Research published in The Lancet suggests that oral contraceptives provide long-term protection against ovarian cancer. The study authors found that taking the pill for 15 years halved the risk of contracting ovarian cancer. They also concluded that even 30 years after cessation of pill use the risk of developing ovarian cancer was significantly reduced. This is the first study that indicates the duration of protection provided from taking the pill even after it has stopped being used.
The study was conducted by the Collaborative Group on Epidemiological Studies of Ovarian Cancer and provided a meta-analysis of 45 epidemiological studies. These studies were conducted in 21 different countries and all investigated oral contraceptive use and the associated risk of ovarian cancer. Of these studies, 32 were case–controlled retrospective studies of women who had developed ovarian cancer, had been questioned about their past oral contraceptive intake and compared with controls who did not have cancer. The other 13 were cohort studies observing women over time and monitoring their oral contraceptive intake and subsequent ovarian cancer development.
In total, data were available for 87,303 women without cancer and 23,257 women diagnosed with ovarian cancer between 1973 and 2001. The results from the study demonstrated that 31% of women with ovarian cancer and 37% of controls had used oral contraceptives. In addition, the authors found that for every 5 years of additional oral contraceptive use, women reduced their chances of contracting ovarian cancer by 20%.
The study also showed how the women remained protected after they had stopped using the contraceptives, although it demonstrated that this protection decreased with time. Those who were currently taking the pill and those who had stopped taking it within the last 10 years had a reduction in risk of 29%, while the risk reduction declined to 19% in those who had stopped taking the pill 10–19 years previously and those who stopped taking the pill 20–29 years ago had a risk reduction of 15%.
The authors estimate that approximately 200,000 incidents of ovarian cancer and 100,000 deaths have been prevented by contraceptive pill use over the last 50 years. They anticipate that with increased use in the future and with the aging of current contraceptive pill users, the number of deaths prevented annually will increase.
The authors are not able to identify why this protection occurs but they speculate that it is the result of ovulation suppression.
Source: Collaborative Group on Epidemiological Studies of Ovarian Cancer. Ovarian cancer and oral contraceptives: collaborative reanalysis of data from 45 epidemiological studies including 23,257 women with ovarian cancer and 87,303 controls. Lancet 371, 303–314 (2008).
New test for cervical cancer screening
Platform: Cervatec™
Manufacturer: mtm laboratories
Diagnostic target: Quantitative detection of p16 to detect cervical cancer and precursor lesions
A new assay, based on the quantitative detection of p16, a tumor suppressor gene with an important role in the regulation of the cell cycle. The p16 gene is upregulated in cervical cancer and is, therefore, a useful biomarker for cervical disease. The test, known as Cervatec™, is intended for use with the conventional Pap test to detect cervical cancer and its precursor lesions. Colorimetric sandwich ELISA quantitatively measures the levels of p16 in lysed cervical specimens. This can be run manually or on automated ELISA platforms.
A prospective study has investigated the results of Cervatec™ and Pap test compared with biopsy-confirmed diagnoses. In the 7500 women, aged 35 and under, that took part in the study Cervatec™ had a 90% sensitivity in the detection of high-grade disease and the Pap test alone had a 39% sensitivity.
Bob Silverman, Chief Commercial Officer of mtm laboratories, commented, “Cervatec™ will improve the certainty for gynecologist and patient that severe lesions, which might otherwise remain undetected by Pap testing alone, are detected early when treatment interventions can be most effective.”
The product is not yet approved by the FDA and will only be marketed outside of the USA.
Source: www.mtmlabs.com
Opposing roles of STAT3 in glioblastoma
It has been shown previously that STAT3 acts as an oncogene in several tumors. Therefore, inhibiting the gene should, in theory, be an effective treatment for these tumors. However, in a recent study published in the February 15 issue of Genes and Development, researchers at Harvard Medical School (MA, USA) found that, depending on the tumor’s genetic make-up, STAT3 could act as an oncogene or a tumor-suppressor gene.
Using genetically modified mice, the researchers studied how EGFRvII and PTEN, mutations of which have been linked to glioblastoma, affect STAT3 function in astrocytes. They found that STAT3 functioned as an oncogene when EGFRvII was mutated but was a tumor suppressor when PTEN was mutated.
Explaining the results with regards to EGFR, Azad Bonni, lead author of the study, commented: “EGFR, in its normal state, is a transmembrane receptor, usually performing its functions at the cell surface. However, when it’s mutated, we find it in the cell’s nucleus interacting with STAT3 – and turning it into an oncogene. STAT3 itself is not mutated or damaged. It’s the process of regulating STAT3 that gets damaged.”
This new finding is not only important for glioblastoma therapy, but also for the understanding of other cancers in which STAT3 is involved, such as breast and prostate cancer.
“The belief that STAT3 can only be an oncogene has been a pretty entrenched dogma in the field,” commented Bonni, “So we performed many, many experiments to make sure this was correct. It took some very persistent investigators in my lab to get the job done. As a result, we’re convinced of our data.”
The results also highlight the need to carry out further research into the field of personalized medicine, as Bonni explained, “This discovery lays the foundation for a more tailored therapeutic intervention, and that’s really important. You can’t just go blindly treating people by inhibiting STAT3.”
Source: de la Iglesia N, Konopka G, Puram SV et al. Identification of a PTEN-regulated STAT3 brain tumor suppressor pathway. Genes Dev. 22(4), 449–462 (2008).
New hope for prostate cancer patients
Mice genetically engineered to develop prostate cancer were protected from the disease after being immunized with an experimental vaccine according to new findings published in Cancer Research.
Currently, men with increased levels of prostate-specific antigen (PSA) are advised to wait watchfully and no treatment is applied until the cancer develops. Anticancer treatments are toxic and costly while therapeutic vaccines are still under development with limited clinical benefit.
“What if instead of a watchful wait, we vaccinate? That could change the course of the disease,” said the lead investigator, W Martin Kast of the Norris Comprehensive Cancer Center (CA, USA). He continues, “By early vaccination, we have basically given these mice life-long protection against a disease they were destined to have. This has never been done before and, with further research, could represent a paradigm shift in the management of human prostate cancer.”
In their experimental vaccine, the research team used prostate stem cell antigen (PSCA), a protein overexpressed in approximately a third of early-stage prostate cancers and in all advanced-stage prostate tumors.
The animals received two different vaccines. The prime dose contained a naked DNA encoding PSCA, and the booster dose was a modified horse virus carrying that DNA. “Confronting the immune system in two different ways forces it to mount a strong response,” explained Kast. At 1 year following immunization, all control mice died while 90% of vaccinated mice survived. “There were tiny nodules of prostate cancer in the (surviving) mice that were surrounded by an army of immune system cells,” said Kast. “The vaccination turned the cancer into a chronic, manageable disease.”
Of note, the vaccine did not induce autoimmunity in the animals, despite PSCA being expressed as a normal protein in various tissues. “Theoretically, the vaccine could produce a response in any tissue that expresses the antigen, but the fact that PSCA is expressed in such low levels in normal tissue may prevent that complication,” explained Kast. The authors cautioned that human studies are needed to confirm that autoimmune diseases do not develop.
“We feel this is a very promising approach,” said Kast. “With just two shots, the vaccine will prime immune cells to be on the lookout for any cell that overexpresses PSCA.”
Source: Garcia-Hernandez Mde L, Gray A, Hubby B, Klinger OJ, Kast WM. Prostate stem cell antigen vaccination induces a long-term protective immune response against prostate cancer in the absence of autoimmunity. Cancer Res. 68(3), 861–869 (2008).
Study finds novel mechanism for resistance acquired against platinum-based chemotherapy
Scientists at the Fred Hutchinson Cancer Research Center (WA, USA) have uncovered a novel mechanism underlying the resistance acquired by some recurrent ovarian tumors to the widely used platinum-based chemotherapy drugs, such as cis-platin and carboplatin. Although these new results are based on ovarian cancer sufferers carrying inherited mutations in the BRCA2 gene, it is possible that they could be extrapolated to BRCA1 as well and help to explain the mechanism of cisplatin resistance in women with mutations in BRCA1.
“Because BRCA1 and BRCA2 have similar functions in terms of DNA repair, we may be able to generalize these findings for women with either mutation,” explained Toshiyasu Taniguchi, senior author of the paper.
BRCA2 is involved in DNA repair, an ability that is disrupted by mutations thereby leading to an increased risk of ovarian and breast cancer. However, at the same time these mutations also make the cells more sensitive to drugs like cisplatin, whose action is mediated via DNA damage. As a result, ovarian tumors respond very well to agents like cisplatin, but over time about 70–80% of patients acquire resistance to them.
“The majority of advanced-stage ovarian-cancer patients die due to acquired resistance to platinum-based drugs. It is a serious problem,” stated Taniguchi.
In this study the scientists found that, in some cases, exposure to cisplatin resulted in the development of secondary mutations in the BRCA2 gene of the cancer cells. These mutations reinstated the DNA repairing abilities of BRCA2 leading to the development of resistance to chemotherapeutic agents.
“Testing whether relapsed tumors have a secondary mutation of BRCA2 may be important to predict clinical outcome,” commented Taniguchi.
“This event is unlike any previous mechanism of resistance to chemotherapy identified in cancers,” enthused Elizabeth Swisher, coauthor of the article. “By identifying the cause of chemotherapy resistance in these cancers, we may be able to better predict who will respond to different chemotherapy agents and find novel ways to resensitize tumors to chemotherapy that otherwise would not have had a good response to treatment.”
These findings could be generalized to other DNA repair genes, which could help to explain drug resistance to various cancers.
Source: Sakai W, Swisher EM, Karlan BY et al. Secondary mutations as a mechanism of cisplatin resistance in BRCA2-mutated cancers. Nature (2008) (Epub ahead of print).
Small breast tumors less likely to be missed with new imager
A recent study has indicated that a new imager can detect breast tumors half the size of the smallest ones detected by standard imaging systems. The imager is designed to identify and guide the biopsy of suspicious breast cancer lesions. Based on positron emission mammography/tomography (PEM/PET), the system is capable of completing an image and biopsy in approximately the same amount of time as a traditional biopsy. This biopsy feature of the system is a unique characteristic.
Initial testing of the device centres on its PET imaging performance, such as spatial resolution and detection sensitivity. Raymond Raylman comments on initial testing of the imager: “We had good performance characteristics, with image resolution below 2 mm. In regular PET, the image resolution is over 5 mm.”
These high-resolution 3D PET images of the breast are produced as the system components are designed to image the unique contours of the breast. The breast is imaged with a movable array of two pairs of two flat detection heads. The PET images highlight suspicious focal uptake of the radiotracer and guide biopsy of that area. On discovery of a suspected lesion, a biopsy is performed with a person-controlled robot arm guided by a single pair of heads. The system is of particular use in imaging tumors in women with dense or fibroglandular breasts, since they often have inconclusive mammograms.
The system was developed in a collaboration between researchers at the Jefferson Lab Radiation Detector and Medical Imaging Group and the West Virginia University. The group aims to enhance the imager by adding components, which will enable CT scans to be taken. On completion of system testing, clinical trials will take place to determine the success of the system in patients. The authors conclude that, “These promising findings indicate that PEM/PET may be an effective system for the detection and diagnosis of breast cancer.”
Source: Raylman RR, Majewski S, Smith MF et al. The positron emission mammography/tomography breast imaging and biopsy system (PEM/PET): design, construction and phantom-based measurements. Phys. Med. Biol. 53, 637–653 (2008).
Adjuvant may be essential in cancer vaccine
Recent findings published in the Proceedings of the National Academy of Sciences USA revealed that the boosting effect of an experimental vaccine against non-small-cell lung cancer (NSCLC) was dependent on the formulation of the priming dose.
“We previously learned that our vaccine could stimulate an immune response recognizing a protein found in lung cancer cells but we did not know how long the response lasted,” said lead author Sacha Gnjatic (Ludwig Institute for Cancer Research). “We now know that this vaccine induces strong and persistent immunity over several years, which can be further ‘boosted’ with additional vaccination.”
In the previous study, patients received different formulations of this vaccine, either with or without the adjuvant AS02B, which both resulted in protection against NSCLC. To the researchers’ surprise, a single booster dose of the adjuvanted vaccine 3 years after priming resulted in strong humoral and T-cell responses in patients who previously received the adjuvanted vaccine, but only induced a very limited response in those who received the nonadjuvanted prime vaccine.
“In the vaccine field, boosters are given to convert negative or weak reactions to positive ones, and we really thought we would see the same thing. One intriguing possibility is that regulatory mechanisms were activated following the original weak response induced by the vaccine without adjuvant. These findings will certainly have ramifications for the whole field to determine the formulation and delivery of future cancer vaccines,” said coauthor Lloyd Old, director of the Cancer Vaccine Collaborative.
Source: Atanackovic D, Altorki NK, Cao Y et al. Booster vaccination of cancer patients with MAGE-A3 protein reveals long-term immunological memory or tolerance depending on priming. Proc. Natl Acad. Sci. USA 105(5), 1650–1655 (2008); Ludwig Institute for Cancer Research, NY, USA: www.licr.org
Lung cancer screening recommended among breast cancer survivors
New research suggests that breast cancer survivors who receive radiotherapy and have a history of smoking should receive screening for lung cancer.
The study demonstrated that patients in receipt of postmastectomy radiotherapy (PMRT) who also smoke, have an increased risk of ipsilateral lung cancer compared with those who do not receive PMRT or smoke. Data used for the study was obtained from women enrolled in the Connecticut Tumor Registry and diagnosed with breast cancer between 1965 and 1989. The records were compared for pathology, breast cancer therapy and smoking history.
In women who did not receive PMRT, those who had smoked had a 5.9-fold increased risk of lung cancer, compared with nonsmokers. Patients who smoked and had undergone PMRT were at a 1.8-fold increased risk, compared with nonsmokers who did not receive PMRT. Smoking and PMRT were associated with an increased risk of all histologic types of lung cancer; the adjusted odds ratios for the joint effects of smoking and PMRT were 10.5 and 37.6% for the contralateral and ipsilateral lung, respectively.
“Given those findings, breast cancer survivors who are or have been smokers and have received radiotherapy may be appropriate candidates for lung cancer screening with spiral commuted tomography,” the researchers commented.
PMRT has been found to reduce the risk for local recurrence as well as offering an improved survival rate for patients with certain high-risk cancers. However, second primary cancers are a potential repercussion of the treatment.
Neuget et al. suggest that smoking history should be taken into account when discussing treatment options with patients with newly diagnosed breast cancer. They conclude, “Research is needed to determine whether or not smoking cessation after radiotherapy may reduce its late effects.”
Source: Kaufman EL, Jacobson JS, Hershman DL, Desai M, Neugut AI. Effect of breast cancer radiotherapy and cigarette smoking on risk of second primary lung cancer. J. Clin. Oncol. 26, 392–398 (2008).