SABCS: Are Common Bone Drugs the TNBC Follow-Up Treatment We’ve Been Seeking?

They reduce the risk of bone metastases following breast cancer in post-menopausal women by 34 percent. And they reduce the risk of death in that same group by 17 percent, regardless of receptor status, node involvement or previous chemotherapy.  

They’re common bisphosphonates, drugs used to build our bones, such as Zometa and Reclast.

This could be a game changer, says Rob Coleman, M.D., who presented the findings at the 2013 San Antonio Breast Cancer Symposium today.  “We finally have defined an addition to standard treatment.”  

Coleman, of the Sheffield Cancer Research Center in England, says he is likely to recommend bisphosphonates to his postmenopausal patients.  They present “at least as large a benefit as the agents we use presently,” he says.

For triple-negative breast cancer patients, bisphosphonates may represent an elusive follow-up drug.  Because TNBC tumors are not fueled by hormones they do not respond to common post-cancer estrogen-fighting drugs  such as tamoxifen or Arimidex.

The results, part of of the Early Breast Cancer Trialists' Collaborative Group (EBCTCG)'s Bisphosphonate Working Group, represent data from multiple studies on nearly 18,000 patients. They hold true for two broad types of bisphosphonates: zoledronic acid (Zometa, Zomera, Aclasta and Reclast) or clodronates (Bonefos, Clasteon, Loron).

The results apply only to postmenopausal patients—natural or chemotherapy-induced. Premenopausal women did not see any cancer-fighting benefit from bisphosphonates.

It’s essential that bisphosphonates be given early in treatment, Coleman 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!

SOURCE:

[S4-07] Effects of bisphosphonate treatment on recurrence and cause-specific mortality in women with early breast cancer: A meta-analysis of individual patient data from randomized trials. 

Coleman R, Gnant M, Paterson A, Powles T, von Minckwitz G, Pritchard K, Bergh J, Bliss J, Gralow J, Anderson S, Evans V, Pan H, Bradley R, Davies C, Gray R, On Behalf of the Early Breast Cancer Trialists' Collaborative Group (EBCTCG)'s Bisphosphonate Working Group. Sheffield Cancer Research Centre

Are You At Risk of the BRCA Mutation?

The good news on BRCA screening is that the U.S. Supreme Court's decision to ban gene patenting opens the field up to more competition. And more competition means lower prices.  Already, costs have been reduced from 20 percent to more than 40 percent from before the decision last June, according to several industry reps I talked to today at the San Antonio Breast Cancer Symposium.  Ideally, competition will also lead to better quality, with reduced errors such as false positives.

If you have not taken the test to determine whether you are at risk of the BRCA mutation, there's an easy start online, the hereditary cancer quiz.  Risk factors for the BRCA mutations include:

• Ashkenazi Jewish women with one first degree relative or two second degree relatives on the same side of the family with breast or ovarian cancer
• Non-Ashkenazi Jewish women who have:
  • two first-degree relatives who had breast cancer; at least one of these two were diagnosed before age 50;
  • three or more first- or second-degree relatives with breast cancer regardless of age at diagnosis;
  • a combination of both breast and ovarian cancer among first- and second-degree relatives;
  • a first-degree relative with bilateral breast cancer;
  • a combination of two or more first- or second- degree relatives with ovarian cancer, regardless of age at diagnosis;
  • a first- or second- degree relative with both breast and ovarian cancer at any age; or
  • a history of breast cancer in a male relative

If you might be at risk, check with your doctor.  Tests are now covered by insurance.

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!

SABCS: Lymphocytes May Signal Chemo Response in TNBC

Tumor-infiltrating lymphocytes may become an additional factor in determining which types of triple-negative breast cancer respond best to chemotherapy.  Seventy-five percent of tumors with the highest levels of lymphocytes—researchers call this lymphocyte predominate breast cancer (LPBC)—had a pathological complete response to doxorubicin and taxane plus carboplatin when compared to non-LPBC tumors. The results came from the GeparSixto trial (GBG 66) in Germany.

Pathologically complete response is especially important in disease-free survival of TNBC.

Triple-negative tumors typically have more lymphocytes than other types of breast cancer, but not all lymphocytes are created equal.  Tumors with CD8t  lymphocytes are associated with a strong response, while those with myeloid are not, according to the GeparQuattro trial conducted in Australia.

Researchers speculate that CD8t  lymphocytes work with the immune system to make chemo more effective.

Both studies were presented at the 2013 San Antonio Breast Cancer Symposium.  

For another take on the research, check out Medscape's piece.

SABCS: Managing Metastatic TNBC

Lisa Carey, M.D., of the University of North Carolina, provided an update on the management of metastatic triple-negative breast cancer at the 2013 San Antonio Breast Cancer Symposium today.  It was a clear overview of previous research, demonstrating that TNBC is a family of diseases, with varying subtypes that react differently to treatment. 

Some of her points:

• 49 percent of all TNBC cases are basal-like.

• 30 percent are claudin-low, a new subtype that researchers are just beginning to understand.

• Preclinical studies show that platinum drugs may be especially effective against basal-like TNBC.

• Conventional chemotherapy is effective against metastatic TNBC; however, as with all stage IV disease, the duration of response is often short. Several studies have found median survival after diagnosis of stage IV disease of approximately 1-2 years.

• PARP inhibitors are effective against BRCA-associated TNBC.

• Weekly paclitaxel was more effective than ixabepilone and less toxic than albumin-bound nab-paclitaxel in the CALGB 40502 study.

• Eribulin (a halichondrin B analogue) was effective in the EMBRACE study.

• A phase III comparison of eribulin and capecitabine may show a slight advantage for TNBC.

• Both eribulin and capecitabine are “reasonable choices” for TNBC. 

• Alternatives include anthracyclines, platinum drugs, gemcitabine, and doublet regimens.

• Bevacizamab (Avastin) plus chemo improved progression-free survival in metastatic TNBC but had zero effect on overall survival.  Researchers do not know why.

• Randomized clinical trials are ongoing.

• Androgen-fighting drugs may successfully fight androgen-sensitive subsets of TNBC, as demonstrated at last year's SABCS.

"To advance therapy in metastastic TNBC, we will need to better match the tumor to the target," she said.  TNBC may demonstrate that the old strategy of "one size fits all" treatment no longer works for any type of cancer.

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!

Rutgers Taking a Holistic Look at Cancer

The goal is to pinpoint treatment to specific genetic traits

One of the most significant recent breakthroughs in the war on cancer is the rise of precision medicine, the process of identifying the tiniest molecular and genomic details within a cancer, then using those details to fine-tune treatment. 

An explosion in knowledge about the genetic mutations that cause tumors allows physicians to pinpoint DNA changes that drive cancer cells and tailor treatments faster and more confidently, based on each patient's genetic profile.

“What we have learned through the years is that cancer is not a single disease, but rather a collection of diseases, each with unique features,” says Shridar Ganesan, associate director for translational science at Rutgers Cancer Institute of New Jersey and associate professor of medicine at Rutgers Robert Wood Johnson Medical School. 

“Instead of determining cancer type only by the organ in which it originates, time-saving genomic analysis opens the door for additional classification by the set of changes present in each cancer, which can guide more precise, or tailored, therapy,” notes Ganesan, a medical oncologist.

Despite these advances, cancer treatment remains a race against time – a struggle to find the best way to beat the disease.

Enter Big Data.

Aided by supercomputing resources, Rutgers doctors and scientists are analyzing genomes and human tissues – and identifying cancer patterns – far faster than ever before.

This novel approach to cancer diagnosis and treatment teams physicians, scientists, pathologists, geneticists, systems biologists and others from the Cancer Institute with computer engineering experts at the Rutgers Discovery Informatics Institute (RDI²). Enhancing the relationship further is collaboration with another university entity – RUCDR Infinite Biologics, the world’s largest university-based biorepository, located within the Human Genetics Institute of New Jersey.  

“We have the latest technology to come up with potential solutions very fast,” says Manish Parashar, director of RDI² and professor in the Rutgers School of Engineering’s Department of Electrical and Computer Engineering. 

The scientists at RDI² receive patient tissue samples from the Cancer Institute that have been digitized at high-resolution and work closely with the institute’s medical imaging experts to understand the computational and data challenges and come up with a treatment plan.

“Our team provides the computational engine to review thousands of images, so our collaborators at the Cancer Institute can analyze these images, search the database, test hypotheses and answer important questions,” Parashar says. “We take the imaged samples and radiology studies from one patient and ask, ’Have I seen a case like this before?’”

By optimizing the data mining and pattern matching algorithms developed by a research team led by David J. Foran, bioinformatics executive director at the Cancer Institute, the software can be run in a high-performance computing environment. “That way the analysis can be completed in a matter of minutes, rather than days, ” Parashar says.  

Data crunching and analytics expertise provided by RDI² and biomaterials and technical support from RUCDR Infinite Biologics – coupled with evaluation by a team of scientific, clinical and bioinformatics experts at the Cancer Institute – is shaping a revolution in how best to determine therapy – a vast improvement over the time-intensive, trial-and-error approach that clinicians have faced for years.  

While other U.S. cancer centers engage precision medicine experts to target the more common breast and prostate cancers, the Cancer Institute at Rutgers is believed to be one of the few centers addressing the challenges of rare and poor prognosis cancers – such as ovarian cancers, pancreatic cancers, sarcomas and certain pediatric cancers – for which traditional therapies usually aren’t working.  A clinical trial there is focused on the genomic makeup of a tumor, offering hope to poor prognosis patients.

Potential to Spur New Partnerships

The partnership between the Cancer Institute and RDI² evolved from joint projects over several years, while Cancer Institute investigators have benefited from research sequencing capabilities from RUCDR Infinite Biologics since 2012. The collaborations grew even stronger over the past several months as Rutgers prepared to integrate with the Cancer Institute and most of the other schools, centers and institutes that made up the former University of Medicine and Dentistry of New Jersey. The Cancer Institute of New Jersey, along with most of the former UMDNJ, joined Rutgers on July 1.

Such an enriched research environment is conducive to groundbreaking discoveries and new treatment options – allowing New Jerseyans to remain close to home to receive the most advanced cancer care. 

 “Joining forces and areas of expertise offers Rutgers the opportunity to develop customized approaches for extracting genomic information from tumors, interpret the genomic variation and offer options to patients that may not be available elsewhere,” says Jay A. Tischfield, scientific director and CEO of RUCDR Infinite Biologics. In addition, the enhanced collaboration has the potential to spur new partnerships with pharmaceutical and biotechnology companies and additional grant-funding opportunities.

This initiative also provides an opportunity to invest in the future of the precision medicine field, enabling students from Robert Wood Johnson Medical School and the School of Engineering to work together, Parashar says. “This allows them to talk to both sides: precision medicine pathology and the radiology side, as well as the computer science and computer engineering side.

“That’s one of the key goals – getting students equipped with the necessary multidisciplinary skills that combine understanding how to deal with Big Data and understanding the science you want to do with it,” Parashar says.

[Release from Rutgers University]

The Brain, not just the ovaries, produces estrogen

MADISON, Wis. - A University of Wisconsin-Madison research team reports today that the brain can produce and release estrogen—a discovery that may lead to a better understanding of hormonal changes observed from before birth throughout the entire aging process.

The new research shows that the hypothalamus can directly control reproductive function in rhesus monkeys and very likely performs the same action in women.

Scientists have known for about 80 years that the hypothalamus, a region in the brain, is involved in regulating the menstrual cycle and reproduction. Within the past 40 years, they predicted the presence of neural estrogens, but they did not know whether the brain could actually make and release estrogen.

Most estrogens, such as estradiol, a primary hormone that controls the menstrual cycle, are produced in the ovaries. Estradiol circulates throughout the body, including the brain and pituitary gland, and influences reproduction, body weight, and learning and memory. As a result, many normal functions are compromised when the ovaries are removed or lose their function after menopause.  

"Discovering that the hypothalamus can rapidly produce large amounts of estradiol and participate in control of gonadotropin-releasing hormone neurons surprised us," says Ei Terasawa, professor of pediatrics at the UW School of Medicine and Public Health and senior scientist at the Wisconsin National Primate Research Center. "These findings not only shift the concept of how reproductive function and behavior is regulated but have real implications for understanding and treating a number of diseases and disorders."

For diseases that may be linked to estrogen imbalances, such as Alzheimer's disease, stroke, depression, experimental autoimmune encephalomyelitis and other autoimmune disorders, the hypothalamus may become a novel area for drug targeting, Terasawa says. "Results such as these can point us in new research directions and find new diagnostic tools and treatments for neuroendocrine diseases."

The study, published today in the Journal of Neuroscience, "opens up entirely new avenues of research into human reproduction and development, as well as the role of estrogen action as our bodies age," reports the first author of the paper, Brian Kenealy, who earned his Ph.D. this summer in the Endocrinology and Reproductive Physiology Program at UW-Madison. Kenealy performed three studies. In the first experiment, a brief infusion of estradiol benzoate administered into the hypothalamus of rhesus monkeys that had surgery to remove their ovaries rapidly stimulated GnRH release. The brain took over and began rapidly releasing this estrogen in large pulsing surges.

In the second experiment, mild electrical stimulation of the hypothalamus caused the release of both estrogen and GnRH (thus mimicking how estrogen could induce a neurotransmitter-like action). Third, the research team infused letrazole, an aromatase inhibitor that blocks the synthesis of estrogen, resulting in a lack of estrogen as well as GnRH release from the brain. Together, these methods demonstrated how local synthesis of estrogen in the brain is important in regulating reproductive function.

The reproductive, neurological and immune systems of rhesus macaques have proven to be excellent biomedical models for humans over several decades, says Terasawa, who focuses on the neural and endocrine mechanisms that control the initiation of puberty. "This work is further proof that these animals can teach us about so many basic functions we don't fully understand in humans."

Leading up to this discovery, Terasawa said, recent evidence had shown that estrogen acting as a neurotransmitter in the brain rapidly induced sexual behavior in quails and rats. Kenealy's work is the first evidence of this local hypothalamic action in primates, and in those that don't even have ovaries.

"The discovery that the primate brain can make estrogen is key to a better understanding of hormonal changes observed during every phase of development, from prenatal to puberty, and throughout adulthood, including aging," Kenealy says.

High Fat Diet in Puberty Linked to Basal-Like Breast Cancer

Young women who eat excess amounts of saturated fats during their teenage years increase their risk of basal-like breast cancer, according to a study published in Breast Cancer Research. Many basal-like tumors are also triple-negative.

In research conducted on mice, scientists at Michigan State University found that a diet high in saturated animal fat caused excess cell growth that altered the normal structure of the breast and altered immune cells.

And the effects of the high-fat diet were found even if the mice did not gain weight.  That means that the "findings are relevant to a much broader segment of the population than just those who are overweight," according to microbiology professor and co-author researcher Richard Schwartz. "This shows the culprit is the fat itself rather than weight gain."

• 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.  
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Is Engrailed 1 the key to metastases in basal-like tumors?

Lab research points to an over expression of the protein Engrailed 1 in basal-like tumors, which may be why these tumors are more likely to metastasize.  Scientists have developed a chain of amino acids to fight the protein, which is not present in non-basal tumors.  The treatment will have to be tested through clinical trials.

Researchers at the UNC School of Medicine, working with cell lines in a lab, have discovered why some of the most aggressive and fatal breast cancer cells are resistant to chemotherapy, and UNC scientists are developing ways to overcome such resistance.

"Patients with basal-like breast cancer tend to initially respond well to chemotherapy, but it's common for patients to relapse even more aggressively," said Beltran, the first author of a paper published in the journal Oncogene. "We believe that relapse is caused by a small number of cancer cells that have stem cell properties that allow them to survive chemotherapy. In these cells we've identified the overexpression of Engrailed 1."

Adriana S. Beltran, PhD, a research assistant professor in the department of pharmacology, found that the protein Engrailed 1 is overexpressed in basal-like carcinomas and designed a chain of amino acids to shut down the protein and kill basal-like tumors in the lab.

Beltran and her colleagues – UNC pharmacologist Lee Graves, PhD, and former UNC pharmacologist Pilar Blancafort, PhD – discovered that Engrailed 1 is not involved in the rapid proliferation of cells that cause tumor growth. Nor is Engrailed 1 present in luminal tumors – the most common form of breast cancer. The culprit protein only appears in basal-like breast cancer.

In fact, Engrailed 1 is normally confined to the brain, where it protects neurons from cell death and helps maintain their normal activity. The absence of the protein in the brain has been linked to the onset of Parkinson's disease. But there is no known function of Engrailed 1 within breast tissue.

"We think that Engrailed 1 confers protective features to breast cancer cells, similar to the features observed in long-lived neurons," Beltran said. "This may explain why these cells survive and become resistant to chemotherapy in our experiments."

The researchers found Engrailed 1 through a series of experiments designed to find genes highly expressed in basal-like cells but not in luminal breast cancers. They discovered that Engrailed 1was most highly expressed in cell lines isolated frominflammatory breast cancer. Working with the UNC Michael Hooker Proteomics Center, Beltran and colleagues also determined that Engrailed 1 was associated with the gene EPRS, which expresses an enzyme that controls messenger RNA and protein synthesis, particularly in proteins involved with inflammation.

"Inflammation is associated with cancer development," Beltran said. "It's interesting to us that Engrailed 1, alone, is able to control inflammatory responses that may promote more aggressive forms of cancer.

Why Engrailed 1 is manifested in cancerous breast tissue remains a mystery. "Nature seems to always find a way," Beltran said. "Cancer cells are part of nature; everything in nature strives to survive."

But Beltran and her colleagues might have found a way to stop Engrailed 1. After studying how Engrailed 1 binds to DNA and other proteins, the researchers created a synthetic peptide – a chain of amino acids – that can stifle the binding power of Engrailed 1. In cell lines – not in animals or patients – Beltran and colleagues used their peptide to disrupt Engrailed 1 from binding to its protein partners and DNA.

"Cancer cells need Engrailed 1 to live," Beltran said. "The peptide abolishes all interactions of Engrailed 1, and as a consequence Engrailed 1 cannot perform its functions, causing rapid cell death of the cancer cell.

"The goal now is to validate our findings in animal models."

If Engrailed 1 turns out to be as critical to basal-like metastasis as it seems from this basic research, then a drug could be developed to fight cancer relapse in some of most deadly forms of breast cancer.

From the University of North Carolina Health Care.

• 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!