of what is preventing immunotherapy treatments from working.

"This finding may shed some light on why response rates to immunotherapy treatments remain low in triple negative breast cancer," Vincent said. "We are looking to understand why patients who don't respond don't respond, and what we can do to render their tumors immunotherapy responsive."

Vincent is helping to lead a clinical trial testing this strategy to improve responses to checkpoint inhibitors. Researchers also believe these findings may also underscore the need to study other cancer types at a genomic level to understand differences in response rates to immunotherapy treatments.

"This speaks to the mission of UNC Lineberger, which is to conduct groundbreaking basic science research, but always with the mission of extending and improving the lives of patients as our end goal," Vincent said.


https://medicalxpress.com/news/2017-08-immune-cells-contribute-treatment-resistance.html



Edited by 123Donna - Aug 31 2017 at 8:48am
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 Sarahlou Quote  Post ReplyReply Direct Link To This Post Posted: Aug 18 2017 at 10:00pm
A friend is in a clinical trial using Keytruda and has had success with it shrinking her tumor. She has TNBC.
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