Abstract
The Oncologic Drugs Advisory Committee (ODAC), a US FDA advisory panel, voted overwhelmingly to recommend withdrawing the marketing authorization for bevacizumab (Avastin®; Genentech, Inc., CA, USA) for first-line use in metastatic breast cancer.
The original approval for bevacizumab was controversial since it was based on a single trial (E2100), which demonstrated that progression-free survival was increased by 5.5 months in patients treated with bevacizumab and paclitaxel compared with paclitaxel alone (11.3 and 5.8 months, respectively), although no statistically significant overall survival advantage was observed.
“Given the known toxicity of bevacizumab … the panel felt that the risk:benefit ratio was not sufficiently favorable to recommend continued approval in this indication.”
The ODAC decision to recommend removing approval of the drug for this indication follows two further trials (AVADO and RIBBON 1), which demonstrated considerably shorter progression-free survival advantage for the addition of bevacizumab (0.9 and 1.2 months, respectively) and no overall survival advantage. Given the known toxicity of bevacizumab, including the potential for cardiovascular side effects, bleeding and gastrointestinal perforation, the panel felt that the risk:benefit ratio was not sufficiently favorable to recommend continued approval in this indication. The chair of the panel, Wyndham Wilson of the National Cancer Institute (MD, USA) highlighted out that some of the side effects of bevacizumab can be fatal and stated that their first responsibility was to do no harm to patients. “We have to take into account risks, and there are definite risks,” he stated.
Gabriel Hortobagyi, Professor of Breast Medical Oncology at the MD Anderson Cancer Center (TX, USA), who attended the ODAC meeting as a consultant to Genentech was disappointed with the decision. “Bevacizumab is clearly active in breast cancer, and there is more experience with this agent in metastatic breast cancer than with many, if not most, other agents evaluated for the metastatic breast cancer indication,” he argued. “Anecdotally, bevacizumab combinations can produce dramatic responses in individual patients, and it is my clinical impression that responses of such quality are seldom seen with the same chemotherapy programs without bevacizumab. As a frequent user of this agent, I have also found that it is very well tolerated by the great majority of patients; in very few do I need to modify dose or schedule, and in even fewer do I need to discontinue treatment because of toxicities.”
He concluded, “I am concerned, in part, because this recommendation might remove an important treatment option from patients with metastatic breast cancer. I am also concerned because ‘clinical benefit’ remains poorly defined. This precedent will set many drugs currently under development up for failure.”
Source: Medscape medical news: Will the FDA revoke bevacizumab's approval for breast cancer? www.medscape.com/viewarticle/725509
Study shows that microbiocide vaginal gel offers protection against HIV and herpes infections in women
A safety and effectiveness study (the CAPRISA 004 study) investigating a vaginal gel aimed at preventing women from becoming infected with genital herpes and HIV has shown promising results. It is suggested that if these results prove to be reproducible, widespread use of the gel could prevent over half a million HIV infections over the next 10 years in South Africa alone.
The study led by Quarraisha Abdool Karim (Columbia University, NY, USA) and conducted by the CAPRISA and CONRAD (VA, USA) found that the microbiocide gel, which contains 1% tenovir, was 39% effective at preventing transmission of HIV infection during sex and 51% effective at preventing transmission of herpes infection. “Tenofovir gel could fill an important HIV prevention gap by empowering women who are unable to successfully negotiate mutual faithfulness or condom use with their male partners” commented Karim.
The CAPRISA 004 study is only the first step in the assessment of the efficacy of tenovir vaginal gel and further studies and trials are needed before the gel can be widely used.
Sources: CONRAD: www.conrad.org; CAPRISA: www.caprisa.org
New diagnostic test for prevalent sexually transmitted infections
The US FDA has given clearance to a new molecular diagnostic test that simultaneously detects gonorrhea and chlamydia.
Abbott has received clearance to market two more of their products, designed to be used together – an assay for chlamydia and gonorrhea and a device for the collection of various bodily samples. The assay, the Abbott RealTime Chlamydia trachomatis/Neisseria gonorrhea, simultaneously detects two of the USA's most prevalent sexually transmitted infections. This also includes a new variant strain of chlamydia recently discovered in Sweden. The test has been used in the EU since 2008.
The Abbott m2000 System is a unique device for the collection and room-temperature transportation of multiple samples, including urine samples and endocervical, vaginal and male urethral swab specimens. Molecular or nucleic acid amplification tests are currently the standard method for detecting chlamydia and gonorrhea infections, and are widely used. The advantage of nucleic acid amplification tests over traditional culture methods is that they are generally more sensitive and specific and can identify more positive specimens.
Klara Abravaya, senior director of research and development at Abbott Molecular comments, “because many people with chlamydia are coinfected with gonorrhea, it's important to test for both diseases simultaneously. Left untreated, chlamydia and gonorrhea can lead to pelvic inflammatory disease, urethritis and sterility.”
The Centers for Disease Control and Prevention report an increase in chlamydia infections between 2007 and 2008, with 1.2 million infections reported in 2008. Furthermore, there are likely to be further cases as under-reporting is thought to be a common problem. Prevalence of gonorrhea infections has remained fairly stable in recent years.
Source: www.abbott.com
In brief…
Study finds increased risk of placental abruption for women with anti-thyroid peroxidase antibodies
In a study involving more than 17,000 women, researchers at UT Southwestern Medical Center (TX, USA), have found a link between anti-thyroid peroxidase (TPO) antibodies and placental abruption, a rare complication in which the placenta prematurely detaches from the uterus.
In certain autoimmune diseases, thyroid function may become disrupted owing to the body producing antibodies against the TPO enzyme, leading to decreased levels of thyroid hormone and slowed metabolism. However, while these antibodies remain at a low concentration, the thyroid can occasionally maintain normal levels of hormone production.
The project, partially supported by a grant from the National Institutes of Child Health and Human Development (NICHD; MD, USA), involved the team taking samples of serum from women before 20 weeks of pregnancy, and compared the levels of anti-TPO antibodies with the overall health of the mothers and babies after birth.
Over 1012 participants (nearly 6% of the total 17,298 women in the study) tested positive for the anti-TPO antibodies, which are often an indicator of early thyroid disease. Comparing the antibody-positive group against the antibody-negative groups, the researchers found no difference between the overall health of the babies, including factors such as birth weight or complications during delivery.
However, the incidence of placental abruption, which has a fetal mortality rate of between 20 and 40% and is also thought to be a significant contributor to maternal mortality, was found to occur in 1% of antibody-positive women, compared with just 0.3% in the antibody-negative group – representing an approximately threefold increase in risk.
Brian Casey, Professor of Obstetrics and Gynecology at UT Southwestern, urged caution. “Our work shows a link […] but that does not necessarily mean that thyroid supplementation would improve the health of the women or babies”. He also remarked that the findings do not indicate that routinely screening pregnant women for thyroid problems would prove to be beneficial.
The findings appear in Obstetrics and Gynecology and form a part of a national study, which is led by the Maternal–Fetal Medicine Units Network of the NICHD to establish whether pregnancy outcomes can be improved by thyroid hormone supplementation.
The researchers based at UT Southwestern are also exploring the possible relationships between other thyroid-related measurements and birth outcome.
Source: UT Southwestern Medical Center: www.utsouthwestern.edu/utsw/cda/dept353744/files/598836.html
Blood biomarkers may help in early identification of ovarian cancer
A recent study, conducted by Joshua LaBaer of the Biodesign Institute at Arizona State University (AZ, USA), and Arturo Ramirez and Paul Lampe, researchers at the Fred Hutchinson Cancer Research Center (WA, USA) explored a new method for finding biomarkers of ovarian cancer.
Although there have been many advances over the last few years, ovarian cancer is stilla lethal disease for many patients. However, the recent work, part of the Early Detection Research Network program of the National Cancer Institute, has the potential for improving survival rate.
According to LaBaer, “This is a disease for which an early diagnostic test would make an enormous difference in the health of women.” Ovarian cancer can be very treatable if caught early but, unfortunately, the disease is not usually identified until it has progressed to stage III or beyond. “By the time it's caught it has usually speckled the abdomen with advanced tumors”, he explains.
Currently there is only one reliable biomarker for ovarian cancer: CA125. It is a protein that is produced on the surface of cells and then released into the bloodstream. This biomarker is not adequate alone since testing for CA125 can result in both false-positive and false-negative results. In addition, levels of the protein tend to increase with the growth of a tumor, sometimes providing strong evidence of disease only after the cancer has reached later, and often terminal stages.
LaBaer emphasizes that dependable early diagnosis will require multiple markers. One way to search for these markers is by using antibodies. However, traditional means of producing antibodies for research are labor-intensive as they involve the injection of antigens into animals, which then produce the antibodies of interest.
A new method allows antibodies to be created synthetically. The variable region of the antibody (the fragment that binds to the antigen) is made up of amino acids. These single-chain variable fragments (scFvs) can be inserted into bacteria, which act as vectors in the same way that an animal would. Vast libraries of scFvs have been created by encoding the fragments in bacteria.
Ramirez used one of these libraries to discover which antibody fragments would bind to proteins in the blood that carried ovarian cancer. A total of 19 scFvs were found to demonstrate specific affinity for proteins exclusive to the serum of blood containing ovarian cancer.
To screen these 19 ScFvs, Ramirez and LaBaer then teamed up and used a new method that would enable them to screen cancer-associated scFvs against thousands of known protein sequences. This technique is nucleic acid programmable protein array (NAPPA). NAPPA involves proteins that are synthesized freshly for each experiment, therefore eliminating the need for purification, and enables thousands of different proteins to be displayed.
Of the 19 fragments, approximately two-thirds stuck to the same protein in the NAPPA array. This suggests that the protein may be a potential consistent biomarker for ovarian cancer.
To follow-up this work, the researchers plan to confirm the potential of proteins discovered and assess their clinical value.
Sources: Ramirez AB, Loch CM, Zhang Y: Use of a single chain antibody library for ovarian cancer biomarker discovery. Mol. Cell. Proteomics 9(7), 1449–1460 (2010); Arizona State University: www.asu.edu