FAST BREAKING PAPERS

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Essential Science Indicators^SM from Thomson Reuters lists highly cited papers in 22 broad fields of science. These papers comprise the top 1% of papers in each field and each year. The lists are updated every two months to reflect their current citation counts and also include new papers that enter the top percentile.

ScienceWatch.com here identifies a subset of these papers having the largest percentage increase in citations in their respective fields from one bimonthly update to the next. We call these "fast breaking papers" because they represent very recent scientific contributions that are just beginning to attract the attention of the scientific community. For full details and citation histories of these papers, see Essential Science Indicators listings of highly cited papers.

Some papers have comments sent in by the author(s) of the paper which may include images and descriptions of their work.

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Cough medicine could help doctors identify how breast cancer patients metabolize tamoxifen

The test needs to be refined and improved so that fewer blood samples are required and it is easier to use; it also needs to be tested in another group of patients. If this proves to be successful, then the researchers will have to develop a dosing strategy and test it in a phase III trial in order to compare it with current practice.

By ECCO-the European CanCer Organisation,[RxPG] Cough medicine could be used as way of predicting how well individual patients metabolise tamoxifen used in the treatment of their breast cancer, according to new research presented at the 22nd EORTC-NCI-AACR [1] Symposium on Molecular Targets and Cancer Therapeutics in Berlin today (Friday).

The findings suggest that it could be possible to use cough suppressant syrup as a probe, which would enable doctors to identify patients with altered metabolism and use this information to improve individual treatment, making it more effective and reducing the chances of side-effects.

Tamoxifen, which is widely used both to treat and prevent breast cancer, is metabolised by the body into endoxifen, which is responsible for the drug's anti-cancer activity and which can cause tamoxifen-related side-effects. Two enzymes, CYP2D6 and CYP3A, are responsible for metabolising tamoxifen into endoxifen, and the metabolite forms only if there are sufficient quantities of these enzymes.

Mrs Anne-Joy de Graan, a PhD student in the medical oncology department at the Erasmus Medical Centre in Rotterdam (The Netherlands), who presented the study, explained: At present, all patients treated with tamoxifen in The Netherlands are prescribed a fixed dose of 20 mg or 40 mg. But there is a large difference in the toxicity (for example, hot flushes, endometrial cancer and thrombosis) and efficacy of this agent. This is thought to be the result of variance in endoxifen concentrations between patients. Recently, research has focused on whether this variation in endoxifen levels is caused by patients' individual genetic make-up. We know that there are genetic variations that cause women to be 'poor metabolisers'. This means that these women cannot form enough endoxifen due to absence of CYP2D6 enzymatic activity. In addition, other factors can influence a way a woman metabolises tamoxifen, such as CYP3A enzymatic activity, the use of other medicines, alcohol consumption and smoking.

Mrs de Graan and her colleagues at Erasmus studied the use of dextromethorphan, the active ingredient in cough suppressant medicine, in 40 breast cancer patients who had been taking tamoxifen for more than three weeks. Dextromethorphan is metabolised in the same way as tamoxifen and is harmless to the patient. It is a so-called 'probe' drug, a harmless substance that can be used to predict the metabolism of another drug. We used dextromethorphan to evaluate its use as a probe drug for tamoxifen metabolism, she said.

The researchers gave their patients 30mg of dextromethorphan as liquid cough syrup and then asked them to take their oral tamoxifen two hours later. Over the next 24 hours they took different blood samples to measure both dextromethorphan and tamoxifen metabolites, and then calculated how well dextromethorphan metabolism predicted and correlated with tamoxifen metabolism.

We found that dextromethorphan is a very good way to predict endoxifen concentrations, said Mrs de Graan. One patient was taking the anti-depressant, paroxetine, which is known to inhibit CYP2D6, and the dextromethorphan probe accurately predicted the resulting lower concentrations of endoxifen.

Measuring dextromethorphan is easier than measuring levels of the metabolite endoxifen and, in addition, it can be applied to other compounds that are metabolised by CYP2D6 and CYP3A.

Tamoxifen is prescribed to women for as much as five years in the adjuvant setting, so it is highly important to know beforehand if the therapy is going to be effective. When it is known that a woman metabolises tamoxifen poorly, a switch in drugs or an increase in dose can be considered. Looking at a patient's genetic make-up (genotyping) is one possible way to predict the metabolism of an individual patient, but it only looks at one gene for one enzyme involved in the metabolism of tamoxifen: CYP2D6. However, tamoxifen is also metabolised by another enzyme: CYP3A. Furthermore, a patient's metabolism is not only influenced by genes, but also by other factors such as co-medication and environmental factors. The dextromethorphan phenotyping test takes all these factors into account in predicting tamoxifen metabolism, said Mrs de Graan.

The test needs to be refined and improved so that fewer blood samples are required and it is easier to use; it also needs to be tested in another group of patients. If this proves to be successful, then the researchers will have to develop a dosing strategy and test it in a phase III trial in order to compare it with current practice.

Research today focuses more on the treatment of the individual patient. We now know that every patient responds differently to therapy. It is largely unknown why one patient experiences more or fewer side effects or why some patients respond better or worse to therapy. Therefore, it is highly important to identify prognostic factors that predict this response. We believe that tailored therapy will optimise treatment with systemic therapy. The current dosing strategy does not take individual differences into account like co-medication, DNA difference, life-style factors like smoking behaviour, and alcohol consumption. Genotyping tamoxifen-treated patients is just one step towards individual treatment, but different results are reported in the literature. We investigated another way of predicting tamoxifen metabolism by phenotyping, which takes various individual differences into account. Future research will tell which strategy for individualising treatment will be the best to implement in daily practice. Our dextromethorphan test could aid in future studies on the association of tamoxifen and CYP2D6 genotype and phenotype, and ultimately in the personalisation of tamoxifen treatment, concluded Mrs de Graan.

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I-SPY 2 STUDY SPEEDS UP TREATMENT FOR BREAST CANCER

The trial data for the first time will be public, which means that breast cancer researchers across the country will have unprecedented information about what the tumors look like before, during and after treatment, plus long-term outcomes. Usually, the drug developer owns the data and keeps it private.

By University of Colorado Denver, [RxPG] AURORA, Colo. (Nov. 16, 2010) A clinical trial that aims to speed up the study of new treatments for certain subtypes of breast cancer now has a designated study site at the Diane O'Connor Thompson Breast Center at the University of Colorado Hospital. This study, called I-SPY 2, (Investigation of Serial Studies to Predict Your Therapeutic Response with Imaging and Molecular Analysis 2) will evaluate which medical treatments are most effective for different types of tumors. So-called personalized medicine in cancer is gaining ground as new drugs are developed that target known gene mutations. In the past, it could take hundreds of thousands of dollars and several years to study a single drug, says Anthony Elias, MD, breast cancer program director and associate director for clinical research at the University of Colorado Cancer Center (UCCC). This trial sets up a new kind of mechanism that lets us test multiple drugs at nearly two dozen cancer centers at once, starting with three drugs that have been shown to target known gene abnormalities in common subtypes of breast cancer, Elias says. Rapid discovery is the name of the game.

UCCC is participating with 20 leading cancer centers in the United States and Canada recruiting and treating patients as part of this large-scale clinical trial aimed at quickly developing new breast cancer drugs. Women who participate will have a new diagnosis of breast cancer and can not have received any previous treatment including surgery. Their breast tumor biopsy is tested using three high-tech biological screening tools. The results will tell doctors what gene mutations are driving their cancer. If the gene testing results show a tumor it may be less likely to respond to currently available chemotherapy agents, the patient will be invited to enter the drug trial.

HER2 and triple negative breast cancers are usually bad actors, but some of the ER positive breast cancers can also be aggressive, Elias says. Each drug we're studying has been shown to work against at least one of these breast cancer subtypes.

About 80 percent of study participants will be randomized to receive a study drug in addition to chemotherapy before surgery and 20 percent will receive standard care, which is chemotherapy before surgery. For women with this type of breast cancer, chemotherapy before surgery is already the standard for shrinking tumor size and improving surgical outcomes, says Christina Finlayson, MD, surgical oncologist and director of the Diane O'Connor Thompson Breast Center. The study will run for five years and could eventually test dozens of new drugs.

Doctors will be looking for pathologic complete response, no sign of tumor in the breast tissue and lymph nodes at the time of surgery, as an indication that the study drug made a difference. A complete pathologic response before surgery indicates that the tumor was successfully treated with the medication.

As each woman completes the study treatment, testing of tissue obtained at surgery and information about her outcomes will help researchers decide which treatment will be offered to the next women to join the trial, which is not typically how cancer drug studies work.

If the first patients respond well to the drug, it's more likely that subsequent patients will get that drug, Elias says. After a certain number of patients, we can decide if a drug is a success, a failure or needs further evaluation. We hope we can study three or four drugs every nine months or so, which is about twice as fast as usual. And since the study mechanism will be in place, when we're done testing one drug, we can start studying another drug without creating a whole new trial. That will save years of time and millions of dollars.

The trial data for the first time will be public, which means that breast cancer researchers across the country will have unprecedented information about what the tumors look like before, during and after treatment, plus long-term outcomes. Usually, the drug developer owns the data and keeps it private.

With this data available for the first time, researchers at UCCC and elsewhere will be able to use it to figure out why people may not get a good response, what pathways are important, what biomarkers are really at play, Elias says. I-SPY 2 has the power to move the field forward faster than any trial before it. It will create an enormous resource for the future.

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SCIENCE IN TAIWAN

Taiwan’s world share of science and social-science papers over a recent five-year period, expressed as a percentage of papers in each of 21 fields in the Thomson Reuters database. Also, Taiwan’s relative citation impact compared to the world average in each field, in percentage terms.

Field	% papers fr. Tiawan	Impact vs. world
Engineering	4.49	-7
Computer Science	4.12	-16
Materials Science	2.99	-7
Physics	2.55	-19
Economics & Business	2.28	-43
Taiwan's overall percent share, all fields: 1.93
Pharmacology & Toxicology	1.90	-19
Chemistry	1.77	-11
Clinical Medicine	1.62	-30
Mathematics	1.49	-11
Agricultural Sciences	1.35	+15
Biology & Biochemistry	1.31	-32
Geosciences	1.27	-13
Environment/Ecology	1.27	-23
Microbiology	1.16	-31
Social Sciences	1.14	-21
Space Science	1.11	-14
Immunology	1.06	-48
Molecular Biology & Genetics	1.04	-41
Neuroscience & Behavior	0.90	-39
Plant & Animal Science	0.89	-4
Psychiatry/Psychology	0.82	-42

Between 2005 and 2009, Thomson Reuters indexed 100,232 papers that listed at least one author address in Taiwan. Of those papers, the highest percentage appeared in journals indexed under the heading of engineering, followed closely by computer science. As the right-hand column indicates, the citations-per-paper score for Taiwan in engineering was 7% below the world mark (2.04 cites per paper for Taiwan versus the world average of 2.19). On the other hand, the impact of papers from Taiwan-based authors exceeded the world average by 15% in agricultural sciences, and was also comparatively strong in plant & animal science and materials science.

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