Abstract
The largest studies yet performed on the genomes of breast cancer tumors have revealed that the disease is much more complicated than previously thought.
Three recent studies, all published in Nature, have looked at the genetic basis of breast cancer. The findings suggest that the genetic basis of the disease is more complicated than previously thought, with ten different subtypes of the disease and a continuum of mutations that cause it.
The first study, conducted by researchers from Cancer Research UK (London, UK), the Wellcome Trust (London, UK), British Columbia cancer research center (BC, Canada), the University of British Columbia (Vancouver, Canada), the University of Cambridge (Cambridge, UK) and many other institutions, studied both DNA and RNA from almost 1000 tumors, to evaluate both the genome and transcriptome in breast cancer patients.
The results suggest that there are ten genetically distinct subtypes of breast cancer and that these subtypes correlate with different clinical presentations of the disease.
“These findings prove the importance of personalizing cancer drug treatment so that it targets the genetic make up of a particular tumor rather than presuming one therapy can treat multiple, similar-looking tumors.”
Carlos Caldas, one of the researchers from Cancer Research UK, explains that “Essentially, we've moved from knowing what a breast tumor looks like under a microscope to pinpointing its molecular anatomy.” He thinks that future research following these results will mean that “eventually we'll know which drugs it will respond to.”
In addition, this study highlighted new genes linked to breast cancer, as well as implicating cellular signaling pathways that have already been characterized in the pathogenesis of the disease; two results that may lead to the development of new treatments.
A second study, involving a collaboration from multiple countries, including Belgium, the UK, Canada, The Netherlands and Norway, has found nine new genes that are linked to breast cancer, and revealed new insights into the complexities of mutations.
From the analysis of 100 tumors, driver mutations that cause cancer were found in 40 genes, including nine that had not been previously linked to breast cancer: AKT2, ARID1B, CASP8, CDKN1B, MAP3K1, MAP3K13, NCOR1, SMARCD1 and TBX3. The researchers also noted that the numbers of driver mutations varied between cancers, from a single driver in many cases, to some cases with as many as six. In the set of tumors studied, more than 75 combinations of mutations were found.
Andy Futreal from the Wellcome Trust Sanger Institute, commented on the importance of these findings for the treatment of breast cancer, “One of the most striking things about breast cancer is how it progresses differently in each patient and how each patient responds differently to therapy.” Futreal believes that “our results can help us to understand these differences.” The ultimate goal is to use knowledge of these differences to develop new treatments for breast cancer.
This news follows another study from the British Columbia Cancer Agency, which studied the genomes of triple-negative breast cancer, the type that is currently most difficult to treat. This study, led by Sohrab Shah (University of British Columbia), found that triple-negative breast cancer is much more genetically variable than previously thought.
Steven Jones, a coauthor on this study from the British Columbia Cancer Agency explains the significance of their results: “The genetic diversity of these tumors, even though they're clinically similar, probably explains why they are so difficult to treat.” Jones continues, “these findings prove the importance of personalizing cancer drug treatment so that it targets the genetic make up of a particular tumor rather than presuming one therapy can treat multiple, similar-looking tumors.”
Taken together, the results of these three studies emphasize the need for personalized medicine in breast cancer treatment, taking the field further towards this goal. Caldas hopes that these results will “pave the way for doctors in the future to diagnose the type of breast cancer a woman has, the types of drugs that will work, and those that won't, in a much more precise way than is currently possible.”
– Written by Alisa Crisp
Sources: Curtis C Shah SP, Chin ST et al. The genomic and transcriptomic architecture of 2000 breast tumors reveals novel subgroups. Nature doi:10.1038/nature 10983 (2012) (Epub ahead of print); Stephens PJ, Tarpey PS, Davies H et al. The landscape of cancer genes and mutational processes in breast cancer. Nature doi:10.1038/naturel 1017 (2012) (Epub ahead of print); Shah SP, Andrew Roth A, Goya R et al. The clonal and mutational evolution spectrum of primary triple-negative breast cancers. Nature doi:10.1038/nature 10933 (2012) (Epub ahead of print).
Study demonstrates greater effectiveness for long-term reversible contraception over more commonly prescribed methods
A study published recently in the New England Journal of Medicine has suggested that long-term reversible contraceptives such as IUDs or contraceptive implants may be up to 20-times more effective in preventing unplanned pregnancies than any other forms of contraception, including birth-control pills, the patch or a vaginal ring.
“The effectiveness of long-acting reversible contraception is superior to that of contraceptive pills, patch or ring and is not altered in adolescents and young women.”
The study recruited 7486 patients, who were then provided with the reversible contraceptive of their choice following counseling regarding effectiveness, side effects and the risks and benefits of the different methods available. Following provision of the chosen contraceptive, the women in the study were interviewed by telephone at 3 and 6 months, and then every 6 months until the end of the 3-year study. The women included in the study were permitted to cease or change contraceptive method at any point. Throughout the study, any women who thought that they might be pregnant when interviewed were asked to report for a urine pregnancy test; if participants were pregnant they were asked whether the pregnancy was intentional and what method of contraception they were employing at the time of conception. The rates of contraception failure were compared between long-acting reversible contraception and other contraceptive methods that are commonly prescribed. The results were also stratified according to whether participants were under 21 years of age or 21 years of age and older.
From the study analysis, 334 unintended pregnancies were identified and contraceptive failure rates were found to be 4.55 per 100 participant-years for contraceptive pills, patches or a vaginal ring; this was compared with 0.27 per 100 participant-years for patients utilizing IUDs or a contraceptive implant. It was also found that women under the age of 21 that were using pills, patches or a vaginal ring experienced an unintended pregnancy risk that was almost twice as high as that of older women. In study participants using the longer-term forms on contraception, age did not appear to be a factor in risk of unintended pregnancy.
The authors of the study concluded that “The effectiveness of long-acting reversible contraception is superior to that of contraceptive pills, patch or ring and is not altered in adolescents and young women.” Commenting on the results of the study, lead author Brooke Winner from the Washington University School of Medicine (MO, USA) said, “We know that IUDs and implants have very low failure rates – less than 1% … but although IUDs are very effective and have been proven safe in women and adolescents, they only are chosen by 5.5% of women in the USA who use contraception … This study also is important because it showed that when IUDs and implants are provided at no cost, about 75% of women chose these methods for birth control.”
– Written by Sean Fkzpatrick
Sources: Winner B, Peipert JF, Zhao Q et al. Effectiveness of long-acting reversible contraception. N Engl. J. Med. 366(21), 1998–2007 (2012); Washington University School of Medicine (MO, USA): https://news.wustl.edu/news
HlNl vaccination of pregnant women linked to improved fetal and neonatal outcomes
Data from the birth record database in Ontario (ON, Canada) – Better Outcomes Registry and Network (BORN) – have recently been collated and analyzed to evaluate whether vaccination of pregnant women during the 2009–2010 H1N1 pandemic had any affect on the health of their babies.
“…vaccinated mothers were a third less likely to have a stillborn child. This is one of the only studies large enough to evaluate the association between maternal flu vaccination and stillbirth – a very rare event.”
During the study, the following outcomes from the BORN database were recorded: preterm birth, small-for-gestational-age births, fetal death and 5-min Apgar scores of below seven. Outcomes of those who received the vaccine during pregnancy were compared with those who did not. In total, 42% of the expectant mothers received the vaccine and the results indicated that vaccine recipients were 34% less likely to have a stillbirth, 28% less likely to deliver before 32 weeks and 19% less likely to give birth to a child with a birth weight for gestational age in the bottom third percentile.
Researchers from Ottawa Hospital Research Institute (ON, Canada), the Children's Hospital of Eastern Ontario Research Institute (ON, Canada) and the University of Ottawa (ON, Canada) collaborated on this project and have recently published their findings in the American Journal of Public Health. Overall, the results demonstrated positive outcomes for pregnant women receiving the influenza vaccine during the second and third trimesters. Lead author Deshayne Fell from BORN commented that, “These are all significant results, but especially interesting is the finding that the vaccinated mothers were a third less likely to have a stillborn child. This is one of the only studies large enough to evaluate the association between maternal flu vaccination and stillbirth – a very rare event.”
In addition, no adverse outcomes were recorded during the perinatal period either, a fact that coauthor Mark Walker finds promising; “Pregnant women are generally very, very careful about what they put into their bodies. For healthcare providers … such a large-scale study that shows no adverse perinatal outcomes resulting from the H1N1 flu vaccine will be extremely helpful when discussing maternal vaccination.”
– Written by Emily Reeve
Sources: Fell DB, Sprague AE, Liu N et al.; for Better Outcomes Registry and Network (BORN) Ontario. HlNl influenza vaccination during pregnancy and fetal and neonatal outcomes. Am. J. Public Health. 102(6) e33–e40 (2012); University of Ottawa news release: www.media.uottawa.ca/mediaroom/news-details_2594.html
US FDA-approved drug could boost cancer vaccine's efficacy
Researchers have demonstrated that the US FDA-approved drug, daclizumab, improves the survival of breast cancer patients taking a cancer vaccine by 30% in a proof-of-concept study.
While cancer vaccines can be successful over a short period of time, eventually the immune system stops responding and the tumor begins to grow once more. Tregs are integral to this reduced response as they regulate the immune system to reduce its response once infection has been cleared. Tumors exploit Treg cells and the cells even surround the tumor preventing tumor-fighting cells from reaching the cancerous cells within.
Daclizumab is a therapeutic, humanized, monoclonal antibody currently approved to prevent rejection in kidney transplantation. The drug targets the CD25 receptor on the surface of T cells. Tregs require IL-2 for most of their functions and it is with the CD25 receptor that IL-2 binds; therefore, Tregs are depleted of IL-2 in the presence of daclizumab.
A team of researchers, from the Perelman School of Medicine (PA, USA) and the Abramson Family Cancer Research Institute at the University of Pennsylvania (PA, USA), hypothesized that daclizumab would be effective in depleting Tregs and, thus, enabling restoration of the immune system when needed.
“Daclizumab worked incredibly well, there were no detectable side effects, and the T-cell conversion in the patients on daclizumab lasted 2 months.”
During the proof-of-concept study, published in Science Translational Medicine, daclizumab was administered to ten patients with metastatic breast cancer prior to them receiving an experimental breast cancer vaccine developed at the University of Pennsylvania. By depleting the Tregs of IL-2, the authors found that the cells converted to normal T cells and no longer surrounded the tumor, thus increasing the immune response.
Robert Vonderheide, a senior author of the study, discussed the study's promising results: “Daclizumab worked incredibly well, there were no detectable side effects, and the T-cell conversion in the patients on daclizumab lasted 2 months. Their tumors didn't shrink, but in six out of the ten patients the tumors did stop growing and the daclizumab patients had an increased survival of about 7 months compared with patients on the cancer vaccine alone.”
The authors feel this proof-of-concept study has a wide scope of therapeutic implications in the cancer field. It is well known that Tregs can block the immune system response to many types of cancer, meaning that the application of antibodies, such as daclizumab, may also be successful in increasing the immune response against other cancer types.
– Written by Caroline Purslow
Sources: Rech AJ, Mick R, Martin S et al. CD25 blockade depletes and selectively reprograms regulatory T cells in concert with immunotherapy in cancer patients. Sci. Transl. Med. 4(134), 134ra62 (2012); University of Pennsylvania press release: www.uphs.upenn.edu/news/News_Releases/2012/05/fda