New Study Reveals Six Distinct Subtypes Of Triple-Negative Breast Cancer That Respond Differently To Chemotherapy

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Main Category: Breast Cancer
Also Included In: Cancer / Oncology
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"Triple-negative breast cancer (TNBC)", is one of the most life threatening forms of breast cancer. It is aggressive, least responsive to standard therapy and accounts for 10 to 20 percent of all breast cancers. In a recent breakthrough six distinct subtypes of this cancer have been recognized by scientists from the Vanderbilt-Ingram Cancer Center.

Molecular features of these six distinct subtypes have been described by the Director of the Cancer Center Jennifer Pietenpol, Ph.D., and colleagues in the July issue of the Journal of Clinical Investigation. As reported in the article, the response of all six cancer subtypes to chemotherapies was assessed both in culture cells as well as animal models. The authors further stated that the ability to determine the specific subtype of TNBC would enable the physicians to prescribe targeted chemotherapy to patients suffering from this disease. It would also pave the way for discovery and development of new drugs to cure this difficult-to-treat form of breast cancer.

Dr. J. Pietenpol writes:

"It's a pretty significant health problem from the standpoint that 11 percent of Caucasians, 17 percent of Hispanics, and 25 percent of African-Americans have this type of breast cancer."

Standard chemotherapy works well for some patients for an initial period of treatment, but eventually the tumors recur. Recurrence is followed by poor prognosis (due to lack of targeted therapy), and statistics reveal that more than 70% of patients with metastatic TNBC survive for less than 5 years.

The term "triple-negative breast cancer," said Dr. Pietenpol, "is just a definition of what (the cancer) isn't."

Approximately 60% of breast cancers are driven by estrogen receptors (ER) and progesterone receptors (PR), and another 20-30% by the HER2 receptors. All three of these receptors are absent in patients with TNBC, thus the name 'triple-negative'. The absence of these receptors means that the tumors are less likely to respond to hormone therapies like tamoxifen and to therapies targeted to HER2 like trastuzumab (Herceptin).

587 cases of TNBC among 21 publicly-available breast cancer data sets were identified by Postdoctoral fellows Brian Lehmann, Ph.D., and Joshua Bauer, Ph.D., along with biostatistician Xi (Steven) Chen, Ph.D. Upon analysis of the genomic data, unique gene expression profiles (sets of genes that are either turned "up" or "down" in the tumors) were revealed.

The six distinct subtypes identified by the researchers were - two "mesenchymal" types (M and MSL) controlled by genes associated with cell differentiation and growth factor pathways; two "basal-like" types (BL1 and BL2) linked with cell cycle and DNA damage response genes; an "immunomodulatory" (IM) group, controlled by the genes of the immune system; and a "luminal" subgroup (LAR) driven by the "male" sex hormone (androgen) signaling.

Cell lines that represented each one of the six distinct subtypes were determined and a number of available chemotherapies were tested in them by the researchers. Animal models of these distinct tumor subtypes were also generated by implanting the identified cells into mice.

Scientists found that the mesenchymal-like subtypes (M and MSL) responded to dasatinib and experimental drug NVP-BEZ235; basal-like subtypes (BL1 and BL2) responded to cisplatin; and the LAR subtypes were sensitive to bicalutamide.

The results of this study have outlined an approach to identify molecular differences within this form of breast cancer and also informs about various molecular targets for each subtype. This study can help to significantly advance drug discovery and development efforts for TNBC.

Dr. Pietenpol said:

"In our opinion, the big breakthrough is just being able to say 'this isn't one disease.' Being able to distinguish distinct biological subtypes of TNBC could help guide the design of select clinical trials for subtypes of breast cancer, point toward new biomarkers for patient selection for a given therapy, and identify new targets for drug discovery. This really is the first step in translating genomic information into personalizing therapy for women with a very difficult-to-treat breast cancer."

"Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies"
Brian D. Lehmann, Joshua A. Bauer, Xi Chen, Melinda E. Sanders, A. Bapsi Chakravarthy, Yu Shyr and Jennifer A. Pietenpol
J Clin Invest. doi:10.1172/JCI45014.

Written by Barry Windsor

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posted by Arnold Glazier, MD on 1 Jul 2011 at 9:18 am

The scientific data and evidence are clear and unambiguous. Cancer is an unpredictable, stochastic evolutionary process. At the genetic and epigenetic level, every patient’s cancer is different and every cancer cell in a patient is also different and generally has thousands of unique genetic alterations. The number of different types of cancer cells that could evolve is estimated to exceed 10 to he 68,000 power (i.e., 1 followed by 68,000 zeroes).

The empirical characterization of a sample or sub-set of cancer cells from a patient provides inadequate information to comprehensively target all the cancer cells in the patient. There is no such thing as a representative sample of cancer cells. Every cancer cell is different. Given billions of cancers present in a patient it is likely that some cells will have evolved that lack a particular target or which are resistant to targeted therapy. Drug resistance has been observed to all drugs that target particular genetic alterations. A single cancer cell that evades therapy can potentially cause progressive disease.

Although the genetic and epigenetic complexity of cancer is nearly unlimited, tumor cell evolution is constrained. For a discussion of the constraints to tumor cell evolution and requirements for the cure or control of cancer please read or listen to the three-part New Cancer Mentality interview series, Cancer in the Post-Genomic Era: Where do we go from here? What will it take to prevent, cure, or control cancer? An Overview on the Requirement for the Cure of Cancer is at:
http://www.curecancerproject.org/beta/media/Overview%20on%20Requirements.pdf
Thank you. Arnold Glazier, M.D.

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Nile Therapeutics Phase 2 Study Of CD-NP In Patients With Acute Decompensated Heart Failure Meets Primary Endpoint, Has Good Trends On Renal Function

Main Category: Heart Disease
Also Included In: Urology / Nephrology;  Clinical Trials / Drug Trials;  Pharma Industry / Biotech Industry
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Nile Therapeutics, Inc. (Nasdaq: NLTX), a biopharmaceutical company focused on the development of novel therapeutics for cardiovascular disease, announced results of its Phase 2 study evaluating its lead compound CD-NP in patients with acute decompensated heart failure (ADHF) and mild to moderate renal insufficiency. Study results demonstrated that multiple doses were characterized as well tolerated with favorable drug activity in this acute patient population.

The open-label, single-blind, placebo-controlled Phase 2 study included 77 patients who were randomized into six cohorts at one of four doses of CD-NP (1.25, 2.5, 3.75 and 5 ng/kg/min) or placebo. Two cohorts were enrolled at each of the 1.25 and 2.5 ng/kg/min dose levels. Patients received study drug for up to 72 hours and were followed for 30 days. The primary objective of the study was to assess the safety and tolerability of CD-NP in a renally compromised ADHF population, the intended population of the therapy. Secondary endpoints included several assessments of drug activity.

CD-NP infusion at 1.25, 2.5 and 3.75 ng/kg/min appeared to be well tolerated. A dose-dependent effect on blood pressure was observed, with minimal or mild blood pressure reduction at 1.25 and 2.5 ng/kg/min, and moderate blood pressure reduction at 3.75 ng/kg/min. Dose escalation was limited by significant blood pressure reduction at 5 ng/kg/min.

Secondary and exploratory analyses demonstrated favorable effects of CD-NP on renal function, particularly at the 1.25 and 2.5 ng/kg/min doses. At these doses, CD-NP appeared to preserve or enhance renal function compared to placebo, as evidenced by favorable trends in several biomarkers correlated with kidney function, including creatinine and cystatin-c. Data will be presented at an upcoming cardiology conference.

"The data from this trial appear to indicate that we have identified active doses of CD-NP suitable for evaluation in a larger double-blind, placebo controlled study in acute heart failure patients," said James Young, MD, Professor and Dean of Medicine of the Cleveland Clinic and member of Nile Therapeutics Scientific Advisory Board. "Particularly interesting is CD-NP's apparent effect on kidney function, which would be a unique and clinically important benefit over the current standard of care."

"We are excited and encouraged by this data, particularly by the demonstration of activity in the intended patient population, supporting our belief that CD-NP has the potential to be a valuable new therapy for patients with cardiovascular and renal disease," said Joshua Kazam, Chief Executive Officer of Nile Therapeutics. "We look forward to the continued advancement of the CD-NP program."

About Heart Failure

Heart failure is the fastest-growing clinical cardiac disease in the U.S. according to the American Heart Association, affecting over 5 million Americans. Over 1 million patients in the U.S. each year are hospitalized with ADHF, an acute exacerbation of heart failure. This hospitalization rate is almost double the rate seen 15 years ago, and is the most frequent cause of hospital admission in the U.S. for patients older than 65 years, generating annual inpatient costs of more than $33 billion.

Safe Harbor Paragraph for Forward-Looking Statements: This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that involve substantial risks and uncertainties. All statements, other than statements of historical facts, included in this press release regarding the timing, progress and anticipated results of the clinical development, regulatory processes, clinical trial and data analysis timelines, anticipated benefits of CD-NP, Nile's strategy, future operations, outlook, milestones, the timing and success of Nile's product development, future financial position, future financial results, plans and objectives of management are forward-looking statements. Nile may not actually achieve these plans, intentions or expectations and Nile cautions investors not to place undue reliance on Nile's forward-looking statements. Actual results or events could differ materially from the plans, intentions and expectations disclosed in the forward-looking statements Nile makes. Various important factors that could cause actual results or events to differ materially from the forward-looking statements that Nile makes include Nile's need to raise additional capital to fund its product development programs to completion, Nile's reliance on third-party researchers to develop its product candidates, and its lack of experience in developing and commercializing pharmaceutical products. Additional risks are described in greater detail in the reports Nile files with Securities and Exchange Commission, including those described under the caption "Risk Factors" in Item 1A of its Annual Report on Form 10-K for the year ended December 31, 2009 filed with the Securities and Exchange Commission on March 3, 2010. Nile is providing this information as of the date of this press release and does not undertake any obligation to update any forward-looking statements as a result of new information, future events or otherwise.

Source: Nile Therapeutics, Inc

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Study Finds Benefits Of Dental Therapists In Alaska, Insurance Commissioner Steps Down In Conn.

Main Category: Dentistry
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The New York Times, certified dental therapists in Alaska, "the only state where nondentists may perform extractions and administer fillings. The therapists, who receive two years of training, help fill a vacuum: Alaska has long had trouble attracting and retaining licensed dentists. Sixty percent of Alaska Native children ages 2 to 5 have untreated decay, and 20 percent of Native adults over 55 have no teeth at all. But the American Dental Association, the nation's leading dental society, opposes the use of nondentists for 'irreversible procedures' - including drilling and extraction - citing patient safety. ... Now a two-year foundation-supported study has reignited the debate over which practitioners are qualified to provide dental care, especially to underserved populations in high-poverty areas" (Cohen, 11/1).

Indian Country Today: The research "offered several positive findings specifically about the program, including that dental therapists are technically competent to perform the procedures within their scope of work and are doing so safely and appropriately; they are consistently working under the general supervision of dentists; and they are successfully treating cavities and helping to relieve pain for people who often had to wait months or travel hours to seek treatment. At the same time, patients tend to be satisfied with the care they received, and the program has been well-accepted in tribal villages. ... The [ADA] has opposed Congress expanding the Alaska therapist model, and has suggested that the drastic shortage of dentists in the IHS system is being addressed" (Capriccioso, 11/2).

The Connecticut Monitor: "State Insurance Commissioner Thomas R. Sullivan, whose department sparked controversy last month when it approved rate hikes as high as 47 percent for Connecticut's largest health insurer, resigned Monday to take a job in the private sector, Gov. M. Jodi Rell's office confirmed. Full details of Sullivan's departure, including his next job assignment, were not available late Monday, though the administration confirmed Sullivan would leave his state post in two weeks. Sullivan, who was appointed Connecticut's 30th insurance commissioner by Rell in April 2007, drew criticism last month when his agency gave the green light to the largest rate increase in the state since the national health care reform was enacted" (Phaneuf, 11/1).

The Washington Post: "The largest nurses union in the United States asked the D.C. Health Department on Monday to investigate nurse understaffing at Washington Hospital Center that the union says is jeopardizing patient care. In a 19-page report filed with the department, National Nurses United documented 50 instances of what it described as unsafe patient care this year in all departments in the hospital. No deaths were reported. The reports describe instances of patients not receiving medication on time, newborn infants not being fed promptly and a patient who was rushed back to the operating room after the patient had stopped breathing and suffered cardiac arrest. The union did not know whether the patient survived" (Sun, 11/1).

Kansas Health Institute: "As part of a growing national effort to prevent prescription drug abuse, the Kansas State Board of Pharmacy will soon launch a computerized monitoring program designed to give doctors and pharmacists near-instant access to patient drug histories. ... The Web-based monitoring system chosen by the board is called RxSentry, a product of Health Information Designs, which is headquartered in Auburn, Ala. The company also provides drug utilization services to the Kansas Health Policy Authority and prescription monitoring services to government agencies in 10 states" (Ranney, 11/1).

Oregon Public Broadcasting News: "Oregon unveiled part of its plan for implementing the federal health overhaul this week. When the federal government banned health insurance companies from denying coverage to children with pre-existing conditions, two of Oregon's largest insurers stopped offering 'child-only' policies. Regence BlueCross BlueShield of Oregon and HealthNet were worried parents would only sign-up their kids once they became sick -- thus undercutting the premise of insurance. The state's fix is an enrollment window -- from November 1st to December 31st -- so parents can't wait until illness strikes" (Foden-Vencil, 11/2).

This information was reprinted from kaiserhealthnews.org with kind permission from the Henry J. Kaiser Family Foundation. You can view the entire Kaiser Daily Health Policy Report, search the archives and sign up for email delivery at kaiserhealthnews.org.

© Henry J. Kaiser Family Foundation. All rights reserved.

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Nurse Visitation Programs Reduce Repeat Pregnancies In High-Risk Women, Study Finds

Nurse visitation programs after the birth of a child can help reduce repeat pregnancies in high-risk women, particularly teens and women living in rural areas, according to a study published in the Archives of Pediatrics & Adolescent Medicine, MedPage Today reports. Previous research has found that nurse visitation programs can improve outcomes for women and their infants. The new study was designed to demonstrate the real-world impact of large-scale nurse visitation programs on helping partners plan the timing of subsequent pregnancies.

The researchers assessed the Nurse-Family Partnership -- which serves more than 20,000 families annually in 31 states -- focusing on the program's implementation across Pennsylvania from 2000 through 2007. The study included 3,844 first-time mothers receiving public assistance, who were paired with NFP nurses. A control group consisted of 10,938 first-time mothers who were not enrolled in the program.

During the first three years of the program, there was no advantage for preventing a subsequent pregnancy within two years. By 2004 to 2005, 16.8% of women paired with nurses became pregnant within two years, compared with a 19% of women not in the program. Among women ages 18 and younger, 17.9% of program participants became pregnant, compared with 23.3% of their peers who were not in the program. Women living in rural areas -- especially teens in rural areas -- particularly benefited from the program, with a reduction in second pregnancies that was two times that of urban-dwelling women.

Implications for Health Reform

In an editorial accompanying the study, Kay Johnson of Dartmouth Medical School wrote that the findings support current evidence of the benefits of nurse visitation programs. Such evidence is important under the federal health reform law (PL 111-148), which will fund state-based nurse visitation programs across the U.S. beginning in 2011. The law specifies that at least 75% of federal funds go toward "evidence-based" programs, according to Johnson.

"Congress set an expectation for states to report results on selected benchmarks in three years and to show measurable change in outcomes in five years," Johnson wrote. She added that "states launching new home visiting programs with [health reform] funding are not likely to report improved outcomes in less than three years and that the five-year time frame is more realistic." Johnson noted that the findings "suggest that urban sites may need more intensive programs, staff capacity, community linkages, and/or technical assistance to achieve the same results as rural sites" (Phend, MedPage Today, 11/1).

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