Abstract
Researchers hope that new findings will help to further personalize breast cancer treatment in the future.
Metastatic recurrence rates of breast cancer have been effectively reduced by adjuvant chemotherapy regimes after surgery, although there are still a considerable number of women who suffer recurrent cancer at distant metastatic sites despite the use of adjuvant treatment. Therefore, the results of the study carried out by a group of investigators from the Dana-Farber Cancer Institute (MA, USA) have important implications for the future treatment of breast cancer. The study, published in Nature Medicine, could lead to the development of a new genetic test for breast cancer that may help to guide physicians in choosing the best first course of treatment for individual patients.
The study's investigators wanted to identify the genes that are crucial for tumor response to specific chemotherapy drugs, which is necessary in order to improve outcomes. They set out to search for specific molecular properties observed only in tumors that cause some patients to suffer recurrences after breast cancer surgery despite adjuvant chemotherapy. Based on their structures and functions, the investigators identified two probable gene candidates that might be involved the drug resistance of tumors. The two genes are called LAPTM4B and YWHAZ.
Led by Andrea Richardson and Zhigang Charles Wang, the investigators identified two genes that enabled cancer cells to be resistant to the effects of anthracyclines when abnormally active. This class of chemotherapy agents include doxorubicin, daunorubicin and epirubicin, which are often used as adjuvant therapy in breast cancer. However, the overexpression of the two genes did not protect laboratory-grown breast cancer cells against other classes of drugs, including paclitaxel and cisplatin.
Breast tumor samples were taken from a total of 85 patients and analyzed by the investigators who identified a particular gene signature associated with only the drug-resistant samples (which occurred in approximately 1 in 5 samples). The clinical records on file were matched with the drug-resistant samples that came from those patients who had poorer outcomes, and those without the abnormal gene signature were matched with patients whose cancer did not recur.
“These results suggest that tumors resistant to anthracyclines may still be sensitive to other agents”, commented Richardson, who is also on the faculty at Brigham and Women's Hospital and Harvard Medical School. “So this would be very useful as a test to help pick the therapy that's going to be most effective for these patients”.
Eric Winer, the director of the Breast Oncology Center at Dana-Farber remarked that, “While this work remains preliminary, it may ultimately help us use the anthracyclines in a much more thoughtful manner and allow us greater ability to personalize our breast cancer treatments to the tumor and the patient”.
Source: Li Y, Zou L, Qiyuan Li et al.: Amplification of LAPTM4B and YWHAZ contributes to chemotherapy resistance and recurrence of breast cancer. Nat. Med. DOI: 10.1038/nm.2090 (2010) (Epub ahead of print).
Emergency contraceptive pill ellaOne® may be effective at preventing pregnancy for up to 5 days after sexual intercourse
A study recently published in The Lancet that set out to compare the efficacy and safety of a newer form of emergency contraceptive, ulipristal acetate, with the most commonly administered form, levonorgestrel (Plan B®), found that ulipristal acetate appears to be more effective for a longer period of time and may prevent unwanted pregnancy for up to 5 days after unprotected sexual intercourse, compared with a window of 3 days with Plan B. Available by prescription in Europe under the brand name ellaOne® (HRA Pharma, France), it could provide healthcare workers and women with an effective, alternative form of emergency contraception (EC).
Anna Glasier and colleagues from the Family Planning and Well Woman Services at Dean Terrace Centre (UK), enrolled women with regular menstrual cycles who attended a family planning clinic in order to obtain EC within 5 days of unprotected sexual intercourse. A total of 2221 women were randomly assigned to receive a single, supervised dose of 30 mg ulipristal acetate (n = 1104) or 1.5 mg Plan B (n = 1117) orally in a randomized, multicenter, noninferiority trial. Of these women, 1696 received the EC within 72 h of sexual intercourse (ulipristal acetate, n = 844; levonorgestrel, n = 852). Participants were followed-up 5–7 days after expected onset of subsequent menses and the primary end point measured was pregnancy rate in women who received EC within 72 h. The study found that there were 22 pregnancies in the group that received levonorgestrel compared with 15 in the group that received ulipristal acetate. In the 203 women who received EC between 72 h and 120 h after sexual intercourse, there were three pregnancies, all of which were in the levonorgestrel group. Ulipristal acetate appeared to work consistently for up to 5 days, whereas levonorgestrel decreased in effectiveness over time.
Glasier explained that the discrepancy may be due to the different modes of action between the two pills; Plan B contains synthetic progesterone and mimics the effects of the natural hormone by interfering with ovulation as the egg develops, whereas ellaOne delays ovulation. However, Glasier cautioned that more safety data are needed before the new drug can be recommended for over-the-counter use, and estimated that the drug costs approximately three-times more than Plan B. The study was designed and funded by HRA Pharma.
Source: Glasier AF, Cameron ST, Fine PM et al.: Ulipristal acetate versus levonorgestrel for emergency contraception: a randomised non-inferiority trial and meta-analysis. Lancet DOI: 10.1016/S0140-6736(10)60101-8 (2010) (Epub ahead of print).
In brief…
Lancaster C, Gold K, Flynn H, Yoo H, Marcus S, Davis M: Am. J. Obstet. Gynecol. 202(1), 5–14 (2010). Stress and anxiety can increase the risk of depression during pregnancy, a new study suggests. Researchers from the University of Michigan reviewed the results of 57 studies carried out between 1980 and 2008 in order to determine the main risk factors contributing to depression in pregnancy. A history of depression, stress, anxiety, smoking, a lack of social support, low income and poor education, as well as relationship quality were all associated with an increased risk of antepartum depression in bivariate analysis. In multivariate analysis life stress, lack of social support and domestic violence each continued to demonstrate a link with depressive symptoms. It is important for physicians to know how to identify an increased likelihood of depression during pregnancy since it can cause problems for both mother and baby. These include preterm delivery, pre-eclampsia, sleeping difficulties and problems with mother–infant bonding. However, it should be noted that not all women who experience these risk factors will go on to develop clinical depression.
Walker E, Rodriguez A, Kohn B et al.: J. Clin. Oncol. 28(4), 634–640 (2009).
Acupuncture has been found to reduce hot flashes in breast cancer patients, as well as improving energy, wellbeing and sex drive. Eleanor Walker and her team from the Department of Radiation Oncology at Henry Ford Hospital (MI, USA) carried out the first randomized controlled trial comparing acupuncture and drug therapy. Acupuncture was found to have a longer-lasting effect on the reduction of night sweats and hot flashes, the side effects often suffered by women receiving hormone therapy for breast cancer. A total of 50 breast cancer patients were randomly assigned to receive 12 weeks of either acupuncture or venlafaxine treatment. They were then monitored for up to 1 year after treatment. Acupuncture was found to be as effective as venlafaxine and did not result in adverse side effects such as nausea, dizziness and dry mouth that drug treatment did. Most women receiving acupuncture also reported an increase in energy, clarity of thought and a sense of wellbeing, while some also reported an increased sex drive.
Study suggests that human papillomavirus testing is more efficient than smear tests for over 35s
The results of a new study suggest that invasive cervical cancers could be detected earlier if human papillomavirus (HPV) testing was used in the first instance rather than smear testing.
Human papillomavirus has been strongly linked to cervical cancer. Testing women for the presence of the virus could help to detect cancers earlier, begin treatment sooner and consequently reduce the number of cervical cancer deaths.
Researchers from the Centre of Cancer Prevention (Italy) studied data from 95,000 women between the ages of 25 and 60 years collected over a period of 3.5 years. They found that fewer women who were tested for HPV developed cancer compared with those who only received smear tests.
The HPV test was found to be more sensitive, but less specific, than cytology for detecting cervical intraepithelial neoplasia. The HPV test is more effective than smear testing because it detects persistent high-grade lesions earlier and provides a longer low-risk period. However, in women under the age of 35 years there is a risk of over-diagnosis, since the test detects problems that would spontaneously correct themselves.
“The HPV test was found to be more sensitive, but less specific, than cytology for detecting cervical intraepithelial neoplasia.”
Owing to the high number of transient HPV infections in young women, the test will probably have a greater role in the future of cancer detection in older women. The researchers advise that the HPV test should be used in the first instance in women over 35 years and, following the test, only those with a positive result should be referred for a smear test and any necessary treatment.
“Our data support the use of standalone HPV testing as the primary screening test” claims Guglielmo Ronco, from the Centre of Cancer Prevention, who led the research.
It is also thought that the HPV test could reduce the frequency of screening. The study's results suggest that the HPV test would only need repeating once every 5 years rather than the 3-year repeat period recommended for the smear test.
“We might be able to spot the warning signs even earlier and it might, in future, mean that women go for screening less often.” commented Lesley Walker, director of cancer information at Cancer Research UK.
Source: Ronco G, Giorgi-Rossi P, Carozzi F et al.: Efficacy of human papillomavirus testing for the detection of invasive cervical cancers and cervical intraepithelial neoplasia: a randomised controlled trial. Lancet Oncol. DOI: 10.1016/S 1470-2045(09)70360-2 (2010) (Epub ahead of print).
Breast cancer drug approved for new indication
The US FDA has extended its approval for the drug lapatinib (Tykerb®, GlaxoSmithKline, PA, USA) to allow its use in combination with letrozole (Femara®, Novartis AG, PA, USA) to treat postmenopausal women with hormone-positive and HER2-positive advanced breast cancer, for whom hormonal therapy is indicated.
Lapatinib is an orally administered small-molecule tyrosine kinase inhibitor that is specific for the HER2/ErbB2 receptor. It was already approved for use in combination with capecitabine and in the treatment of advanced or metastatic HER2-positive breast cancer in women who had progressed on previous therapy that had included an anthracycline, a taxane and trastuzumab.
More than 192,000 women are diagnosed with breast cancer annually. Of these, approximately 70% have hormone receptor-positive tumors. Many tumors that initially respond to antihormonal therapy, such as letrozole, go on to develop resistance. Therefore, there is a need for combination therapies to combat this resistance and improve the prognosis of these women.
The approval for this combination was based upon the results of a double blind trial in which progression-free survival was increased from 13 weeks with letrozole alone to 35 weeks with the combination therapy (p = 0.02). It is not yet possible to determine whether overall survival is improved by the combination.
There were no new side effects compared with previous studies of lapatinib in advanced breast cancer, with the most common adverse events being diarrhea, rash, nausea and fatigue. Lapatinib use should be avoided in pregnancy and has been associated with decreases in heart function, liver damage and lung tissue inflammation.
“This drug combination of Tykerb plus Femara provides women being treated for advanced breast cancer with an important treatment option. This entirely oral treatment regimen works by targeting both HER2 and the hormone receptors, thereby slowing the cancer cells' ability to grow or spread,” explained Richard Pazdur, director of the Office of Oncology Drug Products, in the FDA's Center for Drug Evaluation and Research.
Source: FDA expands use of approved breast cancer drug. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm199374.htm