Breaking Research News from sources other than Breastcancer.org
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Lumpie this is important, I don’t know where else to put this article. Hope it’s ok
AARP supports responsible solutions to reduce health care spending without shifting costs onto Medicare beneficiaries or reducing their access to care.
Congress has acted to prevent mandatory funding cuts to Medicare and other programs vital to millions of older Americans that were set to occur as a result of the new tax overhaul legislation.
The Tax Cut and Jobs Act, which the president signed today, is projected to add $1.5 trillion to the deficit over the next decade. Under the 2010 "pay-as-you-go" law known as PAYGO, that increase to the deficit would have triggered automatic spending cuts to programs, including a $25 billion cut to Medicare in 2018 alone. But in an AARP-supported move, the House and Senate on Thursday waived the required cuts as part of a temporary spending bill to prevent a government shutdown. Thousands of AARP members contacted their legislators, urging them to act before the end of the year and prevent the Medicare cuts.
Preventing the cuts will help preserve seniors' access to their doctors and hospital services. Medicare covered 56.8 million people last year, including 47.8 million age 65 and older.
Still, even with Congress' action, Medicare and other programs will continue to face budgetary pressure.
Senate Majority Leader Mitch McConnell (R-Ky.) said this week that the Senate is unlikely to tackle Medicare and Social Security in 2018. House Speaker Paul Ryan (R-Wis.) has also ruled out 2018 Medicare cuts. However, Ryan has made reducing the nation's debt and reining in government spending a priority, and has openly discussed Medicare changes such as premium support.
Medicare, Social Security and Medicaid are among the government's biggest programs. The government will spend about $700 billion on Medicare this year, a number the Congressional Budget Office projects will increase to nearly $1.4 trillion in 2027. AARP supports responsible solutions to reduce health care spending that do not shift costs onto Medicare beneficiaries or reduce their access to care.
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IGF and Breast Cancer
Specific protein plays key role in the spread of breast cancer
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Scientists devised a pinpointed immunotherapy regimen that eradicated tumors throughout the body in mice. Credit: Sagiv-Barfi et al., Science Translational Medicine (2018)
Injecting minute amounts of two immune-stimulating agents directly into solid tumors in mice can eliminate all traces of cancer in the animals, including distant, untreated metastases, according to a study by researchers at the Stanford University School of Medicine.
The approach works for many different types of cancers, including those that arise spontaneously, the study found.
The researchers believe the local application of very small amounts of the agents could serve as a rapid and relatively inexpensive cancer therapy that is unlikely to cause the adverse side effects often seen with bodywide immune stimulation.
"When we use these two agents together, we see the elimination of tumors all over the body," said Ronald Levy, MD, professor of oncology. "This approach bypasses the need to identify tumor-specific immune targets and doesn't require wholesale activation of the immune system or customization of a patient's immune cells."
One agent is currently already approved for use in humans; the other has been tested for human use in several unrelated clinical trials. A clinical trial was launched in January to test the effect of the treatment in patients with lymphoma.
Levy, who holds the Robert K. and Helen K. Summy Professorship in the School of Medicine, is the senior author of the study, which will be published Jan. 31 in Science Translational Medicine. Instructor of medicine Idit Sagiv-Barfi, PhD, is the lead author.
'Amazing, bodywide effects'
Levy is a pioneer in the field of cancer immunotherapy, in which researchers try to harness the immune system to combat cancer. Research in his laboratory led to the development of rituximab, one of the first monoclonal antibodies approved for use as an anticancer treatment in humans.
Some immunotherapy approaches rely on stimulating the immune system throughout the body. Others target naturally occurring checkpoints that limit the anti-cancer activity of immune cells. Still others, like the CAR T-cell therapy recently approved to treat some types of leukemia and lymphomas, require a patient's immune cells to be removed from the body and genetically engineered to attack the tumor cells. Many of these approaches have been successful, but they each have downsides—from difficult-to-handle side effects to high-cost and lengthy preparation or treatment times.
"All of these immunotherapy advances are changing medical practice," Levy said. "Our approach uses a one-time application of very small amounts of two agents to stimulate the immune cells only within the tumor itself. In the mice, we saw amazing, bodywide effects, including the elimination of tumors all over the animal."
Cancers often exist in a strange kind of limbo with regard to the immune system. Immune cells like T cells recognize the abnormal proteins often present on cancer cells and infiltrate to attack the tumor. However, as the tumor grows, it often devises ways to suppress the activity of the T cells.
Levy's method works to reactivate the cancer-specific T cells by injecting microgram amounts of two agents directly into the tumor site. (A microgram is one-millionth of a gram). One, a short stretch of DNA called a CpG oligonucleotide, works with other nearby immune cells to amplify the expression of an activating receptor called OX40 on the surface of the T cells. The other, an antibody that binds to OX40, activates the T cells to lead the charge against the cancer cells. Because the two agents are injected directly into the tumor, only T cells that have infiltrated it are activated. In effect, these T cells are "prescreened" by the body to recognize only cancer-specific proteins.
Cancer-destroying rangers
Some of these tumor-specific, activated T cells then leave the original tumor to find and destroy other identical tumors throughout the body.
The approach worked startlingly well in laboratory mice with transplanted mouse lymphoma tumors in two sites on their bodies. Injecting one tumor site with the two agents caused the regression not just of the treated tumor, but also of the second, untreated tumor. In this way, 87 of 90 mice were cured of the cancer. Although the cancer recurred in three of the mice, the tumors again regressed after a second treatment. The researchers saw similar results in mice bearing breast, colon and melanoma tumors.
Mice genetically engineered to spontaneously develop breast cancers in all 10 of their mammary pads also responded to the treatment. Treating the first tumor that arose often prevented the occurrence of future tumors and significantly increased the animals' life span, the researchers found.
Finally, Sagiv-Barfi explored the specificity of the T cells by transplanting two types of tumors into the mice. She transplanted the same lymphoma cancer cells in two locations, and she transplanted a colon cancer cell line in a third location. Treatment of one of the lymphoma sites caused the regression of both lymphoma tumors but did not affect the growth of the colon cancer cells.
"This is a very targeted approach," Levy said. "Only the tumor that shares the protein targets displayed by the treated site is affected. We're attacking specific targets without having to identify exactly what proteins the T cells are recognizing."
The current clinical trial is expected to recruit about 15 patients with low-grade lymphoma. If successful, Levy believes the treatment could be useful for many tumor types. He envisions a future in which clinicians inject the two agents into solid tumors in humans prior to surgical removal of the cancer as a way to prevent recurrence due to unidentified metastases or lingering cancer cells, or even to head off the development of future tumors that arise due to genetic mutations like BRCA1 and 2.
"I don't think there's a limit to the type of tumor we could potentially treat, as long as it has been infiltrated by the immune system," Levy said.
The work is an example of Stanford Medicine's focus on precision health, the goal of which is to anticipate and prevent disease in the healthy and precisely diagnose and treat disease in the ill.
More information: I. Sagiv-Barfi el al., "Eradication of spontaneous malignancy by local immunotherapy," Science Translational Medicine (2018). stm.sciencemag.org/lookup/doi/ … scitranslmed.aan4488
Provided by Stanford University Medical Center
"Cancer 'vaccine' eliminates tumors in mice, researchers find" January 31, 2018 https://medicalxpress.com/news/2018-01-cancer-vaccine-tumors-mice.html
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Sounds too good to be true.
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I read that article early this morning and was wishing it was available now. Too bad the red tape takes so long. Can you just imagine if this really worked for us. Going to show it to MO and if there are any sort of human trials going on I’d give it a try.
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They are going to try it on lymphoma patiets first. I hope it gets on the fast track!
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When I first met my MO she said if needed she could start a clinical trial. Going to discuss this with her on Wednesday. Seems like there hasalways been something that makes it so I don’t qualify for any trials.
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You can do the search yourself. Go to www.clinicaltrials.gov
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Scientists at the University of Delaware and the University of Illinois at Chicago have found a new way to kill liver cancer cells and inhibit tumor growth. First, they silence a key cellular enzyme, and then they add a powerful drug. They describe their methods in a new paper published in Nature Communications.
This research could accelerate the development of new treatments for liver cancer, which is currently difficult to cure. Often surgery is not an option for liver cancer, and the available drugs are only modestly effective. More than 82 percent of liver cancer patients die within five years of diagnosis, according to the National Institutes of Health.
Manipulating cells to kill cancer
This project originated in labs at the University of Illinois at Chicago, where researchers grew liver cancer cells and manipulated their expression of an enzyme called hexokinase-2. Then, the cells were treated with metformin, a diabetes drug that decreases glucose production in the liver.
The research group of Maciek R. Antoniewicz, Centennial Professor of Chemical and Biomolecular Engineering at the University of Delaware, designed a set of experiments to measure how cancer cells respond to the loss of hexokinase-2, an enzyme that helps cells metabolize glucose, their food source.
Antoniewicz is an expert in metabolic flux analysis, a technique for studying metabolism in biological systems. His research group is one of only a few in the world with expertise in a technique called 13C metabolic flux analysis of cancer cells, and he recently published a paper in Experimental & Molecular Medicine describing his methods.
"The complexities of mammalian metabolism require a systems-level analysis of the underlying networks and phenotypes, and this is what my lab specializes in," he said.
The UD cohort used mass spectrometry to analyze the cancer cells and then determined intracellular metabolic fluxes for cells with and without hexokinase-2. They suspected that cells deprived of hexokinase-2 would starve and die, but surprisingly, they found that targeting hexokinase-2 alone had only a marginal impact on stopping cancer cell growth. Another weapon, metformin, was needed to complete the job.
"The importance of our paper is that we show that targeting hexokinase-2 can indeed be a successful strategy for cancer therapy, when you also target a second compensatory mechanism with the drug metformin," said Antoniewicz.
His work provided important clues to what this second target should be, providing fertile ground for the next phase of research.
Finally, the research team at the University of Illinois at Chicago tested a combination of hexokinase-2 depletion and sorafenib, a liver cancer drug, on liver cancer tumors in mice. This combo worked better than either treatment alone.
Explore further: Blocking key enzyme in cancer cells could lead to new therapyMore information: Dannielle DeWaal et al. Hexokinase-2 depletion inhibits glycolysis and induces oxidative phosphorylation in hepatocellular carcinoma and sensitizes to metformin, Nature Communications (2018). DOI: 10.1038/s41467-017-02733-4
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Wow:
Scientists develop immune-stimulating injections against cancer
In the study, which was published in the journal Science Translational Medicine, the immune-stimulating injections were shown to not only kill cancer cells within the tumors, but *also kill the metastases* present distantly at other sites in the body.
Experts say this is one of the biggest breakthroughs in modern day cancer research....
https://www.news-medical.net/news/20180202/Scienti...
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Exploring the Future of Breast Cancer Risk Assessment
"From the fattiest breast, up to the most dense breast, there's about a five-fold difference in risk. So, from looking at density alone, your lifetime risk could go from 1 in 20 for the least dense breast to around 1 in 4 for the most dense."
{I knew that having dense breasts made it more difficult to detect breast cancer on mammogram but I did not understand that it increased one's risk of developing breast cancer. Rather miffed that none of my health care providers never share this with me! The article discusses a number of other risk factors, including nuances of genetic risk (SNP profiling), too. It is based on work being done by the NHS (Britain). Interesting.}
https://www.news-medical.net/news/20180201/Explori...
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I’ve spent the better part of today reading this thread and various links. Thanks to all the posters for sharing.
I was told that dense breasts were “normal” with age (said one of the drs who completely missed the enormous tumor).
No one said anything either about the itching I complained of.
Maybe some of the older drs will brush up on their studies.
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Lumpie,
I'm new to this thread but I'm frustrated because my Onc, RO, etc. are telling me something "based on studies" that they can't produce. The study(ies) I'm looking for are for gals like me (mid 50s) stage 2, grade 3 lump with lymph nodes (2), went through TCH for 5 months (continuing on with herceptin until July 2018), had lumpectomy after chemo (NEGATIVE) and am told that I must have 6 weeks of rads, not to mention endocrine therapy. The study should mention stats for those who chose to get rads and those that didn't. Also, there may be another study that doesn't carry much steam (3 weeks of rads, same doses, instead of 6 weeks).
The doctors say that the rads are necessary because it spread from the breast to at least one lymph node. Rads to focus mainly on the lymph node area and the entire breast, supine position.
Edit: I found out that the Bekelman and Emanuel study that promotes 3 weeks, turns out the dosing is higher that with a 6 week regimen. Oops.
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Lumpie- I wonder how they would do the vaccine when you don’t have s big tumor just thousands of the little lobular bastards everywhere
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Dianarose: me, too. My original tumor is long gone. Maybe they will be able to inject any tumor. Since this is still in the research stage, I talking about injecting the primary tumor, I imagine that they are thinking about a time when the injection would occur before any surgery takes place.
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Lumpie- I wish they would focus some on us who are barely hanging on. We need some hope. I’m going to talk to My MO about all of this. Time is not on our side .
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Breast cancer: Protein that drives metastasis uncovered
https://www.medicalnewstoday.com/articles/320764.p...0 -
Dianarose - are your mets her2- ? I posted an article on the ILC boards about how certain mutations changed her2- to her2+therefore need additional therapies.
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Amelia- I’ve always been Her2 + . I was 13 years ago and they checked again in 2016 with a new biopsy. But you are correct that it can change. MO was hoping it changed so I could take other meds.
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Diet may influence the spread of a deadly type of breast cancer, study finds
February 7, 2018 in Medicine & Health / Cancer
A single protein building block commonly found in food may hold a key to preventing the spread of an often-deadly type of breast cancer, according to a new multicenter study published today in the medical journal Nature.
Investigators found that by limiting an amino acid called asparagine in laboratory mice with triple-negative breast cancer, they could dramatically reduce the ability of the cancer to travel to distant sites in the body. Among other techniques, the team used dietary restrictions to limit asparagine.
Foods rich in asparagine include dairy, whey, beef, poultry, eggs, fish, seafood, asparagus, potatoes, legumes, nuts, seeds, soy and whole grains. Foods low in asparagine include most fruits and vegetables.
"Our study adds to a growing body of evidence that suggests diet can influence the course of the disease," said Simon Knott, PhD, associate director of the Center for Bioinformatics and Functional Genomics at Cedars-Sinai and one of two first authors of the study. The research was conducted at more than a dozen institutions.
If further research confirms the findings in human cells, limiting the amount of asparagine cancer patients ingest could be a potential strategy to augment existing therapies and to prevent the spread of breast cancer, Knott added.
The researchers studied triple-negative breast cancer cells, which grow and spread faster than most other types of cancer cells. It is called triple negative because it lacks receptors for the hormones estrogen and progesterone and makes little of a protein called HER2. As a result, it resists common treatments—which target these factors and has a higher-than-average mortality rate.
Research from past studies found that most tumor cells remain in the primary breast site, but a subset of cells leaves the breast and enters the bloodstream. Those cells colonize in the lungs, brain and liver, where they proliferate. The study team wanted to understand the particular traits of the tumor cells circulating in the blood and in the sites where the cancer has spread.
The researchers discovered that the appearance of asparagine synthetase—the enzyme cells used to make asparagine—in a primary tumor was strongly associated with later cancer spread.
The researchers also found that metastasis was greatly limited by reducing asparagine synthetase, treatment with the chemotherapy drug L-asparaginase, or dietary restriction. When the lab mice were given food rich in asparagine, the cancer cells spread more rapidly.
"The study results are extremely suggestive that changes in diet might impact both how an individual responds to primary therapy and their chances of lethal disease spreading later in life," said the study's senior author, Gregory J. Hannon, PhD, professor of Cancer Molecular Biology and director, Cancer Research UK Cambridge Institute, University of Cambridge in England.
Investigators now are considering conducting an early-phase clinical trial in which healthy participants would consume a low-asparagine diet. If the diet results in decreased levels of asparagine, the next scientific step would involve a clinical trial with cancer patients. That trial likely would employ dietary restrictions as well as chemotherapy and immunotherapy, Knott said.
Studying the effects of asparagine also could alter treatments for other types of cancer, investigators say.
"This study may have implications not only for breast cancer, but for many metastatic cancers," said Ravi Thadhani, MD, MPH, vice dean, Research and Graduate Research Education, at Cedars-Sinai.
More information: Simon R. V. Knott et al, Asparagine bioavailability governs metastasis in a model of breast cancer, Nature (2018). DOI: 10.1038/nature25465
Provided by Cedars-Sinai Medical Center
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Thanks for that update, Marijen. Woe is me! I try to eat a healthy diet... now it sounds like I may have to go vegan, too! Recent labs show I need to boost my protein intake. A low asparagine diet would make that more challenging. I'd better go call a dietician....
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I don’t know Lumpie. I don’t think I could live on fruits and vegetables alone. This one is for TNBC mostly
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Hi sweetp6217. Sorry it sounds like your doctors have not made the rationale for your treatment recommendations clear. I do know that radiation following lumpectomy is "standard of care." Of course, you have the right to refuse a treatment you don't want and your care team should respect your choices. Obviosuly, you need good information so that you can make good choices. You might want to take a look at the NCCN standards of care for breast cancer. Those spell out the standard of care for different types of cancer. I have found it to be VERY helpful. It really helps me understand that what is being recommended is within the parameters of what is expected and proven. It also has some footnotes so you can search for information on the clinical trials that resulted in the adoption of standards. If you have a nurse navigator at the facility where you receive care, you might ask for additional information on your plan of care...to sit down and go over it with someone. Sometimes doctors get busy and don't spend the time we think would be helpful. Sometimes the nursing staff - an RN, NP(or PA) or nurse navigator - can help fill the gaps.
Oh... as far as the radiation goes, i tried to check my calendar to see what mine was but ... I can't locate it. I know I did the shorter course. I believe that with the shorter course, we get the same dose but over a shorter period of time. I think they modulate the intensity so it is greater at the tumor bed. But I don't know the details. I tolerated the radiation therapy quite well. I was so glad to be through with the chemo, it seemed like a walk in the park. I have read some of the research and understand that the recurrence rates are much lower with the "whole package" of treatment (including radiation) if you do the lumpectomy. This is particularly a concern specially when you are on the young-ish end of the age spectrum as you are. You can expect to have a lot of years left and you don't want that stuff coming back! Good luck with completing your treatment - whatever you decide to pursue!
https://www.nccn.org/professionals/physician_gls/default.aspx#breast
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New study reveals late spread of breast cancer and backs key role of early diagnosis
August 14, 2017, Wellcome Trust Sanger Institute
Breast cancer cells that spread to other parts of the body break off and leave the primary tumour at late stages of disease development, scientists from the Wellcome Trust Sanger Institute and their collaborators have found.
The results, published today (14 August) in Cancer Cell, show that catching and treating breast cancer before it spreads is a realistic goal. It also opens the door to predicting which drugs will work against breast cancer that has already spread.
It is estimated that 35,000 people in the UK have metastatic breast cancer. The survival rates are poor: around 15 out of 100 women will survive advanced breast cancer for 5 years or more after diagnosis. The prognosis has not improved in the past 20-30 years.
Most of the research into breast cancer has focused on primary breast cancer, and there is little understanding of the biology underpinning breast cancer that has spread to other parts of the body, known as metastatic cancer. This is in part due to the difficulty in acquiring samples of tumours that have spread to other tissues.
In this study, scientists investigated how breast cancer evolves from the original tumour in the breast to tumours that have spread, or metastasised. It has been controversial whether the breast cancer cells that spread to other parts of the body break off and leave the primary tumour in the breast at early or at late stages of cancer development. The team found that most of the genetic changes in the original breast tumour were also present in the metastatic tumours, showing that the cancer cells spread late in disease development.
This shows promise for breast cancer patients as diagnosing and treating the breast cancer at early stages means there is a greater chance of preventing cancer cells spreading to other tissues, such as the lungs, brain and bone.
Dr Lucy Yates, first author from the Wellcome Trust Sanger Institute and Guys and St Thomas' NHS Trust, said: "As the cells that cause the spread of breast cancer leave relatively late, it means they are still quite similar to the cells in the primary tumour. Therefore by studying the genome of the primary breast cancer tumour, in the future we may be able to predict what cells that might have spread 'look' like, and potentially which treatments they will respond to."
In the retrospective study, the team sequenced the DNA of 299 tumours from 170 patients with breast cancer that either returned in the remaining breast—local relapse—or had spread - metastatic breast cancer.
Researchers found that in the time between breast cancer patients being diagnosed with primary cancer and the diagnosis of metastasis, the breast cancer cells had gained genetic changes, or mutations, that increased the aggressiveness of the tumour. This may explain why metastatic breast cancer is currently difficult to treat.
Professor Per Eystein Lønning, joint lead author from the University of Bergen and Haukeland University Hospital in Bergen, said: "Most women who have metastatic breast cancer do not have another biopsy of the cancer, and rarely have it analysed using genetic sequencing. In this study we found that in some cases, the metastatic tumours had particular genetic changes that could be targeted with treatments. We would not have seen these mutations by sequencing the primary tumour alone. Our results suggest that it should be more routine to biopsy the metastasis and have it genetically analysed in order to open up clinical trials of treatment options for metastatic breast cancer."
Studies are now open to recruit patients with metastatic breast cancer across Europe - these studies will first extend the analysis performed here to many more patients, but the ultimate goal is to build a platform for identifying an appropriate clinical trial of new treatments for each patient with metastatic breast cancer.
The use of whole genome sequencing enables researchers to accurately distinguish between tumour types with different treatment strategies. In one particular case, it was thought a patient had primary breast cancer that had relapsed in the breast. However after sequencing the tumour, the team found it was not a relapse but a second primary breast cancer. Genomic data enabled the scientists to tell these two scenarios apart, which would have changed the treatment philosophy used - this would be difficult using standard diagnostic methods.
Dr Peter Campbell, joint lead author from the Wellcome Trust Sanger Institute, said: "Our study shows that in order to catch breast cancer before it spreads, early detection of breast cancer is key, and we provide a good rationale for continuing to improve methods for detecting breast cancer sooner. These results show the power of genetic sequencing in understanding metastatic breast cancer and open the door to personalised treatment for breast cancer in the future."
Explore further: Protein to control breast cancer progression identifiedMore information: Lucy Yates et al. (2017) Genomic evolution of breast cancer metastasis and relapse. Cancer Cell. DOI: 10.1016/j.ccell.2017.07.005
Journal reference: Cancer Cell
Provided by: Wellcome Trust Sanger Institute
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wow, asparagine is in most everything we eat. I would like to know how much is in each of the foods listed so that maybe you could eat some that are low on occasion. Going to talk to MO about this one. I’m not a big eater so I might try this for s few weeks and see if my tumor marker goes down. Can’t hurt.
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Lumpie,
Thank you for the NCCN info. I just visited with the coordinator and she forwarded my query about studies a week ago (to the RO dept). I messaged them, but no go yet. After receiving my herceptin today, the nurse handed me my appointment printout. It suddenly included 6 weeks of rad appointments beginning Monday the 12th. I promptly cancelled all of them since they didn't call me first. They seemed to "forget" that I talked with them last week and am getting a second opinion with another group (tomorrow). Hopefully I won't have to reschedule because my post op window for rads is closing soon. It would be best if I begin no later than the 18th.
I did find a grouping of studies (Oxford 2011) and my odds for recurrance in first ten years if I do rads is 19.3% (not 5%) and without: 35%. I wonder if there is a continuation of this study since some of it began in 1991 (way before Herceptin).
I hope it doesn't snow like they say it might. 8 to 12" overnight.
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sweetp6217: Another cool resource to take a look at is the predict tool on the UK NHS website. Here's the link:
You can plug in characteristics of your cancer and options for treatment and see how your risk changes if you add or forego certain therapies. It's pretty cool. Of course, it assumes you are a "generic" patient but I felt like it provided remarkable insight. I was surprised how relatively little difference in recurrence risk chemo made. Just helps put things in perspective. Did for me, anyway.
My schedule has been crazy so I have had no leisure for research, but here are some references on lumpectomy & radiation cited by Komen:
- Arvold ND, Taghian AG, Niemierko A, et al. Age, breast cancer subtype approximation, and local recurrence after breast-conserving therapy. J Clin Oncol. 29(29):3885-91, 2011.
- Braunstein LZ, Taghian AG, Niemierko A, et al. Breast-cancer subtype, age, and lymph node status as predictors of local recurrence following breast-conserving therapy. Breast Cancer Res Treat. 161(1):173-179, 2017.
These are pretty much "standard of care" commentary but may provide insight:
Canadian Cancer Society:
http://www.cancer.ca/en/cancer-information/cancer-...
American Cancer Society
https://www.cancer.org/cancer/breast-cancer/treatm...
A Memorial Sloan Kettering blog piece:
https://www.mskcc.org/blog/new-breast-surgery-guid...
If I find more, I will post or PM you.... good luck! (Let me know if you have trouble with the links.)
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Researchers identify presence of ER gene fusion proteins in treatment-resistant breast cancer
February 7, 2018At Magee-Womens Research Institute (MWRI) and UPMC Hillman Cancer Center, a large team of clinical and laboratory researchers dedicated to understanding treatment resistance in the most common form of breast cancer have identified a new genetic change in the estrogen receptor (ER) that contributes to therapy resistance. ER-positive breast cancer, diagnosed in two-thirds of breast cancer patients, is fueled by the presence of estrogen in the body. Anti-estrogen therapy is usually successful in treating the disease initially, but ER-positive breast cancers will often recur because tumors develop a resistance to treatment.
Published in the Annals of Oncology, the research identifies the presence of ER gene (ESR1) fusion proteins in treatment-resistant breast cancer. This is the first time that recurrent ESR1 fusion proteins have been identified in human breast cancer, and understanding how they function could lead to improved treatments for the disease.
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"We first identified this change in a patient who had ER-positive breast cancer, received anti-estrogen therapy, had her breast cancer recur and eventually passed away from the disease," said senior author Adrian Lee, Ph.D., director of the Women's Cancer Research Center at MWRI and UPMC Hillman Cancer Center, and professor of Pharmacology & Chemical Biology at the University of Pittsburgh. "A member of our lab noticed the mutation while performing posthumous genetic analysis from tissue in our organ donation program, and over time we were able to identify many more cases of this mutation in patients with recurrent disease." This work was performed in collaboration with Foundation Medicine Inc., a genomic testing company that examined ESR1 fusions in close to 10,000 breast cancers sequenced with the FoundationOne CDx test.
According to Lee, ESR1 fusion proteins "outsmart" traditional treatment by splitting in half and eliminating the binding site that anti-estrogen therapy targets.
"Physicians will continue administering anti-estrogen therapy, not realizing this genetic mutation has occurred," said Lee. "Now that we understand the change, though, we can detect it with a blood test and help improve treatments for this form of the disease."
According to Lee, genetic analysis will soon be the dominant field of ER-positive breast cancer research, eventually leading to improved treatments and patient outcomes.
"Genomic sequencing is telling us so much about breast cancer. I believe the research we are doing in the laboratory will have a significant clinical impact in the near future, and the work we are doing will play a large part in improving patient care and survival," said Lee.
Source:http://www.upmc.com/media/NewsReleases/2018/Pages/lee-breast-cancer-treatment.aspx
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Blood test may help predict which breast cancers will recur
December 8, 2017 by Marilynn Marchione
A blood test five years after breast cancer treatment helped identify some women who were more likely to relapse, long before a lump or other signs appeared, a preliminary study found.
It was the largest experiment so far to use these tests, called liquid biopsies , for breast cancer. Results suggest they someday may help reveal which women need longer preventive therapy and which ones can be spared it.
"It could be providing an early warning sign" for some women that cancer is returning, said Dr. Joseph Sparano of Montefiore Einstein Center for Cancer Care in New York.
On the other hand, "if you had a negative test, there was a 98 percent chance you would not have a recurrence in the next two years" and perhaps could skip further treatment, he said.
Sparano led the study and gave results Friday at the San Antonio Breast Cancer Symposium.
The test—CellSearch, sold by Menarini-Silicon Biosystems—looks for stray cancer cells in the blood.
Breast cancer survivors may be tempted to rush out and get it, but doctors say it's too soon for that. Although it's been used for about a decade to monitor certain patients with advanced cancer during treatment, its value for helping to predict breast cancer relapse risk is not well established, and insurers won't pay the $600 to $900 tab.
The new study should spur more research on this right away, said Dr. Massimo Cristofanilli, a breast cancer specialist at Northwestern University in Chicago who has used these tests and consults for another company developing one.
"Clearly, to me, we have to do something" now that this study suggests a wider role for them, he said.
It involved 547 women in long-term follow-up from an earlier cancer drug study. Two-thirds of them had cancers fueled by estrogen, and in most cases it had spread to lymph nodes but not more widely.
All had surgery and chemotherapy followed by hormone-blocking medicines for five years. Guidelines now recommend considering hormone blockers for up to 10 years, but they have side effects and their benefit beyond five years is fairly small. So finding a way to tell who really needs that would be a big help.
Women in the study had a CellSearch test five years on average after their cancer was found and treated.
Among those with estrogen-fueled disease, 5 percent had cancer cells in the blood test, and they turned out to have a 22-fold higher risk of recurrence within roughly two years compared to women whose blood test was negative.
About 65 percent of women with hormone-positive disease and a positive blood test did not have a new breast cancer within two years, but that doesn't mean the blood test gave a false alarm, Sparano said.
"We haven't followed the patients long enough"—it could be that more tumors become evident with more time, he said.
The blood test seemed to do a good job of identifying which of these hormone-positive patients were at low risk of recurrence, suggesting that women who test negative may be able to forgo an additional five years of hormone-blocking medicines.
The test did not predict recurrence risk in the rest of the women in the study, whose tumors were not fueled by estrogen. They have a lower risk of recurrence after five years to start with.
The study was funded by the Breast Cancer Research Foundation, Susan G. Komen Foundation and the National Cancer Institute.
Explore further: Adjuvant Trastuzumab did not improve outcomes for patients with HER2-low breast cancer0 -
Study sheds new light on mechanism of breast cancer treatment resistance
February 12, 2018, Dana-Farber Cancer Institute
A study by researchers at Dana-Farber Cancer Institute has illuminated a specific mechanism by which estrogen receptor-positive (ER+) breast cancers can become resistant to standard therapies and metastasize.
The scientists say the mechanism explains why breast cancers with mutations in the ER gene itself—the target of drugs such as aromatase inhibitors and tamoxifen—become resistant to these therapies and are prone to become metastatic. Resistance to therapy for ER-positive breast cancer is a common cause of breast cancer mortality and a major unmet need.
Myles Brown, MD, director of the Center for Functional Cancer Epigenetics at Dana-Farber, and Rinath Jeselsohn, MD, of Dana-Farber's Susan F. Smith Center for Women's Cancers, led a research team reporting the findings in Cancer Cell.
A majority of women with breast cancer have tumors that are fueled by the hormone estrogen. Most are treated with therapies that prevent estrogen production or block the estrogen receptor in cancer cells to prevent binding by estrogen, with the goal of starving the tumor of estrogen and interrupting cancer growth.
Such endocrine therapies, including tamoxifen and aromatase inhibitor drugs, can prevent recurrence of early breast cancer, and can slow the progression of metastatic disease. However, in about one-third of patients with metastatic ER-positive breast cancer, treatment with endocrine therapies leads to the emergence of tumor cells that grow even in the absence of estrogen hormone, resulting in treatment-resistant disease that is often incurable.
In studying the molecular causes of resistance to endocrine therapies, scientists found DNA mutations in the estrogen receptor gene in a substantial number of patients with ER-positive breast cancer. In 2013, Jeselsohn and colleagues reported finding ER mutations in the tumors of women with metastatic ER-positive breast cancer. The scientists then created laboratory models of breast cancer to investigate how the mutations (which they estimate occur in about a third of women with metastatic ER-positive breast cancer) cause treatment resistance. In these experiments they found that the mutations caused the tumors to be resistant to the drugs tamoxifen and fulvestrant (another estrogen-blocker) and estrogen deprivation.
In the new report, however, the Dana-Farber scientists revealed another previously unknown effect of three of the mutations in the ER gene. That is, the mutations not only cause resistance to estrogen blockade, but also turn on genes that drive the breast tumors to metastasize to other organs. This kind of unexpected additional action of a mutated gene is termed "neomorphic."
"That tells us that even though the drug therapies are selecting tumors that can grow without estrogen, the mutations also confer a metastatic advantage to the tumor," explains Brown.
The researchers then used the CRISPR-Cas9 gene editing tool to launch a search to identify which genes are essential in cells with the ER mutations. Among the essential genes they found, CDK7 was of particular interest because it was a potential drug target. In fact, Dana-Farber colleague Nathanael Gray, PhD, and his team had previously developed an experimental CDK7 inhibitor called THZ1. Tests in cell culture and in animal models with transplanted breast tumors showed that the combination of THZ1 and the endocrine blocker fulvestrant slowed growth of tumors more strongly than either agent alone.
"These results support the potential of this combination as a therapeutic strategy to overcome endocrine resistance caused by the ER mutants," say the authors of the report.
Jeselsohn said that clinical CDK7 inhibitors are being developed, and that "we hope to test these drugs and develop a clinical trial for patients with ER-positive metastatic breast cancer."
Explore further: Novel therapeutic target discovered for estrogen receptor positive (ER+) breast cancerJournal reference: Cancer Cell
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