Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

DNA marker predicts platinum drug response in breast, ovarian cancer

22.03.2012
Marker identifies tumors unable to repair DNA damage by platinum agents

Scientists from Brigham and Women's Hospital and Dana-Farber Cancer Institute and their colleagues have found a genetic marker that predicts which aggressive "triple negative" breast cancers and certain ovarian cancers will likely respond to platinum-based chemotherapies.

The marker, found on chromosomes within the cancer cells, could lead to a test for identifying patients whose cancers could be effectively treated by a single platinum-based drug, "and avoid the toxicities of other chemotherapy combinations," says Andrea Richardson, MD, PhD, co senior author of the study and a surgical pathologist at Brigham and Women's and Dana-Farber.

The report is being published in the April issue of Cancer Discovery, a journal of the American Association for Cancer Research.

Many cancer treatments work by damaging DNA within tumor cells, rendering the cells unable to grow and divide. While some cancer cells can readily repair broken DNA molecules, allowing them to survive drug or radiation therapy, others have lost this repair capacity, making them vulnerable to DNA-damaging agents.

The new marker, Richardson says, flags breast and ovarian cancer cells that can't repair the type of DNA damage caused by treatment with platinum drugs, including cisplatin and carboplatin. A clinical test for the marker could be particularly valuable in treating triple-negative breast cancers, which are resistant to anti-hormonal therapies or targeted drugs like Herceptin.

"We currently do not have any targeted therapies for patients with triple-negative breast cancer, so if these laboratory findings are confirmed and an assay is created to predict sensitivity to drugs that target defective DNA repair, it would be a major step forward," says Richardson, the primary pathologist for the study. However, she adds, such an assay isn't likely to be developed soon.

The new genetic marker was discovered when Richardson and others studied tumor tissue collected from triple negative breast cancer patients who participated in two clinical trials of platinum drug therapy. Triple-negative tumors develop in about 80 percent of women who carry mutated breast cancer genes BRCA1 and BRCA2. These tumors are characterized by a lack of estrogen, progesterone, and HER2 receptors, which makes them unresponsive to targeted treatments that block those receptors.

The two clinical trials, led by Judy Garber, MD, MPH, of Dana-Farber, were investigating whether platinum drugs would also be effective in so-called "sporadic" triple negative tumors -- those that develop in the absence of BRCA1 and BRCA2 genetic mutations. Overall, about 20 percent of breast cancers are triple negative. Some of these cancers respond to standard chemotherapy drugs, while others don't. The patients whose triple negative tumors do not go away after chemotherapy have a particularly poor prognosis.

A total of 79 patients in the two trials received cisplatin alone or in combination with bevacizumab (Avastin) to shrink their tumors prior to removing them surgically. In both trials, approximately 40 percent of patients had a complete or near-complete disappearance of the cancer after the cisplatin therapy.

The researchers analyzed tissue from the patients before and after the cisplatin treatment, looking for features in the cancer cells' DNA that predicted a favorable response to the pre-operative chemotherapy. They found one -- a high level of partial chromosome losses in the tumor cells that responded to the cisplatin treatment.

The tell-tale pattern, or genetic marker, was finding a high number of chromosome regions showing allelic imbalance, meaning that instead of the normal equal distribution of DNA from both parents, the tumor cells had lost one parental copy of the DNA in parts of many chromosomes. This didn't surprise the researchers: in fact, they expected it, since allelic imbalance is also found in triple-negative breast cancers associated with BRCA 1 and BRCA2 mutations. Specifically, the strongest indicator of defective DNA damage repair was in cancer cells when the regions of allelic imbalance included the tips of the chromosomes, called telomeres.

The scientists also analyzed data on tumor characteristics and treatment outcomes from The Cancer Genome Atlas, a federally funded database, to demonstrate that allelic imbalance predicted defective DNA damage repair and sensitivity to platinum drugs in serous ovarian cancers.

In the future, the scientists say, allelic instability "may prove useful in predicting response to a variety of therapeutic strategies exploiting defective DNA repair."

Along with Richardson, co-senior authors of the report are Daniel Silver, MD, PhD, of Dana-Farber, and Zoltan Szallasi, MD, of Children's Hospital Boston. First authors are Nicolai Birkbak, PhD, and Zhigang Wang, PhD, BM, of Brigham and Women's and Dana-Farber.

The research was supported by grants from the National Cancer Institute and several foundations.

Dana-Farber Cancer Institute (www.dana-farber.org) is a principal teaching affiliate of the Harvard Medical School and is among the leading cancer research and care centers in the United States. It is a founding member of the Dana-Farber/Harvard Cancer Center (DF/HCC), designated a comprehensive cancer center by the National Cancer Institute. It provides adult cancer care with Brigham and Women's Hospital as Dana-Farber/Brigham and Women's Cancer Center and it provides pediatric care with Children's Hospital Boston as Dana-Farber/Children's Hospital Cancer Center. Dana-Farber is the top ranked cancer center in New England, according to U.S. News & World Report, and one of the largest recipients among independent hospitals of National Cancer Institute and National Institutes of Health grant funding. Follow Dana-Farber on Twitter: @danafarber or Facebook: facebook.com/danafarbercancerinstitute.

Bill Schaller | EurekAlert!
Further information:
http://www.dfci.harvard.edu

More articles from Life Sciences:

nachricht Multi-institutional collaboration uncovers how molecular machines assemble
02.12.2016 | Salk Institute

nachricht Fertilized egg cells trigger and monitor loss of sperm’s epigenetic memory
02.12.2016 | IMBA - Institut für Molekulare Biotechnologie der Österreichischen Akademie der Wissenschaften GmbH

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Novel silicon etching technique crafts 3-D gradient refractive index micro-optics

A multi-institutional research collaboration has created a novel approach for fabricating three-dimensional micro-optics through the shape-defined formation of porous silicon (PSi), with broad impacts in integrated optoelectronics, imaging, and photovoltaics.

Working with colleagues at Stanford and The Dow Chemical Company, researchers at the University of Illinois at Urbana-Champaign fabricated 3-D birefringent...

Im Focus: Quantum Particles Form Droplets

In experiments with magnetic atoms conducted at extremely low temperatures, scientists have demonstrated a unique phase of matter: The atoms form a new type of quantum liquid or quantum droplet state. These so called quantum droplets may preserve their form in absence of external confinement because of quantum effects. The joint team of experimental physicists from Innsbruck and theoretical physicists from Hannover report on their findings in the journal Physical Review X.

“Our Quantum droplets are in the gas phase but they still drop like a rock,” explains experimental physicist Francesca Ferlaino when talking about the...

Im Focus: MADMAX: Max Planck Institute for Physics takes up axion research

The Max Planck Institute for Physics (MPP) is opening up a new research field. A workshop from November 21 - 22, 2016 will mark the start of activities for an innovative axion experiment. Axions are still only purely hypothetical particles. Their detection could solve two fundamental problems in particle physics: What dark matter consists of and why it has not yet been possible to directly observe a CP violation for the strong interaction.

The “MADMAX” project is the MPP’s commitment to axion research. Axions are so far only a theoretical prediction and are difficult to detect: on the one hand,...

Im Focus: Molecules change shape when wet

Broadband rotational spectroscopy unravels structural reshaping of isolated molecules in the gas phase to accommodate water

In two recent publications in the Journal of Chemical Physics and in the Journal of Physical Chemistry Letters, researchers around Melanie Schnell from the Max...

Im Focus: Fraunhofer ISE Develops Highly Compact, High Frequency DC/DC Converter for Aviation

The efficiency of power electronic systems is not solely dependent on electrical efficiency but also on weight, for example, in mobile systems. When the weight of relevant components and devices in airplanes, for instance, is reduced, fuel savings can be achieved and correspondingly greenhouse gas emissions decreased. New materials and components based on gallium nitride (GaN) can help to reduce weight and increase the efficiency. With these new materials, power electronic switches can be operated at higher switching frequency, resulting in higher power density and lower material costs.

Researchers at the Fraunhofer Institute for Solar Energy Systems ISE together with partners have investigated how these materials can be used to make power...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

ICTM Conference 2017: Production technology for turbomachine manufacturing of the future

16.11.2016 | Event News

Innovation Day Laser Technology – Laser Additive Manufacturing

01.11.2016 | Event News

#IC2S2: When Social Science meets Computer Science - GESIS will host the IC2S2 conference 2017

14.10.2016 | Event News

 
Latest News

UTSA study describes new minimally invasive device to treat cancer and other illnesses

02.12.2016 | Medical Engineering

Plasma-zapping process could yield trans fat-free soybean oil product

02.12.2016 | Agricultural and Forestry Science

What do Netflix, Google and planetary systems have in common?

02.12.2016 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>