To the NY Times: TNBC is not automatically aggressive and is seldom lethal.

I sent this to the NewYork Times Magazine today, in response to Peggy Orenstein's "Our Feel-Good War on Breast Cancer," published last Sunday, April 28. 2013).

Women with triple-negative breast cancer throughout the country groaned when they saw Peggy Orenstein’s blithe mischaracterization of this type of breast cancer.  She uses the typical shorthand terms “aggressive” and “lethal” to define TNBC, a complex set of diseases that, in many cases, are no more aggressive than other forms of breast cancer. And TNBC is seldom lethal.  Non-metastatic TNBC has an impressive survival rate—as high as 87 percent in some studies. And Her2-positive can be more aggressive than TNBC, as can some forms of hormone-positive breast cancer.

Likewise, triple-negative is not synonymous with basal-like.   There is a strong association between the two, but not all TNBC tumors are basal-like and not all basal-like tumors are triple-negative.

All breast cancers can be aggressive and all can be lethal, but no one type is automatically both. Writers who use such fearful language ignore the psychological impact of their words on women who are already terrified and confused. The fact is that the great majority of women with TNBC survive and go on to live long, meaningful lives. 

Words matter, as do facts.

EGFR treatments again effective against some types of TNBC

We’re getting closer.  For several years, researchers have said that triple-negative breast cancer is not one disease, but many, with numerous studies focusing on the genetic similarities that create subsets of TNBC.  And drug combinations work better that single agents, according to a new article in Genetic Engineering and Biotechnology News  (April 26, 2013).

According to researchers, nearly half of all TNBC cells express the epidermal growth factor receptor (EGFR).  Current clinical trials are testing anti-EGFR drugs that may target these types of TNBC.  Two such antibodies—two EGFR antibodies (panitumumab and mAb111)—show promise.

BUT, I have to warn that the first sentence of the article will make all TNBC patients shudder:

Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer that does not currently have any targeted therapeutics available.

Here’s my reaction to that comment.

• TNBC can be more aggressive than other forms, but it is not always aggressive and the great majority of women with TNBC survive beautifully.

• We need to differentiate between metastatic and non-metastatic TNBC. Non-metastatic TNBC does have therapeutics—chemo often works better for it than for other forms of breast cancer.  Metastatic TNBC does not have targeted therapies yet—but let’s hope this research makes a difference there.

•••••

• Read more about TNBC in my book, Surviving Triple-Negative Breast Cancer.

• Please consider a donation to Positives About Negative to keep this site going.  This work is entirely supported by readers.  Just click on the Donate button in the right of the page.  Thank you!

Combo stops late-stage TNBC in mice

Researchers in Australia have successfully tested a drug combination to fight late-stage triple-negative breast cancer in mice—with a 100 percent success rate.  The treatment trial—at Queensland Institute of Medical Research— demonstrates that targeting radiation to an overload of proteins (known as EGFR) together with a dramatically reduced dose of chemotherapy is effective in stopping both the cancer growth and its recurrence. 

 “It’s when breast cancer reoccurs, or spreads, that most fatalities are reported,” Professor Kum Khanna, from QIMR’s Signal Transduction Laboratory. “This is early stage research, and there’s a long way to go, but it’s the first time we’ve seen a therapy that stops the recurrence and treats the spread of these triple-negative breast cancers.” . 

Researchers hope that the process can successful go through stage 1, 2, and 3 clinical trials within ten years.

Ten years!!!!!!!!!  Hurry, folks.  We're waiting.

Read the news release here.

Read more about TNBC in my book, Surviving Triple-Negative Breast Cancer.

Please consider a donation to Positives About Negative to keep this site going.  This work is entirely supported by readers.  Just click on the Donate button in the right of the page.  Thank you!

Protein Inhibits Growth of TNBC Tumors

A monoclonal antibody targeting a protein known as SFPR2 has been shown by researchers at the University of North Carolina to inhibit tumor growth in pre-clinical models of triple-negative breast breast cancer, according to research published in the April 19 issue of Molecular Cancer Therapeutics,

The UNC lab first discovered the role of SFRP2 in tumor growth while working to develop an alternative to Avastin (bevacizumab), which targets the protein VEGF. Although Avastin is of benefit to some patients with cancer, not all tumors respond to the drug, and of those that respond, some eventually progress. To find a solution for patients whose tumors are resistant to Avastin, researchers began looking at other proteins that could be used as therapeutic targets.  Avastin is not approved by the FDA for use with breast cancer.

“We previously microdissected blood vessels from malignant human breast cancers and compared gene expression to blood vessels microdissected from normal tissue. We found a number of genes that were highly over-expressed in the malignant blood vessels compared to normal. One of those genes was SFRP2,” said research leader Nancy Klauber-DeMore, MD, professor of surgery and a member of UNC Lineberger Comprehensive Cancer Center.

Researchers found that SFRP2 is expressed in a variety of human cancers, including breast, prostate, lung, pancreas, ovarian, colon, kidney tumors, and angiosarcomas. “Demonstrating that a monoclonal antibody to SFRP2 inhibits tumor growth in pre-clinical models opens up a new potential for drug development. This treatment is not presently available for human studies, but our efforts are focused on obtaining funding for further drug development that would lead to a clinical trial” DeMore said.

Read more about TNBC in my book, Surviving Triple-Negative Breast Cancer.

Please consider a donation to Positives About Negative to keep this site going.  This work is entirely supported by readers.  Just click on the Donate button in the right of the page.  Thank you!

Diamonds May Be A TNBC Girl's Best Friend

From a news release from the University of California:

UCLA researchers  have developed a potential new treatment for triple-negative breast cancer that uses nanoscale, diamond-like particles called nanodiamonds.

 

Nanodiamonds are between 4 and 6 nanometers in diameter and are shaped like tiny soccer balls. Byproducts of conventional mining and refining operations, the particles can form clusters following drug binding and have the ability to precisely deliver cancer drugs to tumors, significantly improving the drugs' desired effect. In the UCLA study, the nanodiamond delivery system has been able to home in on tumor masses in mice with TNBC.

 

Findings from the study are published online April 15 in the peer-reviewed journal Advanced Materials.

 

"This study demonstrates the versatility of the nanodiamond as a targeted drug-delivery agent to a tumor site," said Dean Ho, a professor at theUCLA School of Dentistry and co-director of the school's Jane and Jerry Weintraub Center for Reconstructive Biotechnology.  Ho is also a member of the California NanoSystems Institute at UCLA, UCLA's Jonsson Comprehensive Cancer Center and the UCLA Department of Bioengineering. "The agent we've developed reduces the toxic side effects that are associated with treatment and mediates significant reductions in tumor size."

 

The team combined several cancer-fighting components on the nanodiamond surface, including Epirubicin, a  chemotherapy drug that is often administered in combination with other cancer drugs. The new compound was then bound to a cell-membrane material coated with antibodies that were targeted toward the epidermal growth factor receptor, which is often highly concentrated on the surfaces of TNBC cells. The resulting agent is a drug-delivery system called a nanodiamond-lipid hybrid compound, or NDLP.

 

When tested on mice, the agent was shown to notably decrease tumor growth and eliminate the side effects of cancer treatment.

 

Epirubicin can cause serious side effects, such as heart failure and reduced white blood cell count, and it has been linked to an increased risk for leukemia. In the study, all of the mice that were given Epirubicin alone died well before the completion of the study. But all the mice given Epirubicin through the targeted NDLPs survived the treatment, and some of the tumors regressed until they were no longer visible.

 

"Triple-negative breast cancer is often very aggressive and hard to treat, making aggressive chemotherapy a requirement," said Dr. Edward K. Chow, co-first author of the study and an assistant professor at the Cancer Science Institute of Singapore. "The targeting and therapeutic efficiency of the nanodiamond-lipid agents were quite remarkable. The simultaneous tumor regression and improved drug tolerance are promising indicators for the continued development of the nanodiamonds toward clinical translation."

 

The research team is now studying the use of the NDLPs in larger animals. Additional research objectives include determining whether nanodiamonds can enhance the tolerance of a wide spectrum of highly toxic drug compounds, which may improve current treatment options and outcomes. These discoveries will serve as precursors for human trials, the researchers said.

Lymphedema Related to BMI, Higher Stage, and Genes

A news release from the University of California School of Nursing

The risks of developing lymphedema increased significantly for women who had more advanced breast cancer at the time of diagnosis, more lymph nodes removed or a significantly higher body mass index, and a specific set of genes, according to a study of some 400 women who were tracked over four to five years and published online on April 16, 2013 in PLOS ONE.

The study is the first to evaluate genetic predictors of lymphedema in a large group of women using a type of technology, bioimpedance spectroscopy, to measure increases in fluid in the arm. Bioimpedance spectroscopy is a noninvasive procedure that allows one to measure body composition including an increase in fluid in an arm or a leg.

“The genetic markers found in our study make perfect sense,” said senior author Bradley Aouizerat, PhD, a professor at the UCSF School of Nursing in the department of physiological nursing. “These genes are ‘turned on’ later in the development of our lymph system and blood vessels. They appear to play a role in the ability of our lymphatic system to function on an ongoing basis. It is possible in some individuals who have changes in these genes, that lymphedema could develop after an injury like breast cancer surgery because these genes do not function properly.” 

Lymphedema is a swelling or buildup of fluid in the lymphatic tissues, typically in the arms and fingers but also commonly in the patient’s legs and trunk. It can occur after treatment for any form of cancer that affects lymph node drainage. The exact prevalence is unknown, and the onset of the condition can greatly vary, but as many as 56 percent of women who undergo breast cancer surgery develop lymphedema within two years, according to the National Cancer Institute. More than half a million breast cancer survivors in the United States are estimated to be afflicted with the condition.

Lymphedema can be debilitating, causing scarring, discomfort, disfigurement, difficulty in exercising, walking or other daily activities. Some patients are unable to wear their usual clothing or jewelry because of the increased weight and size of their affected limbs. There’s no cure for the condition – treatment generally centers on controlling pain and reducing swelling.

To date, much of the research on lymphedema focused on identifying which women were at greater risk for the development of the condition, and relied only on patient self-reporting or on data from their medical charts.

In the new study, the authors hypothesized that genomic determinants were behind some of the variations in the occurrence of lymphedema as well as the time of onset of the condition.
The study involved 410 women who were at least six months post-treatment for breast cancer surgery on one breast, and either had lymphedema in their upper extremity or did not have the condition.

The women were assessed at the Clinical Research Center at the University of California at San Francisco Medical Center at Mt. Zion, one of eight clinical sites in the Bay Area managed by UCSF’s Clinical and Translational Science Institute.

As part of the research, the women underwent spectroscopy measurements of their arms and genomic DNA was extracted. Genotyping was performed blinded to the women’s lymphedema status.

The researchers found that women with lymphedema had:

• More advanced breast cancer at the time of diagnosis;
• A higher number of positive lymph nodes;
• Were more likely to have a significantly higher body mass index.

The authors also found associations between lymphedema and genes known to play a role in the development of lymphedema—FOXC2 haplotype
A03, LCP2 rs315721, NRP2 rs849530, NRP2 haplotype F01,
SYK rs158689, VCAM1 rs3176861, and VEGFC haplotype B03

“These findings suggest that complex interactions may exist between a variety of patient characteristics and genetic markers that place some women at higher risk for the development of lymphedema,’’ said lead author Christine Miaskowski, RN, PhD, a professor at the UCSF School of Nursing in the department of physiological nursing. “Our hope is that once our findings are confirmed in a future study, we will be able to identify women at higher risk for lymphedema prior to breast cancer surgery, and initiate measures to prevent the development of this devastating condition.”

Omega 3 Fatty Acids in Fish Oil May Slow Triple-Negative

Eat your fish.  Take your Omega 3 supplements.  Here's why:

WASHINGTON, DC (April 9, 2013)—Researchers from Fox Chase Cancer Center have found that omega-3 fatty acids and their metabolite products slow or stop the proliferation, or growth in the number of cells, of triple-negative breast cancer cells more effectively than cells from luminal types of the disease. The omega-3s worked against all types of cancerous cells, but the effect was observed to be stronger in triple-negative cell lines, reducing proliferation by as much as 90 percent. The findings were be presented at the AACR Annual Meeting 2013 on Tuesday, April 9.

Omega-3 fatty acids are found in oily fish like sardines and salmon, and also in oils derived from plants like hemp and flax. Previous studies suggest these compounds can negatively affect critical mechanisms in cancer cells, namely those responsible for proliferation and for apoptosis, or programmed cell death. Lead author on the study Thomas J. Pogash, a scientific technician in the Fox Chase Cancer Center lab of Jose Russo, MD, says the new work underscores the important role common compounds found in food may play in keeping cancer at bay.

“Diet can play a critical role in breast cancer prevention,” says Pogash. “When you compare a western diet to a mediterranean diet, which has more omega-3s, you see less cancer in the mediterranean diet. They eat much more fish.”

Breast cancer is a heterogeneous group of cancers comprising diseases that differ on the molecular level. Patients with different types of breast cancer respond differently to treatments. Four distinct categories of the disease are generally recognized. Two of those, luminal A and luminal B, grow in the luminal cells that line milk ducts in the breast and have receptors for estrogen and progesterone (prognosis is generally better for patients with luminal A than with luminal B). A third category includes tumors that test positive for the HER2 receptor.

Tumors in the fourth category, triple-negative, lack receptors for progesterone, estrogen, and a protein called HER2/neu. As a result, this type of disease is insensitive to treatments like trastuzumab, which disrupts the HER2 receptor, and tamoxifen, which targets the estrogen receptor.

Russo notes that no targeted therapies are currently available for patients diagnosed with triple-negative breast cancer. Combination chemotherapies are the standard of care for early-stage disease.

“This type of cancer, which is found more frequently in Latina and African-American women, is highly aggressive and has a low survival rate,” says Russo. “There is not any specific treatment for it.” [Pat's note:  It can be aggressive, but only in a minority of cases; the great majority of women survive TNBC and go on to live lovely lives. I am seven years past  diagnosis and I am far from unusual.]

When a cancer cell digests omega-3s, the fatty acid is broken down into smaller molecules called metabolites. Russo, Pogash, and their colleagues tested the effect of large omega-3 parent molecules, as well as their smaller metabolic derivatives, on three luminal cell lines and seven lines that included basal-type triple-negative cells.

Omega-3 and its metabolites were observed to inhibit proliferation in all cell lines, but the effect was dramatically more pronounced in the triple-negative cell lines. In addition, the metabolites of omega-3 reduced the motility, or ability to move, by 20-60 percent in the triple-negative basal cell lines.

This study is part of a consortium between Fox Chase Cancer Center and Pennsylvania State University under a five-year grant awarded by the Komen Foundation. Russo is the principal investigator of the project at Fox Chase. Andrea Manni, MD, leader of the Pennsylvania State University team, has extended this work to animal models, studying the anticancer effects of omega-3s and its metabolites on mouse models of triple-negative breast cancer.

Russo and his colleagues are working on two related projects, one on the role of epigenetic events in the mechanism of cell transformation and another on the potential action of peptides of the hormone human chorionic gonadotropin (hCG) on breast cancer prevention.

Metabolic Alterations in Triple-Negative Breast Cancer To Be Cataloged

WASHINGTON, DC (April 9, 2013)—Researchers at Fox Chase Cancer Center have identified a host of small molecules critical to metabolism in cells of triple-negative breast cancer—one of the least understood groups of breast cancer. These molecules, called metabolites, include key players in energy regulation and lipid synthesis. They could help pave the way for helping researchers differentiate among different forms of the disease and ultimately point to new targets for treatment.

“There’s tremendous excitement in the cancer field for the possibility of manipulating metabolism for therapeutic benefit,” says Jeffrey Peterson, PhD, a cancer biologist at Fox Chase who led the studies.

Patients with triple-negative breast cancer constitute about 15 to 20 percent of all breast cancer cases, though incidence is disproportionately higher among young and African-American women. In triple-negative breast cancer, tumor cells lack receptors for two hormones—progesterone and estrogen—and a protein called HER2/neu. This type of cancer is notoriously difficult to treat and does not respond to some of the most effective treatments available for other types of breast cancer, like trastuzumab, which interferes with the HER2receptor in HER2+ breast cancer, or endocrine therapies like tamoxifen.

Triple-negative breast cancer is not one well-defined disease. It’s a large group of diseases that all lack the three receptors but may differ from each other in critical ways, from individual molecules all the way up to clinical prognosis and treatment options. Peterson says that cataloging the small molecules involved in cellular metabolism may help researchers differentiate among these different cancers lacking the three receptors.

“One of our hopes is to understand how this heterogeneous disease can be classified into subtypes,” says Peterson. “We’d like to be able to define each subtype and a biomarker for each of those subtypes, based on the specific metabolites altered in that subtype.”

Like healthy cells, tumor cells take food from the blood and turn it into energy, but their metabolic processes differ from those of healthy cells. In recent years scientists have begun to try to find ways to exploit these differences to selectively kill cancer cells, with the ultimate goal of developing new therapies. Peterson and his colleagues used cutting edge technology, including liquid chromatography-mass spectrometry, to survey the amounts of a wide range of metabolites in cells from nine widely-used cell lines of triple-negative breast cancer.

They also zoomed in to study particular, targeted metabolites more closely. Broad metabolic profiling is new technology, and Peterson and his colleagues are among the first teams of researchers to apply it to the study of triple-negative disease.

They looked at both the metabolic “footprints” and “fingerprints” of the cells. The metabolic “footprint” includes the metabolites that go in to a cell from the surrounding media — or come out the other end of the process. The metabolic “fingerprint” shows all the molecules that work inside the cell during metabolic processes.

“We basically remove all the cells from the media, and then extract all of their small metabolites(less than 1500 dalton) and analyze those,” Peterson says.

He says this catalog of metabolites from these cell lines is a good first step toward using metabolic markers to better understand the disease. Since triple-negative breast cancer is heterogeneous, the next step, he says, is to replicate the study in other cell lines and validate potential biomarkers.

This study grew out of another ongoing project by Peterson and his team. He was the lead author on a paper, published in the journal Nature Biotechnologyin 2011, introducing a new technique to study the action of kinases—which are a class of enzymes that control cellular metabolism. Once that tool was developed, he decided to apply it to the poorly understood triple-negative breast cancer. In another study he’s presenting at the AACR Annual Meeting 2013, Peterson and colleagues show how this technique can be used to identify small molecules that block the kinases important to the growth of triple-negative disease.

“Those small molecules may be the starting point for new therapies,” he says. Ultimately, he says, he’d like to combine the metabolite and kinase studies to develop targeted therapies that stymy the metabolism of cancer cells.

Please consider a donation to Positives About Negative to keep this site going.  This work is entirely supported by readers.  Just click on the Donate button in the right of the page.  Thank you!

Read more about diet and TNBC in my book, Surviving Triple-Negative Breast Cancer.

Short Bouts of Exercise As Good As Formal Regimens

[NOTE:  This is a news release from January from Oregon State University.  I found it while researching other things.  It offers a good perspective on exercise and how to make it work.  Exercise is important in fighting TNBC.  Tied with a healthy diet, it can lead to weight loss, which is a key to reducing risk of recurrence.]

New research at Oregon State University suggests the health benefits of small amounts of activity – even as small as one- and two-minute increments that add up to 30 minutes per day – can be just as beneficial as longer bouts of physical exercise achieved by a trip to the gym.

The nationally representative study of more than 6,000 American adults shows that an active lifestyle approach, as opposed to structured exercise, may be just as beneficial in improving health outcomes, including preventing metabolic syndrome, high blood pressure, and high cholesterol.

“Our results suggest that engaging in an active lifestyle approach, compared to a structured exercise approach, may be just as beneficial in improving various health outcomes,” said Paul Loprinzi, lead author of the study. “We encourage people to seek out opportunities to be active when the choice is available. For example, rather than sitting while talking on the phone, use this opportunity to get in some activity by pacing around while talking.”

Perhaps just as importantly, the researchers found that 43 percent of those who participated in the “short bouts” of exercise met physical activity guidelines of 30 minutes day. In comparison, less than 10 percent of those in the longer exercise bouts met those federal guidelines for exercise.

Loprinzi, who is an assistant professor at Bellarmine University, conducted the research as a doctoral student working in the lab of Brad Cardinal at Oregon State University. Cardinal, a professor of exercise and sport science, is co-author of the study, which is in the current issue of the American Journal of Health Promotion.

“You hear that less than 10 percent of Americans exercise and it gives the perception that people are lazy,” Cardinal said. “Our research shows that more than 40 percent of adults achieved the exercise guidelines, by making movement a way of life.”

Cardinal, who has studied the “lifestyle exercise” model for more than 20 years, said one of the most common barriers people cite to getting enough exercise is lack of time. He said the results of this study are promising, and show that simply building movement into everyday activities can have meaningful health benefits.

“This is a more natural way to exercise, just to walk more and move around a bit more,” Cardinal said. “We are designed by nature as beings who are supposed to move. People get it in their minds, if I don’t get that 30 minutes, I might as well not exercise at all. Our results really challenge that perception and give people meaningful, realistic options for meeting the physical activity guidelines.”

For example, Cardinal said instead of driving half a mile, try biking or walking the same distance; instead of using a riding lawn mower, use a push lawn mower. Instead of sitting through TV commercials, try doing some sit-ups, push-ups, or jumping jacks during the commercial breaks; and instead of sitting and being a spectator at a child's sporting event, try walking around during the halftime break.

The researchers said the participants in this study wore accelerometers, which is an objective tool to measure physical activity. Those who participated in the short bouts of activity could be moving as few as one or two minutes at a time. The people in the “short bouts” group had positive results in areas such as blood pressure, cholesterol, metabolic syndrome, and waist circumference.

For instance, the study showed those in the shorter exercise group who met physical activity guidelines had an 89 percent chance of not having metabolic syndrome, compared to 87 percent for those meeting guidelines using the structured exercise approach.

Loprinzi said the one area where small bursts of activity did not seem to equal the benefits of longer, sustained exercise was in Body Mass Index, or BMI. However, the researchers cautioned that these findings do not necessarily mean that short bouts of activity do not help with weight loss, especially since they did find a benefit on weight circumference.

“There are inherent limitations in BMI as a surrogate measure of fat and health in general,” Cardinal said. “People can still be ‘fit’ and ‘fat.’”

The researchers emphasized that for health benefits, people should seek out opportunities to be physically active.

“In our society, you will always be presented with things that entice you to sit or be less active because of technology, like using a leaf blower instead of a rake,” Cardinal said. “Making physical activity a way of life is more cost-effective than an expensive gym membership. You may be more likely to stick with it, and over the long term, you’ll be healthier, more mobile and just feel better all around.”

A Moment of Beauty

Carolyn Justin Baer took this photograph of Lake Tahoe, where she lived with her husband Bob.   Justin's family selected  this photo for her obituary after she died of triple-negative breast cancer March 21, 2013.    I considered Justin a friend, even though I had never met her, and  I wrote about our friendship for Psychology Today.  But I had not known, until I saw this photograph, that she was such a talented artist.  This amazing shot is a memory of a moment in time, of the beauty that Justin saw and captured, the beauty she left behind with us.  (See more of Justin's remarkable work here.)

Genetic Details of Triple-Negative Breast Cancer

Beyond its most basic definition—negative for receptors for estrogen, progesterone and Her2/neu—triple-negative breast cancer has unique genetic characteristics.  Research published April 1, 2013 in the journal Cancer Research has outlined some of TNBC’s genetic associations.  Researchers keep getting closer to finding what makes TNBC tick.  Once they know that, they can target it.  Put a big red bull’s eye on its nasty old back. 

Some details of the research:

• TNBC is more likely to be associated with TOX3, ESR1, RAD51L1, TERT, 19p13.1, 20q11, MDM4, 2p24.1, and FTO.

• 70 percent of those with the BRCA1 mutation who get breast cancer get TNBC.

• 16  to 23 percent of those with the BRCA2 mutation who get breast cancer get TNBC.

• Variations in the 19p13.1 locus and the MDM4 locus have been associated with TNBC, but not other forms of breast cancer, meaning that these are TNBC-specific.

• TNBC accounts for 12 to 24 percent of all breast cancers.