Archive for the ‘BRCA’ Category

Triple-Negative Breast Cancer Characteristized in Younger Breast Cancer Patients

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Posted 28 Oct 2011 — by James Street
Category BRCA, BRCA1, Breast Cancer, HER2/neu
By Anna Azvolinsky, PhD | October 27, 2011
 A study published online in the Journal of Clinical Oncology analyzed triple-negative breast cancer (TNBC) for distinguishing characteristics. The study compared clinical, pathological, and hormone-related lifestyle characteristics of 1,469 women aged twenty to forty-nine. The authors found Ashkenazi Jewish women with a BRCA1 mutation to have a five-fold higher chance of having TNBC compared to non-Ashkenazi Jewish women.

BRCA1-Gene located on chromosome 17, Courtesy of Armin Kübelbeck, Wikimedia Commons

TNBC in general was associated with:

• a younger age

• a higher tumor grade at diagnosis

•  BRCA1 mutant status (48% of BRCA1 mutant carriers had TNBC, compared with only 12% of non-carriers in the study)

The TNBC women analyzed who were not BRCA1 mutation carriers had higher premenopausal body mass index and earlier age at first full-term pregnancy than those with non-TNBC. Age of first menstruation and other reproductive factors were not found to be associated with a triple-negative status.

TNBC is negative for estrogen receptors, progesterone(Drug information on progesterone) receptors, and HER2, meaning that growth of the cancer is not supported by the hormones estrogen and progesterone, nor by the presence of many HER2 receptors on the cancer cells. For this reason triple-negative breast cancers are not responsive to hormonal therapies such as tamoxifen(Drug information on tamoxifen) or aromatase inhibitors or HER2-targeted trastuzumab(Drug information on trastuzumab).

Approximately 10% to 17% of breast cancers are triple negative and many of these are associated with a BRCA1 mutation. TNBC is difficult to treat because it’s diagnosis is a “lack of” mutation status rather than the presence of mutations that have targeted treatment developed for them. Typical treatment is a combination of therapies such as radiation, chemotherapy, and surgery with novel agents in clinical trials for this indication.

Research explains mystery of the BRCA1 breast cancer gene

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Posted 09 Sep 2011 — by James Street
Category BRCA, BRCA1, Breast Cancer

Doctors have long known that women with a mutated version of the BRCA1 gene face a significantly higher risk of developing breast cancer because their bodies can’t properly repair damaged DNA.

However, the biological mechanisms behind that problem have been unknown.

New research led by scientists from The Salk Institute in La Jolla appears to have cracked some of that mystery and, along the way, uncovered a potential method for detecting breast cancer much earlier than mammograms are capable of doing.

“This allows us to design search strategies for future therapies, both to prevent inherited breast cancer and also to treat the cancers that have already developed,” said Salk biologist Gerald Pao.

The damaged BRCA1 gene is responsible for about 5 percent of the 230,000 new cases of breast cancer diagnosed each year in the United States, according to the National Cancer Institute.

The results of the work by Pao and seven collaborators from Salk, the Netherlands Cancer Institute, Beth Israel Medical Center in New York and the Cleveland Clinic, were published Thursday in the prestigious scientific journal Nature.

Using laboratory mice that were genetically engineered to lack the BRCA1 gene, the scientists found that a certain portion of DNA in the animals’ breast and brain cells weren’t packaged as tightly as it was when the gene was present.

The researchers made the same observations in breast tumor cells taken from humans.

The genetic material is part of a large portion of the genetic code known as “junk” DNA that traditionally was believed to play little or no role in cellular function.

However, more recent research has revealed that some junk DNA actually does contribute to certain cell operations.

In this case, when the junk DNA observed by Pao and his colleagues was loosely packaged it produced RNA (messenger genetic coding) that caused breaks in other parts of the DNA and interfered with normal cell division.

“If you don’t package your DNA correctly, that can lead to all sorts of problems,” Pao said.

The rogue genetic coding is also known as satellite DNA because of its remote position in relation to the main cluster of genetic material.

The initial discovery came seven years ago when Pao and Quan Zhu, a fellow cancer biologist at Salk, accidentally stumbled across the packaging problem.

“One night, Quan and I were looking under the microscope,” Pao said. “Just by chance, we saw that the DNA wasn’t packaged correctly.”

A blood test capable of detecting the RNA produced by the loosened junk DNA could provide an earlier way of diagnosing breast cancer, particularly in younger women whose healthy firmer breast tissue often hides tumors in mammograms, Pao said.

Before that happens, researchers must conclusively tie the disease to the genetic problems triggered by the loose bundling of the junk DNA.

While the work by Pao and his colleagues stopped short of that achievement, the effort still “might herald a breakthrough,” wrote Cambridge Cancer Centre researcher Ashok Venkitaraman in a review of the research that accompanied the Nature publication.

“Regardless of the remaining ambiguities, in describing an association between satellite DNA transcription, BRCA1 loss and genomic instability, (the) work reveals an intriguing new pathway for tumor suppression,” said Venkitaraman, who was not involved in the research.

Battle Over Gene Patents Most Likely Headed to Supreme Court Posted: 8/21/11 04:13 PM ET

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Posted 21 Aug 2011 — by James Street
Category BRCA, Breast Cancer, Finance and Politics of cancer research and treatment, genetic research, Ovarian

Wake Forest University Law Professor

Posted: 8/21/11 04:13 PM ET

Courts need to be the keepers of the Constitution. But the Federal Circuit has failed its duty in the current battle over the patentability of isolated genes and gene sequences that are crucial to the fight against breast and ovarian cancer.

First some history.

The BRCA genes, which contain proteins that inhibit tumor growth, currently occupy center stage in the legal fight over the patentability of isolated genes and gene sequences.

Scientists at the University of Utah first cloned these genes after it was found that mutations in the BRCA1 and BRCA2 genes were linked to various types of breast and ovarian cancer.

Myriad Genetics is the exclusive licensee of the family of patents relating to these isolated genes and genes sequences. As a result, the company controls all sequencing of the BRCA genes as well as the diagnostic testing for the BRCA mutations.

Myriad, however, refuses to grant any licenses for second-opinion BRCA testing. The limited research licenses it has granted are severely restrictive and often prevent research scientists from disclosing the BRCA test results to their test subjects.

As a result of this restrictive licensing, the Association for Molecular Pathology, a non-profit scientific society, along with research scientists, women’s organizations and individuals, challenged the validity of the BRCA isolated gene patents in federal court on Feb. 4, 2010.

The plaintiffs argued that they were unable to access these unpatentable “products of nature” without being subject to an immediate lawsuit for patent infringement. The female plaintiffs further argued that the BRCA isolated gene and method patents gave Myriad an unconstitutional monopoly of this subject matter that prohibited them from acquiring access to life-saving information about their own genes.

In the initial ruling, the United States District Court of the Southern District of New York invalidated the isolated gene patents as patent-ineligible products of nature under the Patent Act since they were not “markedly different” from their naturally occurring counterparts, as required by the leading Supreme Court case, Diamond v. Chakrabarty.

Unfortunately, on July 29, 2011, the Federal Circuit Court of Appeals reversed the District Court. It held that the breaking of chemical bonds during the isolation process produces genetic material that constitutes “a distinct chemical entity” which is smaller and allows for the “new utility” of detecting the BRCA mutations. As such, the BRCA isolated genes and sequences are “markedly different” from the naturally occurring or “native” genes and are patent-eligible subject matter.

The majority and concurring opinions gave great weight to the Patent Office’s long-standing position that isolated genes are patentable. Judge Kimberly Moore’s concurring opinion further emphasized that to hold otherwise would be detrimental to the biotechnology industry that has relied on gene patenting — 20 percent of the human genome is currently patented — to fund continued genomic research and development.

As a former registered Patent Attorney, one question immediately came to mind after reading the Federal Circuit’s majority and concurring opinions.

How can the court allow chemical differences to supersede biological equivalence when the specific utility of the invention, namely detecting mutations linked to breast and ovarian cancer, depends on biological identity? Chemically modifying an isolated gene does not alter its biological heart (nucleotide sequence). Accurately detecting BRCA mutations would be impossible without this biological identity.

Although promoting innovation is a laudable goal, the Federal Circuit’s broadening of what constitutes patent-eligible subject matter missed the bigger Constitutional target.

The Intellectual Property clause of the Constitution empowers Congress to grant exclusive rights, such as patents and copyrights, for “limited timed times to promote Progress of Science and the Useful Arts.”

The Constitutional mandate to promote progress includes more than stimulating innovation and must include balancing any grant of exclusive rights against providing access to basic knowledge. Patenting products of nature such as isolated genes and gene sequences prevents access to these basic research tools during the term of the patent. This impedes rather than promotes progress and is therefore in direct violation of the IP clause.

It is the role of Federal Courts, as the keeper of the Constitution, to ensure that any analysis of the plain language of Section 101 of the Patent Act and controlling case law is in harmony with the Constitutional mandate to promote progress of the useful arts.

The Federal Circuit should have taken this role seriously and upheld the lower court’s invalidation of the BRCA isolated genes and gene sequence patents as patent-ineligible subject matter. Viewing these genes as chemically different despite their biological equivalence is cheating the system.

If the BRCA gene patents were invalidated, Congress could then step in and legislate a new “Constitutional” framework of exclusive rights for this subject matter. Congress would likely gather industry, academic and public stakeholders together to craft a hybrid statute that would promote innovation as well as provide much-needed access to these basic upstream research tools.

Given the strong desires of the plaintiffs in the Molecular Pathology case to gain greater access to the isolated BRCA genes for the public, an appeal for an en banc hearing by the Federal Circuit or an appeal directly to the Supreme Court is likely.

I remain hopeful that the reviewing Court will be mindful of its role as the keeper of the Constitution and interpret the Patent Act’s subject matter limitation to exclude the BRCA genes as patent-ineligible products of nature. Only then, can we begin the appropriate legislative dialogue on drafting a “progress-promoting” isolated bioproducts statute which properly balances access against innovation.

This is going to be a long conversation and the courts must ensure that the public gains uniform access to these much-needed basic research tools.

Wake Forest University Law Professor Simone Rose’s research specializes in the intersection of patent law with biotechnology and stem cell research.