Tumor Suppressor Gene Linked to Improved Response to Chemo in TNBC and Other Breast Cancer Patients

NEWS RELEASE

PHILADELPHIA—Breast cancer patients whose tumors lacked the retinoblastoma tumor suppressor gene (RB) had an improved pathological response to neoadjuvant chemotherapy, researchers atThomas Jefferson University Hospital and the Kimmel Cancer Center at Jefferson report in a retrospective study published in a recent online issue of Clinical Cancer Research.

Many breast cancer patients undergo neoadjuvant therapy to reduce the size or extent of the cancer before surgical intervention. Complete response of the tumor to such treatment signifies an improved overall prognosis. Today, no marker is applied to identify tumors which will respond to such treatment, and as a result, only a subset of patients exhibit benefit from it.

"We found that loss of RB was associated with better pathological response rates in breast cancer patients—at various stages and representing multiple molecular subtypes—who were administered neoadjuvant chemotherapy," said Agnieszka Witkiewicz, M.D., Associate Professor of Pathology, Anatomy and Cell Biology at Thomas Jefferson University.

Erik Knudsen, Ph.D, Professor of Cancer Biology and the Hilary Koprowski Chair in Cancer Biology, was excited that discoveries from his life-long research on the RB-pathway were making their way into the clinic.

"This represents a potential new biomarker that could be used to tailor treatment plans for women considering neoadjuvant therapy and is a testament to the importance of cancer research," he said.

For the study, researchers, including Gordon Schwartz, M.D., Director of the Jefferson Breast Care Center and Adam Ertel, Ph.D., Bioinformatics Specialist, Department of Cancer Biology, performed a combination of gene expression profiling to identify those with RB loss and direct histological analysis in over 1,000 breast cancer patients who had undergone neoadjuvant therapy. These patients represented distinct subtypes of breast cancer and were treated with multiple different therapeutic regimens.

RB loss was associated, the team found, with an improved response to all the neoadjuvant regimens investigated in the major subtypes of breast cancer.

"Together, these data indicate that the loss of RB, which occurs relatively frequently in locally advanced disease, could be a useful tool for defining patients who experience an improved response to neoadjuvant chemotherapy," said Dr. Witkiewicz. "Based on these findings, we have initiated a prospective clinical trial at Jefferson, evaluating the association of RB and another marker, PTEN, with the response to neoadjuvant chemotherapy."

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The clinical trial is open to patients who have a diagnosis of triple negative breast cancer and are eligible for neoadjuvant chemotherapy. (clinicaltrials.gov/ct2/show/NCT01514565).

Seeing the Trees in The Forest, And Where We Fit In

A little evergreen tree has died alongside our road and, as we walked by it yesterday, my husband wondered why.  All the other trees around it are healthy and it did not look like it had been hit by lightning or damaged by wind or attacked by bugs.

The tree is about eight feet tall, so it lived several years.  We are in the Rocky Mountains and this little guy took root on its own, taking seed and growing in that place by the road.

The trees all around it are scrub oak, so maybe the soil was not right for an evergreen.  Maybe it just grew in the wrong place, in soil that could not sustain it.  Still, there are evergreens nearby that soar to the sky, so maybe this little tree was just too weak to begin with.

Could we have done something to save it?  If we were in the city, would we have babied it and maybe kept it alive?  Or would it have died sooner there?

These are the same questions we ponder about why some people get sick, why one disease affects one person more than others, why people who live healthy lives still can’t beat some illnesses, yet people with deplorable habits keep going and going.

It’s the old nature versus nurture argument.  Bad genes or bad environment?  Or both?

I am sort of over being angry at people who have dodged major illnesses—largely because, frankly, there aren’t that many of them.  Seems like most people I know have something to contend with—debilitating arthritis, diabetes, heart disease, Alzheimer’s.  But when I first got cancer I did look around at people who obviously were not living as healthy as I was and wondered, Why me and not them? And then I realized that I had no idea what they were dealing with and I should just stop being so angry and judgmental and get over myself.  It was not their fault I got sick.

Still, you have to wonder about this poker game we all play with our health.  Some seem to be dealt a good hand to begin with, some make the best of a poor hand, some try but can’t make a straight out of a pair of twos, and some look at their cards and just fold. 

I have one friend who never exercises and has a diet full of fat, yet she is in her mid-80s, hale, hearty, and youthful-looking.  Another smoked all his life, drank, and never exercised, yet he is pushing 80 and has nothing seriously wrong physically, although I do think he looks back at his life with serious regret.  Still, the big C didn’t get him, nor did any major illness.  I wouldn’t swap places with him, though, even if I knew my cancer would return.

I also know a wide variety of cancer patients—fighters who refuse to let the disease get the upper hand, questioners who search for their own information rather than listening to the docs, accommodators who go along with whatever the doctor says, worriers who can’t get beyond the fact that they might die.  Most of us are a mix of these traits, fighting one day, living in worry the next.  But we are all built differently, both physically and mentally, so we all react to our disease differently.  Nobody is right, nobody is wrong.  We’re all just us, being our own little trees fighting our own little battles.

We cannot escape our genes—they make us prone to certain diseases, give us the strength to fight others, and offer a blueprint for either a long or a short life.  Still, we can change some of that—the science of epigenetics demonstrates that lifestyle and environmental factors can influence our genetic makeup so that, by improving things such as diet and physical activity and by avoiding unhealthy environmental pollutants including stress, bad air, and chemicals, we can eventually build a healthier DNA.

I was born into a history of cancer.  My grandmother and both of my parents had forms of cancer, although none of them had breast cancer.  I was the pioneer there.  But both parents lived into their 80s and remained in their home until they died, surrounded by their family.  So, I might have a tendency toward cancer, but perhaps my genes also mean I will hang around for a couple more decades.  And my particular mix of nature and nurture has given me an ability to love, to laugh, to process health information in a way that might make me proactive, and to keep going, assuming all will be well, at least at some level.

Maybe I won’t end up as one of the stronger trees in the forest, maybe I will be the gnarled, crooked one.  Maybe disease might slow me, but I feel I am rooted deeply in decent soil—family, friends, community—so I am going to push on, grow how I can, and, in the process, help shade and nurture the other trees around me.

  

Do You Have A Survivorship Care Plan?

When most breast cancer patients finish treatment, docs set up a schedule of regular visits for mammograms, blood work, and general physical monitoring.  In the best cases, they also help you develop a survivorship plan (SCP) to help navigate life as a whole after cancer.  The report, From Cancer Patient to Cancer Survivor: Lost in Translation, written in 2005, offers a blueprint for this transitional period.  In the introduction, the authors note:

Despite the increase in survivors...primary care physicians and other health care providers often are not extremely familiar with the consequences of cancer, and seldom receive explicit guidance from oncologists. Furthermore, the lack of clear evidence for what constitutes best practices in caring for patients with a history of cancer contributes to wide variation in care.

The report's recommendations acknowledge the the period after cancer treatment  should be seen as a "distinct phase of cancer care."   This means going beyond tests and helping patients deal with the fact that they have had cancer and are likely terrified that it will return.  Cancer care may last a lifetime.


Access to affordable health care is a constant in the group's recommendations, which is especially apt as we await the  U.S. Supreme Court's ruling on the Affordable Care Act.  If the act is struck down, require Congress to implement some of its aspects, such as allowing covering for people with preexisting conditions and eliminating lifetime caps on coverage.  Those who have gone through cancer treatment know that good healthcare is a lifesaver.  And the need for care does not stop when treatment ends—nor does the cost get any more reasonable.

Summer 2012: My Life Right Now

We drive up a rutted mountain road, going 15 miles an hour, feeling we are speeding as we dodge rocks and pines and locust trees full of pink blossoms. The road follows a small creek that rushes down the mountain, sliding over rocky beds and through lush grass. We stop to say hello to our nearest neighbors, two miles away.  And then we head here, to our wee cabin, settled in a mountain valley that ends in a 12,000-foot peak. 

It is our little piece of paradise.  From the cabin, we see mountains, trees, and meadow—not one house, not a sign of another human being.  My brother lives a quarter of a mile past us, but we cannot see his house, although we occasionally hear his dogs as they send bears up the trees and scare turkeys off into the meadow. I like the dogs and I love having my brother this close.

Our cabin is 480 square feet, one cozy room plus bath   The kitchen consists of antique cabinets and a skirted sink, something Laura Ingalls might relate to.  Except for the propane refrigerator and stove.

Our bedroom is tucked into a corner, with a four-poster walnut bed I bought at the Salvation Army in 1970, a few months before we were married—and it was an antique then.  Our living room and dining room are a hodgepodge of furniture from antique and junk shops and castoffs from our Iowa house and my parents’ home.  A wooden camping cooler my dad made is our coffee table and the desk is from our son’s room.  He refinished it sometime in the 80s.

We start the day with hot tea on the deck, then a hike, then breakfast on the deck.  Then Joe goes off to putter in the yard or cut down trees, or work in his little shop (aka shed) and I go inside to write or to putz around the cabin, rearranging this, moving that. At night, I have a hot magnesium drink as a nightcap and sit on the deck listening to the creek and watching the stars—you really can see billions and billions from here.

We have no light pollution because we have no lights. We are off the grid here, with solar power, propane gas, and well water.  Oh, and a compost toilet, which is far less nasty than you might think.  In fact, it is quite efficient and has no smell (as long as the fan is working).  Every week, though, we have to dump its drum, which makes our stay in paradise seem a little less idyllic.

Also on the downside is our Internet connection, which is dial-up and simply does not work.   Last year, satellite service came to the mountain but we have not yet signed on—we are waiting to see how it works, and reluctant to sign onto an expensive monthly contract for a place we live in for slightly more than three months. 

So the frequency of my blog posts drops every summer, as I simply don’t have the technology to effectively connect, and I have to wait until I go to town to do anything of any consequence online.  And my Facebook status updates get bunched together—several on one day, none for the rest of the week—for the same reason.

This is a beautiful place and it is ideal writing territory, so I am starting to work on my next book.  This location is not so great for communicating with the frequency with which we are all accustomed.  So my apologies for posting in bits and spurts.  Know that you are all on my mind as I relax and recharge.  And if you are heading north up I-25 between Trinidad and Walsenburg, Colorado, look to your left at the mountain looming there.  I am in its foothills.  Maybe writing.  Maybe staring at a pile of rocks called the East Spanish Peak.  

PHOTO:   This guy walked through the meadow across from out cabin the other day.  My husband Joe caught him, plus some early-morning rays.   NOTE:  And by "caught him" I meant on the camera.

More targeted therapy potential for TNBC: Protein RSK2

NEWS RELEASE

The Canadian Breast Cancer Foundation – BC/Yukon Region (CBCF) is thrilled to announce a game-changing discovery in triple-negative breast cancer (TNBC). This breakthrough points to one of the first personalized therapies for the treatment of TNBC and reports that RSK inhibition has the potential to block TNBC recurrence.

The breakthrough research of Canadian Breast Cancer Foundation – BC/Yukon Region’s (CBCF) Doctoral Breast Cancer Research Fellows Kristen Reipas and Dr. Anna Stratford will today be published in the highly recognized medical journal, Stem Cells.

Supported by University of British Columbia (UBC) Associate Professor in the Faculty of Medicine, Dr. Sandra Dunn, trainees Ms. Reipas and Dr. Stratford have identified a protein critical to the survival of triple-negative breast cancer (TNBC) patients. This breakthrough research has the potential to cure TNBC by targeting a protein called RSK2, which eliminates TNBC cells completely. The study, published June 5, 2012 in Stem Cells medical journal, reports that RSK2 inhibitors have the ability to kill all of the cells including cancer stem cells which give rise to cancer recurrence. This cutting-edge discovery will potentially personalize the treatment of TNBC on an international scale.

"RSK2 inhibition provides a novel therapeutic avenue for TNBC and holds the promise of being one of the first targeted therapies for this challenging form of breast cancer," says Dr. Sandra Dunn, UBC.

TNBC is diagnosed in approximately 400,000 women worldwide and is considered the most difficult breast cancer subtype to treat due to lack of effective therapies. Dr. Dunn’s laboratory at the Child & Family Research Institute at BC Children’s Hospital led the project in collaboration with scientists from Breakthrough Breast Cancer UK and the University of Aukland NZ.

This project began four years ago when UBC Post Doctorate Fellow Dr. Stratford of the Child & Family Research Institute was awarded $214,000 by CBCF BC/Yukon to support her research on this project entitled “The regulation of the Y-box binding protein-1 (YB-1) by p90 ribosomal S6 kinase (RSK) in triple-negative breast cancer.”

In addition, a doctoral candidate in the Experimental Medicine Program at UBC, Kristen Reipas was awarded $35,000 in support of this research study, entitled “Targeting Y-box binding protein-1 eliminates tumor-initiating cells and reduces relapse in triple-negative breast cancer.”

The BC/Yukon Region of CBCF is proud to award the Breast Cancer Research Postgraduate Fellowships every year to the most qualified breast cancer research projects across the province. These awards are intended for qualified health care professionals, MD graduates or recent PhD graduates to provide assistance in launching a career as independent, social, clinical or basic science investigator in breast cancer research.

Canadian Breast Cancer Foundation – BC/Yukon Region

The BC/Yukon Region of CBCF was established in 1992 to make a difference in breast cancer research and breast health for the BC population. Every year CBCF, along with its donors, sponsors and partners, raises funds to support unique and innovative initiatives in prevention, early detection, treatment, research and emerging issues in the health care workforce.

Will biomarkers help ID women with TNBC who benefit from taxanes?

NEWS RELEASE

CHICAGO, June 2, 2012 /PRNewswire via COMTEX/ -- TLE3 Biomarker Over-expressed in HER2-positive, Hormone Receptor-positive, and Triple-negative Breast Cancers --

EGFR status May Facilitate Therapeutic Decision-making in Head and Neck Cancer --

In a poster presentation today, Gargi Basu, Ph.D., and colleagues at Caris Life Sciences, presented results from the first study providing a comprehensive review of transducin-like enhancer of split 3 (TLE3) expression in breast cancer subtypes. They described TLE3 as a transcriptional repressor that influences tumor growth and microtubule stability; its expression in epithelial tumor cells may reflect that these cells require the expression of TL3 to maintain their undifferentiated state. The expression of TLE3 is also associated with response to taxane therapy in patients with breast cancer.

Working with tumor cells collected from 978 breast cancer patients, the investigators employed two different technological platforms used in Caris Target Now -immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) - to gather information on four biomarkers: TLE3 (M-201), ER(1D5), PR(PgR636), and human epidermal growth factor receptor 2 (HER2)/neu (Polyclonal). IHC analysis of the four biomarkers was conducted at the protein level, and FISH was used to determine amplification of HER2/neu. Samples were then sub-classified as hormone receptor (HR)-positive (i.e., estrogen receptor [ER]-positive and/or progesterone receptor [PR]- positive), HER2-positive (either at the protein level or amplified by FISH), or triple-negative (i.e., lacking in ER, PR, and HER2/neu).

Overall, 351 (36%) of the patients were HR-positive, 150 (15%) were HER2-positive, and 477 (49%) were triple-negative. TLE3 was expressed in 82% of the HR-positive patients, 73% of the HER2-positive patients, and 61% of the triple-negative patients. To further investigate TLE3 expression in the patient subtypes, Dr. Basu and colleagues performed a pairwise Fisher's Exact Test between the various pairs; this analysis revealed that for all pairs, the ratios of TLE3-expressing individuals were significantly different. The largest difference was observed between the HR-positives and the triple-negatives (82% vs. 61%, respectively; p=2.509e-10), suggesting that the HR-positives have a higher likelihood of responding to taxane therapy. The HER2-positives, at 73%, had a ratio that was significantly higher than the triple-negatives and significantly lower than the HR-positives.

"We found TLE3 to be over-expressed in the majority of patients with HER2-positive and hormone receptor-positive breast cancer," Dr. Basu observed. "Interestingly, the comparatively low over-expression of TLE3 in the triple-negative subtype makes it especially important to identify those patients in this group who are most likely to respond to taxane therapy. If physicians are provided with such knowledge prior to starting therapy, their chances of selecting appropriate regimens for patients with these subtypes of breast cancer may be greatly improved."

Micro RNAs may explain why African-Amercan and Caucasian Women React Differently to the Same Treatment

NEW RELEASE

Chicago, IL (PRWEB) June 02, 2012

Researchers and doctors at the North Shore-LIJ Health System and the Feinstein Institute for Medical Research have discovered a potential explanation for why breast cancer is not experienced the same way with African American and Caucasian patients. This data will be presented at the 2012 American Society of Clinical Oncology (ASCO) Annual Meeting to be held from Friday through Tuesday (June 1-5) in Chicago, IL.

Breast cancer is more common in Caucasian women than in African American women; however, African American women experience a more aggressive form of breast cancer that occurs almost a decade earlier than Caucasian women. Because of this, African American women have a lower breast cancer survival rate than Caucasian women. To explore the reasons why, researchers and doctors at the North Shore-LIJ Health System and the Feinstein Institute for Medical Research conducted a study to determine 1) why the expression of a genetic marker embedded in deoxyribonucleic acid (DNA), called microRNA, differs between African American and Caucasian women, and 2) if variation in microRNAs may explain the observed survival difference between African American and Caucasian women.

In this study, microRNA profiles from the blood of 32 female patients were collected before removal of breast tumors. The mean age of the patients was 50 years, ranging from age 31 to 68, and 10 of the patients had stage III triple-negative breast cancer (five were African American and five were Caucasian), 10 patients had stage III estrogen-receptor or progesterone-receptor positive breast cancer (five were African American and five were Caucasian), and 12 patients were controls (six were African American and six were Caucasian). Triple-negative breast cancer refers to any breast cancer that does not express three receptors known to advance most breast cancers; estrogen receptors, progesterone receptors and human epidermal growth factor receptor 2 (HER2). Although triple-negative breast cancer is estrogen-receptor negative, progesterone-receptor negative and HER2 negative, and the most successful treatments for breast cancer target these receptors, triple-negative breast cancer typically responds to chemotherapy.

The study found that, 1) female Caucasian patients who had triple-negative breast cancer overexpressed 20 microRNAs (15 times higher than the controls), and none of the microRNAs these patients had were found in any of the African American patients, 2) female African American breast cancer patients overexpressed only six microRNAs (15 times higher than the controls), and none of these microRNAs were detected in Caucasian patients who had triple-negative breast cancer, and 3) four microRNAs in African American patients and eight microRNAs in Caucasian patients were not previously reported in association with breast cancer, which suggests that they may be connected to how the patient reacts to cancer.

“The striking difference in the patterns of microRNA expression between African American and Caucasian breast cancer patients may provide insight into answering why, when receiving similar treatments, outcomes are different between African Americans and Caucasians,” said Iuliana Shapira, MD, director of the Cancer Genetics Program at the North Shore-LIJ Health System’s Monter Cancer Center. “Breast cancer patients who have the most devastating outcome may carry the microRNAs that promote cancer. What we saw in this study is that Caucasian women may carry microRNAs that protect against cancer while African American women do not express those microRNAs. The lack of expressing these microRNAs in African Americans could be the cause of poor outcomes seen in these women. Methods to increase microRNAs in the blood before surgery for cancer, such as giving chemotherapy before surgery for cancer, may improve survival rates in African American women with triple-negative breast cancer.”

About The Feinstein Institute for Medical Research
Headquartered in Manhasset, NY, The Feinstein Institute for Medical Research is home to international scientific leaders in cancer research, Parkinson's disease, Alzheimer’s disease, psychiatric disorders, rheumatoid arthritis, lupus, sepsis, inflammatory bowel disease, human genetics, pulmonary hypertension, leukemia, neuroimmunology, and medicinal chemistry. The Feinstein Institute, part of the North Shore-LIJ Health System, ranks in the top 5th percentile of all National Institutes of Health grants awarded to research centers. For more information visithttp://www.FeinsteinInstitute.org.

Seeing Hope for Patients with Metastatic Breast Cancer

Medpage Today published an interview with  Dr. Carey Anders of the University of North Carolina in Chapel Hill.  Dr. Anders has written a great deal about triple negative breast cancer.  In this piece, she talks about targeted therapies for TNBC and her hope for the future of treatment for metastatic breast cancer.  My favorite part of the interview comes at the end, when she talks about being an oncologist and how she sees her relationship with her patients: 

I'm always struck when people outside of the hospital or even within the hospital find out that I'm an oncologist. They kind of get a sad look on their face and say, "Oh, that must be so hard," and I promptly reply that it's a very positive profession. On most days -- of course, we have our sad days -- but on most days it's a very hopeful profession and a happy profession. We have such wonderful relationships with our patients and families and are working with them in a very poignant time in their life.

I'm very enthusiastic about what we have on the horizon in breast cancer. We're learning so much more in the laboratory about what makes the cancer cells work. And over time that will translate to targeted therapies with the goal of really helping prolong survival, but not making patients experience the side effects in the process. So I'm very enthusiastic.

You can read the transcript or watch the video at Medpage Today. 

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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