Carrots, tomatoes and kale. Oh my.

Susan Landmann has been on a low-fat, largely organic diet since her treatment for TNBC, which was diagnosed in August 2009.  She has been conscientious about her diet, and here's photographic proof of her seriousness of purpose: a refrigerator brimming with beautiful healthy goodies.   Yum.   But Susan is sick of it.  She is about one carrot stick away from chucking the whole thing.  And you know what, if you are too severe with yourself—if you do not allow yourself a treat once in a while—chances are good your diet will not last.

First, let's be clear on the definition of diet.  A true, healthy diet refers to the way you plan to eat for the rest of your life.  It is not a short-term thing until you reach some goal--lose weight, get three years beyond TNBC.  It is forever. A cancer-beating diet should be low in fat, high in veggies and fruits, with lots of nuts, seeds, and whole grains.

But most people cannot sustain this without a break every now and then—some fat, some sweets.  As long as you do not go overboard, some goodies occasionally can actually help you stay on track.

But here is what I have noticed recently.  I seriously fell off my diet for a month or two—the lure of French fries, cookies, and red meat just got to me and, after five years of being a hard-core healthy eater, I returned to some bad habits.  You know what else returned?  The headaches that used to bother me. The pain in my head is pretty immediate and clear proof from my body that it preferred the healthy fare.  It is true that eating well has long-term benefits for our health, but it also has some great short-term benefits in how we feel.  I have more energy, a better attitude, and fewer headaches when I choose not to chew the fat.

Still, severity is never a good thing.  Eating healthy can mean some treats every now and then.  Moderation is such a reasonable concept.

And another thing:  Susan's refrigerator is a lot cleaner than mine.

Breast Cancer Mantra: Slow Down, You Move Too Fast

When my daughter was in college, I went to the office supply store with her to buy an appointment calendar.  It was a challenge—she wanted something portable, but none of those had enough space on individual days to include all her activities.

"Perhaps you have too many commitments," I offered. "Maybe you're doing too much."

She looked at me for a few seconds, then said, "I wonder where I got that."

Rats.  There was so much I wanted to impart to this beautiful young woman, but I did not mean to be a role model of a woman in a hurry.

Nevertheless, I am always in a rush.  Always.  The car ahead of me is always too pokey, usually because the crazy driver is going the speed limit.  Or more.  I am always in the slow lane at checkout, no matter what lane I am in.  I do my yoga in the morning and have to remind myself over and over to be in the moment, that this is about slowing down, not about being done with it so I can go on to whatever is next.  It has been a hard lesson for me, this slowing down.  I am trying to learn it.  Trying, trying, trying.

I look forward to going to our Colorado cabin in the summer because there I can stop, unplug, unwind, and take my time.  I cannot hurry on a mountain hike—my lungs aren't that good.  So I have to slow down, breathe the mountain air, and relax.

This is one of the lessons of cancer—that hurrying gets you nowhere.  That cancer does not care how efficient and productive you are.  It can still catch you.  And, ironically, the best way to outrun it is by slowing down.

So, slow down, you move too fast.  And here's a little Simon and Garfunkel to help you.  Feeling groovy....

Progression-Free Survival for Metastatic TNBC Increased With CDX-011

A potent combo of glembatumumab vedotin, and Celldex known as CDX-011 has increased survival of patients with TNBC who have not responded to previous treatments and whose tumors express the protein NMB (GPNMB).   This according to EMERGE, a randomized  IIB clinical trial. Some details:


• TNBC that has resisted previous therapy stymies doctors who don't know where to turn next.
• Patients in this study have had as many as 11 and a median of six previous therapies.
• CDX-011 is administered intravenously and binds to GPNMB.  It is then released into cells where it interferes with cell growth and may lead to cell death in a cancerous tumor.


According to an article in OncLive:

“In heavily pretreated patients, you typically do not observe any kind of progression-free survival beyond the first therapy,” said Linda T. Vahdat, MD, professor of medicine and director of the Breast Cancer Research Program at Weill Cornell Medical College in New York and lead investigator of the EMERGE study. “These patients had a median of six prior therapies, so to have any kind of progression-free survival is exciting from a research standpoint.”  Read more.

The research is preliminary, but demonstrates that targeted therapy for TNBC may be in the near future.  It was to be presented at the American Society of Clinical Oncology (ASCO) 2012 June meeting, but a bookkeeping glitch kept the paper from consideration.

HDAC Inhibitor Destroys TNBC Cells

From a news release from BioMed Central:

The histone de-acetylase (HDAC) inhibitor panobinostat is able to target and destroy triple negative breast cancer, reveals a new study published in BioMed Central's open access journal Breast Cancer Research. Researchers from Tulane University Health Sciences Center have shown that panobinostat was able to destroy breast cancer cells and reduce tumor growth in mice.

Approximately 15% of breast cancers are found at diagnosis to be triple negative. These aggressive tumours are missing both the estrogen receptor and progesterone receptor, which means that they do not respond to hormonal therapies such as antiestrogens or aromatase inhibitors. They also test negative for the growth factor receptor HER2 and cannot be treated with monoclonal therapy such as Herceptin, so there is a desperate need for treatment options to complement surgery and chemotherapy.

Whether DNA is active or not in cells is tightly controlled. DNA in the nucleus is wound around histones and effectively shut down. When a gene is required the cell acetylates the histone, relaxing the tight control over DNA and allowing the cells machinery access to the gene, eventually leading to protein production.

HDACs have the opposite effect and reduce DNA activity. Aberrant HDACs are possibly responsible for the lack of production of normal cellular controls which allow the uncontrolled growth of cancer cells. The researchers from New Orleans hoped that by blocking HDACs they could restore normal cell function.

The HDAC inhibitor panobinostat was able to increase histone acetylation in triple negative breast cancer cell lines. There was also a concurrent decrease in cell division and increase in apoptosis (programmed cell death). Additionally, a marked increase in the epithelial cell marker E-cadherin was observed, indicative of a less aggressive cell type.

Dr. Bridgette Collins-Burow, who led the study, described the results, "Panobinostat selectively targeted triple negative breast cancer cells and decreased tumor growth in mice. It was also able to partially reverse the morphological changes in cells to a more epithelial type. These results show a potential therapeutic role for HDAC inhibitors, especially panobinostat, in targeting the aggressive triple negative breast cancer."

"Targeting triple-negative breast cancer cells with the HDAC inhibitor Panobinostat,"
Chandra R Tate, Lyndsay V Rhodes, H Chris Segar, Jennifer L Driver, F Nell Pounder, Matthew E Burow and Bridgette M Collins-Burow, Breast Cancer Research (in press)

Contact: Dr. Hilary Glover
hilary.glover@biomedcentral.com
44-203-192-2370
BioMed Central
Source:Eurekalert

Links between TNBC and African-American and young women to be studied

The research at Walter Reed National Military Medical Center and the Windber Research Institute will look at how "triple-negative cancers operate," using tissue samples from Army women.  This may lead to new tools for diagnosis and treatment.

Newswise — RICHLAND, Wash. -- Some types of breast cancer can be successfully treated with drugs such as tamoxifen, but treatment for a type of breast cancer more common in young and black women is still limited to radiation and general chemotherapy. Called triple negative breast cancer, this type of cancer is the focus of a 20-month, $8.6-million research project that aims to find new diagnostic tools and options for drugs.

The project takes advantage of one of the most comprehensive collections of breast cancer clinical samples in the U.S. -- the Clinical Breast Care Project located at the Walter Reed National Military Medical Center in Bethesda, Md., and the Windber Research Institute in Winder, Pa.

Researchers will explore these samples using advanced proteomics technology at the Department of Energy's Pacific Northwest National Laboratory and EMSL, DOE's Environmental Molecular Sciences Laboratory in Richland, Wash. Led by PNNL proteomics researcher Richard D. Smith, the study is funded by the Department of Defense.

"Triple negative cancers are more likely to hit young women and African American women. That's a health disparity issue. We need a better understanding of this disease," said team member Karin Rodland, a cancer biologist at PNNL. "And what's been holding that up has been getting enough samples to thoroughly examine how triple negative cancers operate."

Because the Army has such a large population of women that receive health care for years, as well as a higher percentage of black women than the general U.S. population, the Walter Reed-Windber breast cancer repository will provide many high quality samples with well-documented health histories.

One of the first things doctors check when a woman is diagnosed with breast cancer is whether her cancer will grow in response to any or all of three hormones: one that stimulates cell growth and two sex hormones, estrogen or progesterone -- cancers that can be treated with particular drugs. But many other breast cancers don’t respond. Called triple negative breast cancers, these types represent a wide variety of cancers and are typically more aggressive and harder to treat. [Pat's note:  Triple-negative cancers can be hard to treat, but most do respond well to available regimens of surgery, chemotherapy, and radiation.]

The research team will profile the complement of proteins -- known as the proteome -- that the breast cancer tissues produce, looking for proteins that triple negative cancers share. The shared proteins could suggest new options for drug therapies. In addition, comparing how aggressive the cancers are to the complement of proteins the cancers make or other metabolic products could lead to new diagnostic tools.

In addition to finding leads on diagnostic tools and therapies, the study might reveal proteins and molecular pathways that have gone astray and led to the cancer in the first place.

A recent, unrelated study reported in the news from the journal Nature re-grouped breast cancers into 10 sub-groups based on the cancer's genes and which genes were turned on or off in the cancerous cells. But genes are like a raw movie script -- how the movie turns out depends on many details beyond the words in the script. This new study will look beyond genes to see how cancer cells translated their scripts into live action.

The PNNL research effort will draw on the unique instruments and expertise developed at PNNL and EMSL in support of DOE-funded research in biofuels and bioremediation, which are also applicable to biological questions related to human health.

Could erlotinib before doxorubicin lead to targeted therapy for TNBC?

Lab research on cancer cells demonstrates how important it is to administer chemo drugs in specific order.  According to a news release from MIT:


• Giving the drug erlotinib between four and 48 hours before doxorubicin killed up to 50 percent of triple-negative cells
• Giving the two drugs together, by contrast, killed about 20 percent. 
• Pretreatment with erlotinib affected about 2,000 genes, which shut down pathways to cancer growth. 
• The drugs were less effective when doxorubicin was given first, erlotinib second.
• Researcher Michael Lee says,  “Instead of looking like this classic triple-negative type of tumor, which is very aggressive and fast-growing and metastatic, they lose their tumorigenic quality and become a different type of tumor that is actually quite unaggressive, and very easy to kill."
• NOTE: Erlotinib is currently used to treat lung and pancreatic cancers, not breast cancer.  
• This research is in early stages, and on lab cells, so it will be a while before it might get into practice.  Still it is a step toward targeted treatment for TNBC


The full news release from MIT:

Doctors have long known that treating patients with multiple cancer drugs often produces better results than treatment with just a single drug. Now, a study from MIT shows that the order and timing of drug administration can have a dramatic effect.
In the new paper, published in Cell on May 11, the researchers showed that staggering the doses of two specific drugs dramatically boosts their ability to kill a particularly malignant type of breast cancer cells.  

The researchers, led by Michael Yaffe, the David H. Koch Professor of Biology and Biological Engineering at MIT, are now working with researchers at Dana-Farber Cancer Institute to plan clinical trials of the staggered drug therapy. Both drugs — erlotinib and doxorubicin — are already approved for cancer treatment.

Yaffe and postdoc Michael Lee, lead author of the Cell paper, focused their study on a type of breast cancer cells known as triple negative, meaning that they don’t have overactive estrogen, progesterone or HER2 receptors. Triple-negative tumors, which account for about 16 percent of breast cancer cases, are much more aggressive than other types and tend to strike younger women. 

“For triple-negative breast cancer cells, there is no good treatment. The standard of care is combination chemotherapy, and although it has a good initial response rate, a significant number of patients develop recurrent cancer,” says Yaffe, who is a member of the David H. Koch Institute for Integrative Cancer Research at MIT. 

Uncontrolled growth
For the past eight years, Yaffe has been studying the complex cell-signaling pathways that control cells’ behavior: how much they grow, when they divide, when they die. In cancer cells, these pathways often go haywire, causing the cells to grow even in the absence of any stimulus and to ignore signals that they should undergo cell suicide.

Yaffe became intrigued by the idea that drug-induced changes in these signaling pathways, if staggered in time, could switch a cancerous cell into a less malignant state. “Our previous systems-biology work had primed us to the idea that you could potentially drive a cell from a state in which only a fraction of the tumor cells were responsive to chemotherapy into a state where many more of them were responsive by therapeutically rewiring their signaling networks in a very time-dependent way,” he says.

Specifically, he and Lee thought it might be possible to sensitize cancer cells to DNA-damaging drugs — the backbone of most chemotherapy — by first giving them another drug that shuts down one of the haywire pathways that promote uncontrollable growth. They tested different combinations of 10 DNA-damaging drugs and a dozen drugs that inhibit different cancerous pathways, using different timing schedules. 

“We thought we would retest a series of drugs that everyone else had already tested, but we would put in wrinkles — like time delays — that, for biological reasons, we thought were important,” Lee says. “I think had it not worked, we would have gotten a lot of pushback, but we were pretty convinced that there was a lot of information being left on the table by everyone else.”

Research from MITOf all combinations they tried, they saw the best results with pretreatment using erlotinib followed by doxorubicin, a common chemotherapy agent. Erlotinib, approved by the FDA to treat pancreatic cancer and some types of lung cancer, inhibits a protein found on cell surfaces called the epidermal growth factor (EGF) receptor. When constantly active, as it is in many cancer cells, the EGF receptor stimulates a signaling pathway that promotes uncontrolled growth and division. 

The researchers found that giving erlotinib between four and 48 hours before doxorubicin dramatically increased cancer-cell death. Staggered doses killed up to 50 percent of triple-negative cells, while simultaneous administration killed about 20 percent. About 2,000 genes were affected by pretreatment with erlotinib, the researchers found, resulting in the shutdown of pathways involved in uncontrolled growth. 

“Instead of looking like this classic triple-negative type of tumor, which is very aggressive and fast-growing and metastatic, they lose their tumorigenic quality and become a different type of tumor that is actually quite unaggressive, and very easy to kill,” Lee says.

However, if the drugs were given in the reverse order, doxorubicin became less effective than if given alone. 

Targeted treatment
This treatment worked not only in cancer cells grown in a lab dish, but also in mice with tumors. When treated with a one-two punch of erlotinib and doxorubicin, the tumors shrank and did not grow back for the duration of the experiment (two weeks). With chemotherapy alone, or when the two drugs were given at the same time, the tumors initially shrank but then grew back. 

A combination of high-throughput measurements and computer modeling was used to reveal the mechanism for increased tumor killing, and to identify a biomarker for drug response. The researchers found that the treatment was most effective in a subset of triple-negative breast cancer cells with the highest levels of EGF receptor activity. This should allow doctors to screen patients’ tumors to determine which would be most likely to respond to this novel treatment.

The research is “groundbreaking in its demonstration that the principles of order and time are essential to the development of effective therapies against complex diseases,” Rune Linding, research group leader at the Technical University of Denmark, and Janine Erler, associate professor at the University of Copenhagen, wrote in a commentary accompanying the paper in Cell. “As disease researchers, we must consider network states, and this and other studies serve as a model for a new generation of cancer biologists.”

The concept of staggering drug treatments to maximize impact could be very broadly applicable, Yaffe says. The researchers found similar boosts in tumor killing by pretreating HER2-positive breast cancer cells with a HER2 inhibitor, followed by a DNA-damaging drug. They also saw good results with erlotinib and doxorubicin in some types of lung cancer. 
“The drugs are going to be different for each cancer case, but the concept that time-staggered inhibition will be a strong determinant of efficacy has been universally true. It’s just a matter of finding the right combinations,” Lee says.
The findings also highlight the importance of systems biology in studying cancer, Yaffe says. “Our findings illustrate how systems engineering approaches to cell signaling can have large potential impact on disease treatment,” he says. 
The research was funded by the National Institutes of Health Integrative Cancer Biology Program and the Department of Defense.

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Partial Breast Irradiation in the News

Looks like whole-breast might be slightly better for TNBC and other forms of ER- breast cancer.  And, it may have fewer complications than partial-breast, which is the opposite of what I would have expected. The study on complications was on women over 67, but researchers compared the effects of whole-breast versus partial-breast, so age should not have been a significant factor.  The great majority of women had whole-breast irradiation, so the sample size for partial breast is pretty small, but I am not sure if that is significant in these circumstances.

The study that explains the slightly elevated risk for TNBC patients is here.
And the study on complications is here:

Partial Breast Irradiation Slightly Better in Preventing Local Recurrance

BUT, those that returned locally were more likely to be estrogen negative.

The full press release from The American Society of Breast Surgeons:

COLUMBIA, Md., May 01, 2012 (BUSINESS WIRE) -- Accelerated Partial Breast Irradiation (APBI) also known as brachytherapy, is equally effective--if not more effective-- in preventing local breast cancer recurrence than Whole Breast Irradiation (WBI), according to a study to be presented this week at the American Society of Breast Surgeons (ASBrS) Annual Meeting. Brachytherapy treats only the lumpectomy site, while WBI treats the entire breast. The findings of the ASBrS study contrast with a study from the University of Texas MD Anderson Cancer Center appearing in the May issue of the Journal of the American Medical Association (JAMA). 

Researchers will report on data from the ASBrS MammoSite Registry Trial comprising 1449 breast cancer patients treated with APBI brachytherapy at 97 institutions between May 2002 and July 2004. Eighty-seven percent of these patients were diagnosed with invasive breast cancer and 13% with DCIS, with a median follow up of 60 months.

In the ASBrS study, 50 patients treated with brachytherapy (3.5%) developed an ipsilateral breast tumor recurrence (IBTR), 14 (1.1%) at the initial tumor site and 36 (2.6%) elsewhere in the breast. For invasive cancers, IBTR [local recurrence] was associated with estrogen receptor (ER) negative disease. For DCIS, IBTR was associated with age <50 or close/positive surgical margins.

"Prior studies have demonstrated that the risk of cancer recurrence in the conserved breast is similar for WBI or APBI. Following WBI, most breast recurrences are at the initial tumor site, and relatively few are elsewhere in the breast," says Dr. Peter Beitsch, Director of the Dallas Breast Center, Co-Principal Investigator for the ASBrS MammoSite Registry and lead author on the ASBrS study. "This study demonstrated that for patients treated with APBI, this ratio was reversed: most breast recurrences were elsewhere in the breast and only a minority were at the initial tumor site. These data suggest that although tumor control in the breast appears to be similar for APBI and WBI, disease control at the initial tumor site may be better with APBI."

The findings of the ASBrS study contrast with the MD Anderson Cancer Center JAMA study, which also compared APBI to WBI.  MORE

Partial Breast Irradiation Comes with More Complications

According to research published in the Journal of the American Medical Association, there was no significant difference in survival rates for older women treated with whole-breast irradiation versus those treated with partial breast radiation, or brachytherapy.  But, those with brachytherapy faced more complications:


• The study was on data from 92,735 women 67 or older.
• 6,952 had undergone brachytherapy 
•  85,783 had whole-breast radiation
• 5- year survival rates were similar for the two groups, with overall survival at 87.7 percent.
• Those with brachytherapy had higher rates of infection, complications, and breast pain.
• Complications often led to a full mastectomy or, as the authors say, "failure to preserve the breast."


See the full story at CancerNetwork.