Abstract
Researchers suggest that the findings from their study may be useful in the future to predict which patients are likely to respond to tamoxifen
New understanding of the mechanism of tamoxifen resistance
Women who are diagnosed with breast cancer are prescribed tamoxifen for a period of 5 years in order to prevent the disease from returning. However, some patients develop resistance to the drug, meaning that there is a greater likelihood that the cancer will recur. Understanding how tamoxifen resistance occurs will help in combating this problem. It is already known that tamoxifen functions by acting on certain genes to block the production of estrogen, which aids tumor growth in common types of breast cancer; however, the exact mechanism of action of tamoxifen has not been completely elucidated until now. Researchers from the Cambridge Research Institute, UK have found that tamoxifen blocks a breast cancer gene called ERBB2 via the paired box 2 gene product (Pax2). Lead investigator, Jason Carroll and his team examined 109 breast cancer tumors, all of which had been treated with tamoxifen. Upon analysis, 68 of the tumors were seen to be PAX2-positive, while 41 were PAX2-negative. Published in the journal Nature, the study also revealed that women with PAX2-positive tumors had a “significantly improved” chance of survival without cancer recurrence in comparison to those who had PAX2-negative tumors. The researchers concluded that PAX2 is a crucial player in controlling ERBB2 activity since it acts as a switch to repress ERBB2 activity. In addition, resistance to tamoxifen occurs when ERBB2 remains switched on.
The switch for the HER2 gene is hidden within the gene, Carroll states, referring to PAX2 as “the handle that keeps HER2 switched off.” In the absence of PAX2, or if PAX2 is forced out by another protein called AIB1, then the switch fails. “It's a tug of war,” Carroll explains. “It's a competition between PAX2 and AIB1. The balance between PAX2 and AIB1 determines whether HER2 is switched on or switched off, and this directly dictates whether tamoxifen works or not.”
Discussing the implications of the findings, Carroll remarked: “We knew that women developed resistance to tamoxifen but previously our understanding of why this occurred could be compared with trying to fix a broken car without knowing how the engine worked. Now we understand how all the engine parts operate and we can try to think about ways to make repairs.”
Carroll believes that the information provided from this study could be used to predict which patients are likely to respond to tamoxifen, and which patients are not likely to respond to the drug. “If we can identify the women who are not going to respond to tamoxifen we can think about alternative therapies, which are probably going to be more effective for these women.”
Sir David Lane, chief scientist at Cancer Research UK, which funded the study, explained the significance of the findings: “Tamoxifen has been a huge success story helping to prevent breast cancer recurring for many women. Understanding why it occasionally stops working is really important because it allows us to identify new targets for drug development and who will need such treatments.”
Len Lichtenfeld, deputy chief medical officer of the American Cancer Society, believes that the finding will not have an immediate effect on treatment, but might help direct therapy in the future.
“We have learned a lot about what makes a cancer cell a cancer cell, and how it works. And we have also learned how to better treat breast cancer. Understanding these mechanisms will inevitably open up new treatment opportunities,” Lichtenfeld commented.
Source: Hurtado A, Holmes KA, Geistlinger TR et al.: Regulation of ERBB2 by oestrogen receptor-PAX2 determines response to tamoxifen. Nature (2008) (Epub ahead of print).
New evidence casts doubt over efficacy of popular pregnancy-maintenance drug
A study group of scientists from Stanford University School of Medicine, Lucile Packard Children's Hospital and the Santa Clara Valley Medical Center, CA, USA, have demonstrated that the commonly used drug nifedipine, administered both to halt initial bouts of preterm labor and subsequently maintain a pregnant state in women, may have little or no benefit with regard to its latter function compared with placebo. This new evidence casts doubt over whether its suitability for widespread use for this indication is justified.
Nifedipine is a calcium-channel blocker that has the ability to relax and dilate arterial muscles, making it an effective treatment for conditions such as low blood pressure and angina. More recently, it has been exploited by the obstetrician for prevention of both acute and maintenance treatment of premature births. To prevent the multitude of heath complications that arise from the birth of preterm infants (an observation increasing at an alarming rate in the USA), it is essential that doctors keep the mother in a state of pregnancy for as long as possible. A recent survey by the Society for Maternal–Fetal Medicine found that, of the 29% of obstetricians that regularly prescribe drugs to keep patients from re-entering early labor, 79% classed nifedipine as their first-choice therapy.
In the study, lead author, Deirdre Lyell, and colleagues wished to investigate the drug's efficacy with regard to preventing susceptible women from giving birth before the accepted length of term, in other words, 37 weeks of a 40-week pregnancy. A total of 71 women who had successfully undergone preventative treatment for premature labor between 24 and 32 weeks gestation were randomly assigned either the active drug or placebo once every 6 h, with cessation of treatment at either the 37-week stage or delivery. In addition to monitoring the level of premature delivery between the study contingents, the group also measured the length of time by which pregnancy was delayed and noted health complications observed in the newborns. Lyell discovered that there were no significant differences in any measurement between the control and active groups; in both, premature labor was prevented prior to the 37-week stage in 40% of women and the average delay of delivery was 1 month. In addition, there were no significant differences in health of the baby and birth complications.
“Medication use should be minimized in pregnancy unless it's clearly indicated,” states Lyell. Although adverse reactions with nifedipine are mild and infrequent, common side effects include headache, dizziness, flushing and edema of the lower extremities, and to a lesser extent, dizziness, nausea and constipation. Several case reports have also linked nifedipine to dangerously low blood pressure in pregnant women. “If something has not been shown to be of benefit, it shouldn't be used,” Lyell continued. “Every now and then, there will be a patient who has an unusual side effect…We all want to prevent preterm birth, but prolonged treatment with nifedipine doesn't appear to be an answer.”
Lyell conceded that the study was designed to detect a reduction of premature births of at least 50% and so any advantage conferred that fell under this threshold would not have been detected in this study. She states that further large-scale study of the drug is warranted because a small benefit could be especially significant at early gestational ages, although overall the use of nifedipine appears to offer no benefit.
Source: Lyell DJ, Pullen KM, Mannan J et al.: Maintenance nifedipine tocolysis compared with placebo: a randomized controlled trial. Obstet. Gynecol. 112(6), 1221–1226 (2008).
in brief…
Sidhu RB, Brown JR, Robb JF et al.: Am. J. Cardiol. 102(11), 1482–1486 (2008).
In a recent study, researchers Investigated the relative Impact of gender and age on the development of contrast-induced acute kidney injury (CIAKI) following cardiac catheterization. The large, prospective study included 13, 127 participants who were stratified by age and gender into four age categories (<50, 51–64, 65–79 and >80 years). Within each age category, men and women were compared for the development of CIAKI in the period following angiography. The incidence of postprocedural CIAKI and mortality rates among groups were compared. The results demonstrated that the rates of postcatheterization CIAKI were higher for women compared with men in the age groups 65–79 years (14.5 vs 11.0%; p <0.001) and over 80 years (18.7 vs 15.1%; p = 0.048); however, no differences were observed in the younger cohorts. The researchers conclude that geriatric women are at greatest risk for the development of CIAKI after angiography.
The natural history of invasive breast cancers detected by screening mammography.
Zahl PH, Màhlen J, Welch HG: Arch. Intern. Med. 168(21), 2311–2316 (2008).
Researchers compared cumulative breast cancer incidence in age-matched cohorts of women residing in four Norwegian counties before and after the initiation of biennial mammography. The screened group included all women who were invited for all three rounds of screening during the period 1996–2001 (age range in 1996: 50–64 years). The control group included all women who would have been invited for screening if there had been a screening program in place during the period 1992–1997 (age range in 1992: 50–64 years). Prior to the age-matched controls being screened at the end of their observation period, the cumulative incidence of invasive breast cancer was significantly higher in the screened group than in the controls, as expected. However, even after prevalence screening in controls, the cumulative incidence of invasive breast cancer remained 22% higher in the screened group and higher incidence was observed in screened women at each year of age. The researchers conclude that since the cumulative incidence among controls never reached that of the screened group, it may be that some breast cancers detected by repeated mammographic screening would not develop to be detectable by a single mammogram at the end of 6 years. The authors suggest the possibility that the natural course of some screen-detected invasive breast cancers is to spontaneously regress.
Women who fail to take breast cancer drug may be hindering their chance of survival
A study published in the British Journal of Cancer has demonstrated that many women who are prescribed tamoxifen for breast cancer fail to complete the course, thus decreasing their chance of survival.
“We know that tamoxifen saves lives, so these results are a real concern.”
The researchers, who are based at the University of Dundee, UK, conducted the study by assessing the prescription records of more than 2000 women in order to determine how many patients did not complete their full treatment of tamoxifen. Other health records were also analyzed to see whether there was any association with survival chances. The researchers found that 10% of women who were followed for 1 year had stopped taking tamoxifen. After 3.5 years, it was found that 32% of women had stopped taking the drug and a total of 51% of patients were found to have stopped after 5 or more years. Furthermore, the study demonstrated that younger women were more inclined to discontinue their medication. No difference was observed between rich and poorer groups of women.
Lesley Walker, Director of Information at Cancer Research UK, remarked: “We know that tamoxifen saves lives, so these results are a real concern. It's not disastrous if women simply forget to take the occasional tablet but if they forget regularly and don't complete their treatment we need to know why. We need to make it clear that taking tamoxifen regularly for the full 5 years gives women the best chance of surviving breast cancer. If women are experiencing problems in taking any medication then we urge them to consult their doctor.”
Source: McCowan C, Shearer J, Donnan PT et al.: Cohort study examining tamoxifen adherence and its relationship to mortality in women with breast cancer. Br. J. Cancer 99(11), 1763–1768 (2008).
US FDA approves new drug regime for painful menopause side effect
Wyeth Pharmaceuticals has announced that the US FDA has approved a new lower dose regimen of Premarin® (conjugated estrogens) 0.5 vaginal cream for the treatment of moderate-to-severe dyspareunia in postmenopausal women, becoming the first vaginal estrogen therapy to be approved for this particular indication.
“A new, low-dose regimen of Premarin vaginal cream can now be used to treat painful intercourse, as well as to restore vaginal tissue and reverse vaginal changes in menopausal women.”
The approval follows a successful 52-week trial study consisting of a 12-week randomized, multicenter, double-blind, placebo-controlled study with a subsequent 40-week, open-label, follow-up. Results emerged from the initial 12-week study that both low-dose regimens of the vaginal cream studied; 0.5 g administered 21 days on/7 days off, or twice weekly, significantly improved the dyspareunia score versus placebo by the end of the study period.
In women who had valuable endometrial biopsies at the end of the 52-week study, endometrial safety assessments showed that there were no reports of endometrial hyperplasia or endometrial carcinoma in women participating in either regimen. The most commonly reported side effects reported during the study were headache, infection, abdominal pain, accidental injury and vaginitis.
Gloria Bachmann, Director of the Women's Health Institute, University of Medicine and Dentistry of NJ-Robert Wood Johnson Medical School, New Jersey, USA remarked: “This approval is welcome news, especially when you consider that more than one in four untreated postmenopausal women experience dyspareunia, a symptom of vulvar and vaginal atrophy, which typically does not subside without treatment.”
“…more than one in four untreated postmenopausal women experience dyspareunia … which typically does not subside without treatment.”
A new, low-dose regimen of Premarin vaginal cream can now be used to treat painful intercourse, as well as to restore vaginal tissue and reverse vaginal changes in menopausal women. Eileen Helzner, Assistant Vice President of Global Medical Affairs, Wyeth Pharmaceuticals, commented that, “This indication…gives healthcare professionals and women a new option in treating moderate to severe dyspareunia due to menopause.”
Source: Wyeth: www.wyeth.com
Telomerase template inhibitor restores traztuzumab sensitivity to breast cancer cells in vitro
A recent study published in Breast Cancer Research and Treatment, demonstrated the potential of telomerase template inhibitors in overcoming resistance to more traditional therapies. A group of researchers, led by Britney-Shea Herbert from Indiana University Melvin, IN, USA and the Bren Simon Cancer Center, IN, USA, evaluated whether the telomerase template antagonist, GRN163L (currently in clinical trials for cancer treatment), has the potential to augment the effects of traztuzumab (Herceptin®, Genentech Corporate, CA, USA) in breast cancer.
GRN163L is a short-chain oligonucleotide that binds to the telomerase catalytic domain and competitively inhibits the enzyme. It has been chemically altered to enter cells via the addition of a 5’ lipid chain.
After testing the drug on a number of cell lines, of which two were resistant to traztuzumab, Herbert and her colleagues demonstrated that GRN163L is effective at inhibiting telomerase activity and shortening telomeres in HER2-positive breast cancer cells. The data demonstrate that GRN163L is effective, both on its own and in conjunction with traztuzumab. The two drugs acted synergistically to inhibit growth in HER2-positive breast cancer cells. Furthermore, the telomerase inhibitor restores traztuzumab sensitivity to cells that were previously resistant.
The paper also showed that GRN163L is specific to cancer cells and does not limit the growth rate or viability of ‘normal’ cells. These attributes imply that telomerase template inhibitors, such as GRN163L, may have significant potential in the treatment of cancers that have developed resistance to traditional therapy.
Source: Goldblatt EM, Erickson PA, Gentry ER, Gryaznov SM, Herbert BS: Lipid-conjugated telomerase template antagonists sensitize resistant HER2-positive breast cancer cells to trastuzumab. Breast Cancer Res.Treat. DOI: 10.1007/s10549-008-0201-4 (2008) (Epub ahead of print).
hTERT-inhibiting BMP-7 may be a promising cervical cancer treatment
Research published in Cancer Research by a study group from Monash University, Australia, have demonstrated that bone morphogenetic protein-7 (BMP-7) can halve the size of cervical tumors in mice at an impressively rapid speed of 1 week, suggesting that it may be a promising new treatment for cervical cancer.
“…bone morphogenetic protein-7 (BMP-7) can halve the size of cervical tumors in mice at an impressively rapid speed of 1 week…”
Lead author Jun-Ping Liu explained that BMP-7 was able to halt cellular immortalization via disruption of hTERT enzyme function, triggering a reversal of telomere maintenance that subsequently led to telomere shortening and rapid hTERT repression-dependent cervical cancer cell death.
The study involved both in vitro and tumor xenograft experiments. “A single application of recombinant BMP-7 produces a significant inhibition of telomerase activity critical in telomere maintenance in cultured cervical cancer HeLa cells,” the researchers explain. “Continuous applications of BMP-7 on every second day for two weeks in HeLa cell cultures or xenograft tumours result in sustained depression of telomerase activity and shortening of telomeres.”
hTERT gene repression, such as through the continuous treatment of mouse xenograft tumors with BMP7 results in the sustained inhibition of telomerase activity. Conversely, overexpression of the enzyme enables telomere lengthening and blocks BMP7-mediated tumor growth arrest. Thus, BMP-7 is a negative regulator of telomere maintenance.
“Within 24 h of applying BMP-7 to the cervical cancer cells telomerase production was blocked, thereby stopping the tumor's growth.” the group remarked. “Further, although telomerase is found in healthy cells, BMP-7 did not interfere with telomerase in these cells, only in the cervical cancer cells.”
Previous studies have demonstrated that telomerase also plays a key role in the formation of cancerous tumors. “It's the best indicator of cancer – 85% of all types of cancers require telomerase for the cancer cells to continue spreading,” Liu commented. “What's more, telomerase is not associated with benign tumors; it's a marker for malignant tumors only. If we can control the production of telomerase we can prevent the immortality of cancer cells and therefore cancer formation.”
Liu hopes that his group' finding will one day be used to develop an alternative approach to the treatment of cervical cancer.
Source: Cassar L, Li H, Pinto AR, Nicholls C, Bayne S, Lui J-P: Bone morphogenetic protein-7 inhibits telomerase activity, telomere maintenance, and cervical tumor growth. Cancer Res. 68, 9157–9166 (2008).
Evidence mounts for use of vitamin D as an immune enhancer during pregnancy
Martin Hewison and his team at UCLA, CA, USA recently reported their findings that vitamin D induces immune responses in placental tissues by stimulating production of the antimicrobial protein cathelicidin in vitro.
The active form of vitamin D (1,25-dihydroxyvitamin D) is a potent inducer of cathelicidin. Hewison and colleagues have demonstrated that the abundant levels of 1,25-dihydroxyvitamin D synthesizing enzyme (CYP27B1) found in the cultured human trophoblast cells were able to stimulate cathelicidin production upon exposure to vitamin D, which subsequently led to an increase in cathelicidin-mediated a ntibacterial responses.
Placental cathelicidin production is thought to stave off infection mediated by a host of pathogenic organisms including staphylococcus, streptococcus and Escherichia coli. Vitamin D has had an acknowledged, yet partially understood role in pregnancy and its associated infections for some time; this new study suggests a role for vitamin D as part of an innately conserved mechanism protecting trophoblast cells from infection-associated death through activating, enhancing and sustaining bacterial killing through cathelicidin production. It is thought that placental synthesis of cathelicidin varies widely among pregnant women. This discovery suggests that vitamin D dietary supplements could be used to boost innate immunity in pregnant women.
Source: Liu N, Kaplan AT, Low J et al.: Vitamin D induces innate antibacterial responses in human trophoblasts via an intracrine pathway. Biol. Reprod. DOI: 10.1095/biolreprod.108.073577 (2008) (Epub ahead of print).
Planned C sections do not reduce hepatitis C transmission, report suggests
In a new study, scientists from the National Maternity Hospital, Dublin, Ireland and University College Dublin, Ireland have found that the transmission of hepatitis C (HCV) virus from a pregnant mother to her unborn child is not reduced by cesarean sections.
At present, hepatitis C is one of the most prevalent chronic viral infections in western countries. Worldwide, it is estimated that 150–200 million individuals are affected. The virus is mainly transmitted by contact with contaminated blood but it can also be transmitted from an HCV-infected mother to her unborn baby during birth, in a process known as vertical transmission, although this is a relatively infrequent occurrence.
One of the largest of its kind, the study included 559 mother–child pairs in Ireland and demonstrated that the transmission rates of the virus from mother to child were almost similar with vaginal delivery and planned caesarean, at 4.2 and 3%, respectively.
“The mode of delivery itself was not shown to have a significant influence on the transmission rate of hepatitis C from mother to child,” commented Dr Fionnuala McAuliffe, senior author of the paper.
“The main risk factor associated with the vertical transmission of hepatitis C was the presence of detectable hepatitis C virus in the mother's bloodstream, a condition where viruses enter the bloodstream and hence have access to the rest of the body. Mothers who demonstrated detectable hepatitis C virus had a significantly higher transmission rate (7.1%) to their infants compared with the transmission rate (0%) for those in whom the hepatitis C virus was undetectable during pregnancy,” explained McAuliffe.
“According to these new findings, if the Hepatitis C virus is undetectable antenatally despite the mother being antibody positive the patient can be reassured that the risk of vertical transmission to their child is minimal, and this is a significant development for patient counselling,” c oncluded McAuliffe.
Sources: McMenamin MB, Jackson AD, Lambert J et al.: Obstetric management of hepatitis C-positive mothers: analysis of vertical transmission in 559 mother–infant pairs. Am. J. Obstet. Gynecol. 199(3), 315, E1–E5 (2008).
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