Tumors shrank more when women given Zometa, preliminary study shows

New research adds fresh hope that a drug that strengthens bones might also fight breast cancer. Women who were given the drug, Zometa, as part of their initial treatment had greater tumor shrinkage and were less likely to need radical surgery, according to a preliminary study reported Thursday at a cancer conference in Texas.

In June, doctors were stunned when a big study found that Zometa — given to prevent bone loss caused by certain cancer treatments — also greatly cut the risk that cancer would recur in women who developed the disease before menopause.

Cancer specialists are eagerly awaiting the final results of a second, ongoing study testing Zometa in 3,360 women who had breast cancer after menopause — a much more common situation.

Its leaders gave a mini-report Thursday on 205 participants who had chemotherapy to try to shrink their tumors before surgery.

Those given infusions of Zometa along with chemo had a third more tumor shrinkage and as a result, were less likely to need their whole breast removed versus just the lump, said study leader Dr. Robert Coleman of the University of Sheffield in England.

Eleven percent of Zometa takers had a complete response to treatment — no evidence of cancer in their breasts or lymph nodes — versus 6 percent of women given chemo alone.

Partial studies like this are not enough to change practice, but these results are surprising and deserve further testing, said Dr. Eric Winer of the Dana-Farber Cancer Center in Boston. Such significant benefits from the bone drug before surgery “is not something I would have expected,” he said.

Winer had no role in the work or financial ties to any breast cancer drugmakers. He also is a spokesman for the American Society of Clinical Oncology, the largest group of doctors who treat cancer.

The study was sponsored by Zometa’s maker, Swiss-based Novartis AG, and the study leader consults for the company. With doctor fees, a Zometa infusion can run more than $1,200. In the study it was given every three weeks for four to six months.

Known side effects of Zometa and other bone-building bisphosphonate drugs like Fosamax include bone, joint or muscle pain and in rare cases, jawbone decay. They are mainly used to treat osteoporosis.

Hormone blockers may be better than tamoxifen

Also at the conference, several reports strengthened evidence that newer hormone-blockers called aromatase inhibitors, or AIs, do a better job of preventing cancer recurrences and may give a slight survival advantage over the long-used drug tamoxifen.

These drugs work against estrogen, which helps most breast tumors grow, and are given for about five years after surgery for early stage breast cancer to prevent its return.

Tamoxifen has been used for decades and is sold in generic form for about $70 a month. The newer drugs cost around $300 and come in three brands: AstraZeneca PLC’s Arimidex (anastrozole), Pfizer Inc.’s Aromasin (exemestane) and Novartis’ Femara (letrozole). They only work in women after menopause.

Doctors already know that women who take these newer drugs either as initial treatment or after a few years of tamoxifen have better chances of staying cancer-free. But which of these approaches is best is not known.

Results of a study led by Novartis consultant Dr. Henning Mouridsen of Copenhagen University Hospital in Denmark mostly were a draw. There were trends toward improved survival for women starting on Femara, but the differences were so small they could have occurred by chance alone.

Specialists took issue with a separate analysis of that study, which hinted at a bigger benefit from starting on Femara. And pooled results of prior studies involving 20,000 women suggest that any such advantage is very small.

“At this point in time, there is a slight increase in survival in patients treated with AIs but it is not statistically significant,” said that study’s leader, Dr. James Ingle of the Mayo Clinic in Rochester, Minn.

“The only really fair interpretation is that all of these are the same,” and that women should include one at some point in their treatment as guidelines now recommend, Winer said.

About 90,000 women in the United States and many more worldwide each year face this decision, and key issues are cost and side effects.

Drug side effects

Both drugs can cause hot flashes. Tamoxifen raises the risk of endometrial cancer and blood clots. The aromatase inhibitors can cause more bone loss, vaginal dryness, problems having sex, joint pain and muscle aches.

“Many of us think that overall, they’re drugs that are a little harder to take,” Winer said of the newer drugs.

“When you put it all together it’s almost a balancing act,” depending on each woman’s health history and risks, said Dr. C. Kent Osborne, a breast cancer specialist at Baylor College of Medicine in Houston.

The San Antonio Breast Cancer symposium is sponsored by the American Association for Cancer Research, Baylor and the University of Texas Health Science Center at San Antonio.

Copyright 2008 The Associated Press. All rights reserved.

Pfizer today announced results from a first planned analysis of the TEAM (Tamoxifen, Exemestane, Adjuvant, Multicenter) trial. TEAM was originally designed in 2001 as a comparison of 5 years of upfront AROMASIN® (exemestane tablets) vs. tamoxifen. In 2004, based on results of Intergroup Exemestane Study (IES) the TEAM trial design was revised; the tamoxifen arm was converted into a tamoxifen/AROMASIN sequencing arm. This analysis presented at SABCS represents the first of two co-primary endpoints that will be reported from this trial. The first co-primary endpoint compares early events by measuring disease-free survival (DFS: disease progression or death) at 2.75 years in 9,775 patients randomized to initial therapy with either tamoxifen or AROMASIN.

The analysis of DFS at 2.75 years demonstrated an 11 percent reduction in the risk of DFS events in favor of AROMASIN (HR=0.89; 95% CI, 0.77-1.03). This difference was not statistically significant (p=0.118). A second planned analysis of DFS after five years of therapy is expected in late 2009. Results from TEAM trial sub-studies were also presented at SABCS.

“The TEAM data contribute to the growing knowledge of the role of aromatase inhibitors in the treatment of early breast cancer,” said Dr. Steve Jones, medical director, U.S. Oncology Research, Houston and Texas Oncology, Dallas, TX. “Clinicians take into account patient profile, clinical evidence and guidelines when determining the optimal treatment regimen for patients, and should consider these new data as treatment strategies are evaluated.”

Additional TEAM Study Results

– Additional secondary analyses demonstrated a:

- 15 percent reduction in the risk of recurrence-free survival(RFS) events in favor of AROMASIN (HR=0.85; 95 percent CI, 0.72-1.00; p=0.049)

- 19 percent improvement in the time-to-distant metastasis in favor of AROMASIN (HR=0.81; 95 percent CI, 0.67-0.98; p=0.026)

– When adjusting the primary DFS analysis accounting for discontinuation rates and patients who switched prior to 2.5 years, an analysis showed a 17 percent reduction in the risk of DFS events at 2.75 years in favor of AROMASIN (HR=0.83; 95 percent CI, 0.71-0.97; p=0.021)

- Treatment discontinuation rates for tamoxifen and AROMASIN were 29.5 percent and 18.9 percent, respectively

- 754 patients in the tamoxifen arm switched prior to 2.5 years

– The most common side effects reported in the TEAM trial were consistent with the expected safety profile of these agents. Side effects were coded by NCI CTC (version 2), and included for tamoxifen and AROMASIN (all grades), respectively: hot flashes (33 percent, 28.5 percent); arthralgias (9.2 percent, 18.4 percent); fatigue (16 percent, 16.8 percent); pain (13.2 percent, 14.6 percent); infection (13 percent, 11.9 percent)

– The incidence of bone-related side effects for tamoxifen and Aromasin, respectively, were:

- Osteoporosis (2.2 percent, 4.9 percent)

- Spine/wrist/hip fractures (0.5 percent, 0.6 percent)

TEAM Sub-studies

– Data from the TEAM Pathology study support the prognostic value of PgR in ER+ early breast cancer

– Results from additional TEAM sub-studies (bone, cognitive function, quality of life and physical activities) were also presented

About the TEAM Trial

TEAM is a randomized, open-label, multinational trial in 9,775 postmenopausal women with hormone sensitive early breast cancer. The TEAM trial represents an international collaboration of investigators in 9 countries who conducted the trial following protocols representative of local clinical practice.

TEAM was originally designed in 2001 as a comparison of 5 years of upfront AROMASIN® (exemestane tablets) vs. tamoxifen. In 2004, based on results of IES the TEAM design was revised; the tamoxifen arm was converted into a tamoxifen/AROMASIN sequencing arm. The modified design includes two co-primary endpoints comparing DFS in a pre-planned pooled analysis:

– At 2.75 years in patients randomized to initial therapy with either tamoxifen or AROMASIN (presented at SABCS 2008)

– In patients treated with AROMASIN for 5 years versus patients who received sequential therapy of tamoxifen for 2.5-3 years followed by AROMASIN for a total of 5 years

Secondary endpoints included overall survival, time to new primary breast cancer, recurrence-free survival, time to new primary cancers (other than breast) and safety and tolerability. The TEAM trial includes 19 prospectively planned observational and translational research sub-studies.

“Aromasin has had an important impact on the treatment of women with breast cancer since its approval,” said Dr. Ray Urbanski, senior medical director/Oncology Group Lead. “We are proud of our heritage in breast cancer, and continued commitment to develop new treatment options to meet the unmet needs of these patients.”

About Aromasin® (exemestane tablets)

Aromasin is the only aromatase inhibitor indicated for sequential therapy in postmenopausal women with HR positive early breast cancer after 2-3 years of tamoxifen for a total of 5 years of adjuvant therapy. The use of Aromasin in this setting is supported by the landmark IES trial. Aromasin is also indicated for the treatment of advanced breast cancer in postmenopausal women whose disease has progressed following tamoxifen therapy.

Important Aromasin®(exemestane tablets)Safety Information

AROMASIN should not be used in women who are premenopausal, are nursing or pregnant, have a known hypersensitivity to the drug, or are taking estrogen-containing agents. Dose modification is recommended for patients who are receiving certain medications, including strong CYP 3A4 inducers. In patients with early breast cancer, elevations in bilirubin, alkaline phosphatase, and creatinine were more common in those receiving AROMASIN than either tamoxifen or placebo.

About Pfizer Oncology

Pfizer Oncology is committed to the discovery, investigation and development of treatments and currently has 22 innovative compounds in clinical development across four platforms. By leveraging the strength of our resources and scientific talent, Pfizer Oncology strives to discover and develop novel treatment options to improve the outlook for oncology patients. Pfizer currently devotes more than 22 percent of its total R&D budget to the field of oncology, investing annually in worldwide research initiatives. We also partner with healthcare providers, governments and local communities around the world to provide better quality healthcare and health system support. For more information on the above information, please visit http://www.Pfizer.com.

For more information on AROMASIN and Pfizer Oncology, including full prescribing information for AROMASIN, please visit http://www.Pfizer.com.

Pfizer Oncology

Women have easier and quicker access to the morning after pill since the Food and Drug Administration ruled that the medication could be sold to adults without a prescription, a survey of pharmacies in three large US cities shows.

In 2006, the FDA approved "behind the counter" status for Plan B — meaning that people aged 18 and older can buy the emergency contraceptive over the counter, while younger people need a prescription from a doctor. The medication consists of a high dose of progesterone, and works by preventing the ovaries from releasing an egg, or delaying this release. Unlike the "abortion pill," RU-146, it will not affect an existing pregnancy.

"The sooner you take it the more effective it is, which is why availability is so important," Dr. Rebekah E. Gee of the University of Pennsylvania School of Medicine in Philadelphia, the lead researcher on the study, told Reuters Health. Plan B works best if it is taken within 24 hours of unprotected sex, she added.

To investigate whether the rule change had any effect on the drug’s availability, Gee and her colleagues surveyed pharmacies in Atlanta, Boston, and Philadelphia in 2005 and 2007. The first round of the survey included 1,087 pharmacies, while the second included 795.

In 2005, Gee and her team found, 23 percent of pharmacies reported being unable to dispense Plan B within 24 hours. Two years later, just 8 percent did. And 2 percent of the pharmacists surveyed in 2007 said they would refuse to dispense the drug, compared to 4 percent in 2005.

In Atlanta, where state law permits pharmacists to refuse to dispense emergency contraception if it conflicts with their moral or religious beliefs, the rate of refusal was 9 percent in 2005 and fell to 2 percent in 2007. The percentage of pharmacies that were unable to dispense the drug within 24 hours fell from 35 percent to 14 percent.

Philadelphia has no laws on the books regarding whether a pharmacist can refuse to dispense emergency contraception or requiring pharmacies to stock commonly used medications. In that city, the percentage of pharmacies reporting being unable to dispense the drug fell from 23 percent in 2005 to 10 percent in 2007, while refusal rates were 3 percent in 2005 and 4 percent in 2007.

In Boston, which has laws requiring pharmacies to stock all commonly available medications, rates of being unable to dispense Plan B or refusing to do so were low at both time points.

Plan B is extremely safe, Gee noted, with nausea being the most common side effect. She said she believes it should be available without a prescription to younger people as well. "There’s no evidence that use of Plan B leads to more intercourse or riskier behavior, even though some of its opponents have claimed that," she added. "The data definitely show that that’s not true."

The US has the highest rate of unplanned pregnancies in the industrial world, Gee pointed out, while 1 in 3 US women will have an abortion. Plan B does not reduce rates of unplanned pregnancy in the population at large, she added; she and her colleagues say that this is because it isn’t a replacement for routine contraception. "Only through increased access to more effective methods of contraception and by empowering women to be educated about their reproductive health will we likely see a change in unintended pregnancy rates," they wrote.

American Journal of Obstetrics & Gynecology.

Scientists have long known that women’s preferences for masculine men change throughout their menstrual cycles. A new study from Indiana University’s Kinsey Institute is the first to demonstrate differences in brain activity as women considered masculinized and feminized male faces and whether the person was a potential sexual partner.

The researchers identified regions of the brain that responded more strongly to masculine faces and demonstrated that differences between masculinized and feminized faces appeared strongest when the women were closer to ovulating.

The study, published in an online edition of the journal “Evolution and Human Behavior,” sheds light on the link between women’s hormone levels and their brain responses to masculinized versus feminized male faces, potentially offering insights into female mate preferences. The current study points towards enhancements of both sensory discrimination and risk processing around ovulation in response to masculine faces as possible mediators of women’s mate preferences.

“One area of the brain in which we observed a difference in activation in response to masculinized versus feminized faces — specifically during the follicular phase — was the anterior cingulate cortex, which is a region involved in decision-making and the evaluation of potential reward and risk,” said neuroscientist Heather Rupp, research fellow at the Kinsey Institute for Research in Sex, Gender and Reproduction at Indiana University. “Activation in this region has been previously reported to correlate with ‘high risk’ nonsocial choices, specifically monetary risk, so it is interesting that it is observed to be more active in response to masculinized male faces, who may be both riskier but more rewarding to women.”

Previous studies have shown that women’s sexual preference for facial characteristics vary depending on their menstrual phase. These fluctuating preferences are thought to reflect evolutionarily founded changes in women’s reproductive priorities. Around the time of ovulation women prefer more masculinized faces — faces with features that indicate high levels of testosterone. These facial cues predict high genetic quality in the male because only such males can afford the immune-compromising effects of testosterone. Testosterone may be costly for the males’ mates as well because high testosterone levels also are associated with high rates of offspring abandonment.

Around the time of ovulation, a female’s preference apparently shifts from avoiding negligent parenting to acquiring the best genes for her offspring. At other points during the cycle, women will prefer more feminized male faces, as they might signal a higher willingness of the males to invest in offspring.

Rupp and her team set out to explore the link between hormone levels and brain responses to masculinized versus feminized male faces. Pictures of 56 male faces were masculinized and feminized using standard computer-morphing software. Twelve heterosexual women, averaging about 25 years old, were tested during the follicular phase, which is closer to ovulation and higher fertility time, and the luteal phases of their menstrual cycles. Before each test session their blood was collected for hormone analyses. While brain activity was measured using functional Magnetic Resonance Imaging, women viewed the masculinized and feminized male faces, indicating their interest in the man depicted as a potential sexual partner.

Researchers found differences in brain regions related to face perception, decision making and reward processing that responded more strongly to masculinized than feminized faces, suggesting that “neural activation in response to face stimuli is sensitive to facial masculinization, even in the absence of differences in subjective ratings.” Differences between masculinized and feminized faces appeared strongest during the follicular phase, closer to ovulation.

The article appears in the journal’s online edition and will appear in print in January.

Co-authors include Thomas W. James, Department of Psychological and Brain Sciences; Ellen D. Ketterson, Department of Biology; Dale R. Sengelaub, Department of Psychological and Brain Sciences; Erick Janssen, Kinsey Institute; Julia R. Heiman, Kinsey Institute and Department of Psychological and Brain Sciences.

The study was supported by National Institutes of Health.

Indiana University.

Blood sample from mother less invasive than current screening procedures

Doctors may soon be able to diagnose inherited diseases such as cystic fibrosis, thalassaemia and sickle cell anemia in fetuses by simply testing a blood sample taken from the mother. Until now, prenatal diagnoses of such disorders have been possible only through invasive procedures like amniocentesis, which carry a risk of fetal miscarriage.

Amniocentesis is the extraction of a small amount of fluid from the sac surrounding a developing fetus. But scientists in Hong Kong and Thailand may have found a way to diagnose in fetuses such “monogenic” diseases, which are caused by a single error in a single gene in the human DNA.

“Such diseases can be diagnosed by a simple blood test (taken from the mother) … and by counting the relative ratio of the mutant genes against the normal genes,” said lead researcher Dennis Lo at the Chinese University of Hong Kong.

This is only possible because fetal DNA circulates in maternal blood, a discovery Lo and his colleagues made several years ago. Many scientists have since been trying to find the best way to differentiate fetal DNA from maternal DNA, before they can even get down to looking for any anomalies in the fetal DNA. But these efforts have not met with much success.

In an article published in the Proceedings of the National Academy of Sciences, Lo and his colleagues said they had devised a counting system that could “bring non-invasive prenatal diagnosis of monogenic diseases closer to reality.”

Using highly precise digital blood testing technology, both mutant and normal DNA sequences are counted in maternal plasma and that is then used to calculate the number of mutant genes inherited by the fetus and to determine the probability of the fetus developing any monogenic disease. Lo, however, noted that the accuracy of this method would depend on the concentration of fetal DNA in maternal blood.

Thalassaemia is a blood related genetic disease that can result in reduced fertility or even infertility. Early treatment can improve the quality of life of patients. Cystic fibrosis affects the respiratory, digestive and reproductive systems and can lead to fatal lung infections.

Copyright 2008 Reuters.

Two new compounds created by a University of Central Florida professor show early promise for destroying breast cancer tumors. The compounds disrupt bonding of a cancer-related protein.

Associate Professor James Turkson’s compounds disrupt the formation and spread of breast cancer tumors in tests on mice. The compounds, S3I-201 and S3I-M2001, break up a cancer-causing protein called STAT3, and researchers have observed no negative side effects so far.

“The compounds are very promising,” Turkson said. “They’ve worked very well in mice, and now we’re looking for partners to help us take these compounds to the next level of trials.”

Turkson’s research has been published in the academic journals Proceedings of the National Academy of Sciences and ACS Chemical Biology, and he has obtained patents for both compounds.

Turkson is passionate about his research and has a very personal reason for wanting to find a cure for cancer. During his first year of college, his 52-year-old mother was diagnosed with uterine cancer and died. He dedicated his life to finding a cure.

The two compounds developed in his lab hold promise in part because they efficiently disrupt the abnormally active STAT3 protein he said.

“We all have the STAT3 protein in our bodies, and under normal circumstances it causes no harm. But in breast cancer patients, the protein is abnormally active. It never shuts off.”

When that happens, the protein goes into overdrive and is bent on supporting the proliferation of breast cancer cells. The protein even creates a network of blood vessels to feed the cancer cells, support their growth and eventually promote the spread of the cancer into the blood, bones and organs.

“Our compounds go after STAT3, stripping away its power,” Turkson said.

Both compounds disrupt the bonding process that one STAT3 molecule goes through to connect with another in the body. If the STAT3 can’t bond to stay abnormally-active, cancer cells can’t develop. The network of blood vessels that formed to feed the cancer cells also shuts off.

Left without their source of food, the existing cancer cells die off. The body’s immune system, which until now has been tricked by the abnormally active STAT3 into thinking the tumor cells are harmless, also recognizes that something is wrong. The immune system re-activates, recognizes any remaining cancer cells as harmful and destroys them.

Turkson worked with researchers at the H. Lee Moffitt Cancer Center and Research Institute, and the Beckman Research Institute and the Comprehensive Cancer Center of the City of Hope National Medical Center.

Turkson is a native of Ghana, West Africa. He completed his studies and obtained his honors B.S. degree in Biochemistry with Chemistry at the University of Ghana. He earned a Ph.D. in Pharmacology from the University of Alberta in Canada.

He completed post-doctoral fellow training in Molecular Oncology at the H. Lee Moffitt Cancer Center and Research Institute in Tampa, where he served as an assistant professor before joining UCF’s Burnett School of Biomedical Sciences in 2005.

While Turkson continues to look for partners to further his research, he’s already working on a similar compound for pancreatic cancer.

In that case the compound would enhance the potency of another drug and use the body’s immune system to make the effect more powerful.

University of Central Florida.

Women are more likely than men to be hospitalized for chest pain for which doctors cannot find a cause, according to the latest News and Numbers from the Agency for Healthcare Research and Quality. In 2006, there were 477,000 admissions of women to U.S. community hospitals for unspecified chest pain compared with 379,000 admissions for men.

Unspecified chest pain is usually characterized by a feeling of pressure, burning, or numbness. Although it is not clear why women receive this diagnosis more than men, there is some evidence that heart disease develops differently in women than men and that symptoms may be different. Medical experts believe that physicians may not always be aware of this gender difference.

The federal agency also found that men were more likely to be hospitalized for heart disease or heart attacks than were women in 2006.

Specifically:

- Women made up 56 percent of all admissions for unspecified chest pain, but only 38 percent of all admissions for coronary artery disease.

- Roughly 451,000 women, compared with 747,000 men, were hospitalized for coronary artery disease. This disease results in narrowing of the arteries.

- Heart attacks, which are usually caused by heart disease, sent 269,000 women to hospitals, compared with 406,000 men. Women made up 40 percent of all admissions for heart attacks.

- Hospitalizations for congestive heart failure were roughly the same for women (565,000) and men (534,000).

- Hospitalizations for irregular heart beat were also similar for women (379,000) and men (369,000).

This AHRQ News and Numbers summary is based on data in HCUP Facts and Figures, 2006, which provides highlights of the latest data from the 2006 Nationwide Inpatient Sample, a part of AHRQ’s Healthcare Cost and Utilization Project. The report provides data on leading reasons for hospitalization, such as arthritis, asthma, childbirth, cancer, diabetes, depression, and heart conditions, on procedures performed on hospital patients, and on related topics.

AHRQ