NEOADJUVANT CHEMOTHERAPY FOR ALL WOMEN UNDER 35?

Neoadjuvant chemotherapy might be particularly critical for very young women with certain early breast cancers because of biologic differences in their tumors, according to research presented here at the 35th Annual San Antonio Breast Cancer Symposium.

"I would personally approach all young women with these cancers by suggesting neoadjuvant chemotherapy," said lead investigator Sibylle Loibl, MD, PhD, from the University of Frankfurt in Germany. "Some people think they don't need chemotherapy at all, but I think they do," she explained.

"Breast cancer in the very young woman seems to be different.... There is something behind age that drives the biology of the cancer and makes it more chemo-responsive," she noted.

In a meta-analysis of 8 trials involving 8949 patients, Dr. Loibl and her colleagues found that women younger than 35 years were more likely to achieve a pathologic complete response (pCR) after neoadjuvant chemotherapy than women 36 to 51 years (23.6% vs 17.5%) and than women older than 51 years (13.5%; P < .0001).

Additionally, those with a pCR saw benefits in both disease-free survival and local recurrence-free survival, she said.

The superior pCR rate in young women after chemotherapy was driven by better pCR in 2 types of tumors: triple-negative tumors and luminal-like tumors, she added.

Specifically, women 35 years and younger achieved higher rates of pCR in triple-negative tumors than women 36 to 51 years (45% vs 35%) and than women older than 51 years (25%; P = .004).

Similarly, women 35 years and younger achieved higher rates of pCR in luminal-like tumors than women 36 to 51 years (approximately 11% vs 8%) and than women older than 51 years (6%; P = 0.013).

She said she expects the findings will influence clinical practice.

"I think the luminal-like patients, when they're very young, will be treated more often now with chemo. For women with triple-negative tumors, it's reassuring; we can tell them you have an almost 50% chance that everything will be gone and you'll have an excellent survival," she said.

All subjects in the meta-analysis received neoadjuvant anthracycline/taxane–based chemotherapy, and some received trastuzumab.

Generally, "in younger women, we tend to be more aggressive with chemotherapy," said Carlos Arteaga, MD, PhD, associate director of clinical research and director of the breast cancer program at the Vanderbilt-Ingram Cancer Center in Nashville, Tennessee, during a meeting press conference.

"The importance of this study is that it suggests there are some biological differences that go beyond luminal B that we have to study," he said.

Dr. Loibl and Dr. Arteaga have disclosed no relevant financial relationships. Study coauthor Gunter von Minckwitz, MD, PhD, reports being a consultant/advisor for sanofi-aventis, Roche, Amgen, AstraZeneca, Boehringer, and Eisai; and conducting scientific studies/trials for Amgen, Pfizer, GSK, sanofi-aventis, Roche, Novartis, BMS, Celgene, Cephalon, Boehringer Ingelheim, and Eisai. Coauthor Carsten Denkert, MD, reports receiving grant/research support from Siemens Medical Solutions and Sividon Diagnostics; consulting for Celgene, Amgen, and Sividon; and being a shareholder in Sividon Diagnostics. Coauthor Christian Jackisch, MD, reports being on the speaker's bureau for Roche and GSK. Coauthor Michael Untch, MD, reports receiving grant/research support from and being a consultant for Bristol-Myers Squibb and Amgen.

The Weight-Loss Nutrient You're Not Eating

Fiber: Weight-loss superfood?The U.S. often isn't the first nation to come to mind when you think of countries with healthy eating habits to adopt, but it turns out we may be influencing how our friends across the Atlantic dine.

The "all things fiber" trend taking over American supermarkets is also on the rise in Spain, Germany, Poland, and the U.K., where 62 percent of people say consuming enough fiber is important, a new European report found. Fiber even trumps calories, as only 56 percent said reducing calories was important.

This study intrigued me because while there are a number of foods with fiber added on the market-everything from pasta to yogurt-the latest nutrition data indicates that the average intake in the United States is less than half the recommended 14 grams per 1,000 calories (which works out to roughly 25 grams a day for women and 38 for men). And when I talk to my clients, most don't know much about this nutrient, other than it's generally good for you.

In a nutshell, fiber is a type of carbohydrate that your body can't digest or absorb, and there are two primary types: soluble and insoluble. Soluble is the soft, sticky type found in oats, barley, beans, and the "meat" of fruits, which helps to lower cholesterol and soften waste so it can pass through your system more easily. Insoluble is the tough type, found in whole wheat and the skin, stalks, and seeds of fruits and veggies, that helps to push waste through the GI tract and improve bowel regularity.

Fiber also has a number of weight-control benefits, which I've often touted on this blog. First, it fills you up, but because you don't break it down and absorb it into your bloodstream, you don't have to worry about burning off fiber in order to prevent it from getting socked away in your fat cells.

There is also some research showing that for every gram of fiber you eat, you eliminate about seven calories. That means if you gobbled 30 grams a day, it would essentially "cancel out" 210 of the calories you ate, which could result in shedding up to 20 pounds in a year's time.

Lastly, fiber has been found to slow the digestion and absorption of other carbs, which results in a slower, steadier rise in blood sugar and a delay in the return of hunger.

RELATED: In addition to fiber, be sure you're eating these eight super nutrients that help you slim down.

But fiber's powers don't stop at weight loss. It may also reduce the risk of death from any cause, according to a recent paper in the Archives of Internal Medicine. Women who ate about 25 grams of fiber a day were 22 percent less likely to die during the nine-year study than those who ate only 10 grams daily. And the risk of death from heart disease, infections, and respiratory diseases was reduced by as much as 50 percent in in the high-fiber eaters, with the greatest benefit seen from consuming grains. Pretty powerful stuff!

To boost your intake and hit the daily target, I recommend bulking up on naturally fiber-rich foods, primarily fruits, veggies, whole grains, beans, and nuts. Just a cup of raspberries, a cup of black bean soup, a medium orange, and an ounce of almonds packs more than 25 grams, so meeting the recommendation doesn't require a drastic change in your diet.

Some good general rules of thumb for upping your intake include:

• Choose more fruits with edible seeds, skins, and membranes, including apples, raspberries, and oranges.
• Reach for veggies with tough stalks and edible skin, such as artichokes and broccoli.
• Opt for whole rather than refined grains. Oats, barley, quinoa, brown and wild rice, and 100% whole-wheat versions of bread, pasta, and crackers are good options.
• Replace meat with beans or lentils at least five times a week.
• Snack on nuts and seeds, or use them to garnish salads, stir-fries, cereal, and yogurt.

Oh, and one more thing: As you increase your fiber intake, be sure to drink plenty of extra water. It's key to help the fiber move through your system. Too little H2O and too much fiber can be a recipe for bloating and constipation, or a pretty uncomfortable tummy ache!

CELL PHONE ADDICTION

Cell phone use and text messaging can become as addictive as any other behavior, such as compulsive shopping, gambling, and overeating, new research shows.

Investigators from Baylor University in Waco, Texas, found that both materialism and impulsiveness drive addictive tendencies toward cell phone use and text messaging.

"People understand substance addictions. They understand that we can take a drug that impacts parts of our brain and reinforces the pleasure principle, so we're addicted to that particular substance. But it's no different with behavioral addiction," said lead investigator James Roberts, PhD, in a video clip in which he discussed the study.

"We get some kind of reward from the use of our cell phone that produces pleasure — a lot of dopamine and serotonin in our brain — that keeps us coming back. So I think, and the research tells us, that behavioral addictions like cell phone addiction are just as real as substance addiction."

The article was published online November 17 in the Journal of Behavioral Addictions.

Materialism, Impulsiveness

The study included 191 business students at 2 US universities who completed a paper and pencil survey administered during class.

The questionnaire took approximately 15 minutes to complete and contained scales that measured materialism, impulsiveness, and mobile phone and instant messaging use.

Addictive tendencies toward mobile phone use and instant messaging were measured by mobile phone technology addiction (MPAT) and instant messaging technology addiction (IMAT) scales; responses were recorded on a 7-point Likert scale.

Mean scores for MPAT and IMAT were 5.06 and 2.52, respectively.

Impulsiveness was measured using Puri's 12-item scale, in which students were asked to rate how well 12 adjectives described them. The mean impulsiveness score was 3.2.

Materialism, best understood as the importance placed on worldly possessions, was measured using Mowen's 4-item scale. For this scale, respondents were asked to rate how accurately 4 personality traits described them.

On each of the respective scales, a higher score reflected a higher level of dependency, impulsiveness, or materialism.

Greater Potential for Addiction?

Results showed that both materialism ( P < .001) and impulsiveness ( P = .029) significantly predicted MPAT scores. Similarly, materialism ( P = .001) and impulsiveness ( P = .029) significantly predicted IMAT scores.

"Note that the impact of materialism on either addictive behavior is large relative to that of impulsiveness," the authors write.

The larger effect that materialism had on cell phone use in the current study relative to texting may also reflect the fact that cell phones are a sign of conspicuous possession.

In contrast, texting may be seen more as a private engagement and does not signal any particular status.

Dr. Roberts noted that whenever people display addictive behavior, it has negative effects on quality of life.

With cell phone and texting addiction, "it's an opportunity cost, so we are crowding out so many more important activities, including family and friends and other pursuits, that might bring us true happiness," he said.

Furthermore, cell phones are becoming "increasingly dangerous," because they offer more and more opportunities to interact with them, so their potential for addiction is greater, Dr. Roberts added.

Caution Warranted

Petros Levounis, MD, Columbia University College of Physicians and Surgeons, New York City, toldMedscape Medical News that gambling and compulsive sexual behavior come closer to the definition of frank addiction than cell phone and texting behaviors.

"We also have a long way to go before we develop reliable diagnostic criteria [for cell phone addiction and texting] to guide us in further research and clinical practice," he added.

On the other hand, Dr. Levounis does believe that the symptoms of those with these new technological addictions "share a lot of similarities with the more classic addictions of alcohol and drug abuse."

Journal editor Zsolt Demetrovics, PhD, Eötvös Loránd University, Budapest, Hungry, agreed that excessive use of cell phones and texting has similar characteristics to other addictions.

On the other hand, Dr. Demetrovics was uncertain whether overuse of cell phones should be viewed in the same light as a classic addiction.

"To consider something as a disorder or illness, the behavior must impair one's life significantly. And at this moment, we do not see these dramatic consequences in a large population," he told Medscape Medical News.

Nevertheless, Dr. Demetrovics believes it is important to pay attention to these behaviors, especially because they can cause some harm.

"But we should not overdramatize them as serious illnesses," he emphasized.

Weight loss surgery tied to increase in drinking

People who had weight loss surgery reported greater alcohol use two years after their procedures than in the weeks beforehand, in a new study.

"This is perhaps a risk. I don't think it should deter people from having surgery, but you should be cautious to monitor (alcohol use) after surgery," Alexis Conason, who worked on the study at the New York Obesity Nutrition Research Center at St. Luke's-Roosevelt Hospital Center, told Reuters Health.

Researchers said it's possible some patients may turn to drinking if surgery successfully stops their ability to overeat without addressing their underlying issues. Or, the effects of certain types of stomach-shrinking procedures on alcohol tolerance may influence drinking habits.

Still, the new study can't show whether people were drinking in a dangerous way - and there was no clear increase in drug use or smoking after surgery.

"This does not mean that everyone who has gastric bypass surgery has problems with alcohol or becomes an alcoholic," said Conason.

Her team's study involved 155 people getting gastric bypass or gastric banding surgery, mostly women. Participants started the study with an average body mass index, or BMI, of 46 - equivalent to a five-foot, six-inch person who weighs 285 pounds.

Surgery is typically recommended for people with a BMI of at least 40, or at least 35 if they also have health problems such as diabetes or severe sleep apnea.

Alcohol use dropped immediately following surgery, from 61 percent of people who initially reported drinking to 20 percent at one month post-surgery.

But by three months, drinking rates had started to creep back up. And at two years out, people were drinking significantly more often than before their procedures, according to findings published Monday in the Archives of Surgery.

That was primarily the case for those who had gastric bypass surgery, not banding. On a scale from 0 to 10 of drinking frequency, where 0 represented never, 5 was sometimes and 10 always, gastric bypass patients reported an increase from 1.86 before surgery to 3.08 two years later.

CHANGES IN TOLERANCE
Conason said gastric bypass, in particular, has been shown to drastically lower alcohol tolerance - to the point that some post-surgery patients have a blood alcohol content above the legal driving limit after just one drink. For some, that could make drinking more appealing, she added.
The new findings are "proving more support for the idea that we really need to talk to patients about alcohol use, especially those undergoing (gastric bypass)," said Wendy King, an epidemiologist and weight loss surgery researcher at the University of Pittsburgh, who wasn't part of the study team.

According to the American Society for Metabolic and Bariatric Surgery, about 200,000 people have weight loss surgery every year. The procedures cost about $20,000 each.

Although some researchers have questioned the long-term benefits of surgery, one recent study found three-quarters of people who'd undergone gastric bypass had lost and kept off at least 20 percent of their initial pre-surgery weight six years later (see Reuters Health story of September 18, 2012).

One limitation of the new study is that only one-quarter of the initial participants were still in touch to report their current alcohol and drug use at the two-year mark - so the researchers don't know how everyone else fared.

Psychiatrist Dr. James Mitchell, who has studied alcohol use after weight loss surgery at the University of North Dakota School of Medicine and Health Sciences in Grand Forks, said there's also a need for research going out more than two years - to see if alcohol use keeps increasing.

Researchers said people who've had weight loss surgery should talk with their doctors soon if they notice themselves wanting to drink more.

"The health risks of obesity are such that people with severe obesity should not forgo bariatric surgery because of this," Mitchell, who was not involved in the new study, told Reuters Health.

But he said everyone should be warned about this possibility - and people with a history of alcohol abuse should be particularly careful.

"I don't have the impression (doctors) are talking a tremendous amount about these things," Conason said. "I think we should be. I think we should be educating patients about all the potential risks and benefits."

NEW CLASS OF DRUGS FOR OSTEOPOROSIS-CATHEPSIN K INHIBITORS

The investigational agent odanacatib appears to be an effective treatment for postmenopausal osteoporosis that persists after 3 years of alendronate therapy, according to a phase 3 trial presented here at ACR 2012.

Treatment with odanacatib significantly improved bone mineral density (BMD) at the femoral neck, hip, trochanter, and lumbar spine, compared with placebo, in postmenopausal women previously treated with alendronate. In addition, the novel agent was generally safe and tolerable.

The phase 3 trial was stopped early after an independent data and safety monitoring committee determined that odanacatib had a favorable risk/benefit profile.

"Odanacatib is a cathepsin K inhibitor that inhibits bone resorption while maintaining bone formation, whereas bisphosphonates reduce bone resorption and bone formation," said lead author Roland Chapurlat, MD, from Hôpital Edouard Herriot in Lyon, France.

"In this study of women with low bone mass after alendronate treatment, we saw no issues of excess bone formation or abnormal stress fractures," he explained.

Dr. Chapurlat noted that most studies of women with osteoporosis do not enroll previously treated women, but this study sought to determine if the drug had a benefit in previously treated patients.

The randomized double-blind placebo-controlled 24-month trial was conducted at 42 sites in 12 countries. Investigators enrolled 246 women 60 years or older with osteoporosis, and randomly assigned them to receive odanacatib 50 mg once weekly or placebo. All patients received vitamin D and calcium supplementation.

The mean age of the participants was 71.3 years, most were white, 73.7% had a history of any fracture, and 68.3% had a fracture history after menopause. The mean duration of previous alendronate therapy was 5.5 years; 55% had taken alendronate for 3 to 5 years.

"Long-term alendronate [treatment] results in persistent suppression of bone turnover, and there is a residual effect even after stopping," Dr. Chapurlat said.

For the primary end point of femoral neck BMD at 24 months, there was a 2.67% difference favoring odanacatib ( P < .001), and for total hip BMD, there was a 2.7% difference favoring odanacatib ( P < .001). For both these end points, the effect of odanacatib was seen after 6 months because of the residual effect of alendronate, Dr. Chapurlat reported.

A 3.18% difference in BMD at the trochanter and a 2.57% difference in BMD at the lumbar spine also favored odanacatib at 24 months ( P < .001 for both, compared with placebo).

At 24 months, odanacatib significantly reduced markers of bone resorption ( P < .001) and significantly increased markers of bone formation ( P = .011).

There were no significant differences in adverse events in the 2 treatment groups, although the rate of discontinuations related to adverse events was higher in the odanacatib group than in the placebo group (9% vs 3%).

The rate of fracture was lower in the odanacatib group than in the placebo group (4.9% vs 13.2%). "The study was not designed to look at fracture efficacy," Dr. Chapurlat stated.

An ongoing phase 3 trial of 16,000 women will show fracture rate; those results are expected next year, he said.

In contrast to bisphosphonates, odanacatib and denosumab are not deposited in the bone, so they should not have a long-term effect on bone turnover after drug discontinuation.

"They block osteoclasts and don't reside in the bone," said Stanley Cohen, MD, medical director of the rheumatology training program, clinical professor of internal medicine at the University of Texas Southwestern Medical School in Dallas, and past president of the ACR.

"What happens to patients who were taking alendronate and still have low bone mass? Will they respond with improvement in bone density? The answer is yes," Dr. Cohen stated.

Dr. Cohen doubts that odanacatib will replace bisphosphonates "because they cost pennies and their benefits are outstanding. But we need to define better which patients should be treated and for how long, in light of the rare cases of atypical fracture reported with long-term treatment," he said.

If long-term follow-up shows that odanacatib does reduce bone resorption and allows new bone formation to continue, this drug is likely to play a role in the treatment of osteoporosis, Dr. Cohen said.

Abbott hepatitis C drugs bring high cure rates in trial

 A trio of oral medicines from Abbott Laboratories Inc to treat hepatitis C produced unprecedented cure rates in patients who had failed to benefit from standard treatment, as well as very high cure rates for newly treated patients, Abbott said on Saturday.
Detailed data from the mid-stage trial, called Aviator, were released Saturday at the annual meeting of the American Association for the Study of Liver Disease (AASLD) in Boston.
Investors and patients have very high hopes for the Abbott drugs - a protease inhibitor called ABT-450, a polymerase inhibitor ABT-333 and ABT-267 from a class known as NS5A inhibitors. They are used without interferon, an injectable standard treatment that causes flu-like symptoms.
Abbott said it plans to move ahead with large Phase III studies of the three drugs, used either with or without the standard antiviral pill ribavirin, based on favorable results seen in patients treated for eight weeks or twelve weeks in the Aviator study. Patients in the study had the most common, and hardest-to-treat, strain of hepatitis C known as Genotype 1.
Some 93 percent of patients who failed prior therapy had a sustained virologic response (SVR), meaning they were considered cured, after 12 weeks of taking the trio of new drugs, plus ribavirin.
"Nobody anywhere has broken the 50 percent mark in (cure rates) for this population," Scott Brun, a senior Abbott research executive said in an interview. "These are robust results."
Abbott said it aims to be the first company to market an interferon-free regimen to patients with Genotype 1 infections.
Four of 448 patients in the study discontinued treatment due to adverse events, a dropout rate that Abbott said suggested the medicines were very well tolerated.
About 97 percent of previously untreated patients were considered cured after 12 weeks of treatment with the three Abbott drugs, plus ribavirin. Moreover, similarly impressive cure rates were seen among patients taking the three drugs, plus ribavirin, for 8 weeks.
Without ribavirin, 87 percent of previously untreated patients were considered cured after 12 weeks on Abbott's three drugs, Abbott said.
Rival drugmaker Gilead Sciences Inc stole a bit of Abbott's thunder on Saturday by releasing data showing a 100 percent cure rate among previously untreated genotype 1 patients who took only two of its oral treatments, plus ribavirin, for 12 weeks.
A pair of new hepatitis C drugs approved last year, Vertex Pharmaceuticals Inc's Incivek and Merck & Co's Victrelis, significantly boosted cure rates and cut treatment duration to as low as 24 weeks for some patients. But the protease inhibitors must still be taken with interferon, an injected drug that often causes severe flu-like symptoms that lead many hepatitis patients to delay or discontinue treatment.
Gilead, Bristol-Myers Squibb Co and Vertex are racing to develop interferon-free treatment regimens. They are expected to become blockbuster products, if approved, because of their far shorter treatment times and better cure rates, compared with existing drug regimens.
Many analysts view Gilead as current leader both on timing and perceived advantages of its experimental hepatitis C program.
An estimated 3 million Americans are believed infected with the virus, which quietly damages the liver over years or decades and is the biggest reason for liver transplants in the United States. Abbott said as many as 170 million people worldwide are infected.

ASPIRIN AS TARGETED TREATMENT IN PIK3CA MUTATED COLORECTAL CANCER

Aspirin, the mainstay of the medicine cabinet, appears to resemble a high-tech targeted therapy in the treatment of patients with a subtype of colorectal cancer, according to astudy published in the October 24 issue of the New England Journal of Medicine.

Patients with PIK3CA-mutated tumors who regularly used aspirin after their diagnosis had a significant survival benefit — a 46% reduction in overall mortality and an 82% reduction in colorectal-specific mortality. However, patients with wild-typePIK3CA who regularly used aspirin after diagnosis did not have a mortality benefit of any kind.

These findings come from a retrospective analysis of 2 large cohort studies in the United States: the Nurses' Health Study and the Health Professionals Follow-up Study.

If the findings are validated prospectively, clinicians could have a new biomarker — and adjuvant therapy — for colorectal cancer, say the authors, led by Xiaoyun Liao, MD, PhD, from the Dana-Farber Cancer Institute in Boston, Massachusetts.

Given how common the PIK3CA mutation is, this might be big news, according to an expert not involved with the study.

"Since more than 1 of 6 primary colorectal tumors harbors PIK3CA mutations, targeted use of adjuvant aspirin could have a major effect on the treatment of colorectal cancer," writes Boris Pasche, MD, from the University of Alabama at Birmingham, in an accompanying editorial.

"Aspirin may well become one of the oldest drugs to be used as a 21st-century targeted therapy," he says.

This study adds to the literature from multiple cohort studies on the antitumor effect of aspirin in colorectal cancer. Earlier this year, British investigators reported that aspirin use is associated with reduced tumor progression and recurrence in patients with a diagnosis of colorectal cancer.

However, the study by Dr. Liao and colleagues is novel because it shows that aspirin can work in a subset of patients who are identifiable by a relatively easily detected biomarker, PIK3CA.

Nevertheless, the value of mutated PIK3CA as a predictive biomarker needs to be confirmed, said Alok Khorana, MD, from the James P. Wilmot Cancer Center at University of Rochester Medical Center in New York, who was not involved with the study.

In the meantime, "it is perfectly reasonable to consider daily aspirin after a diagnosis of colorectal cancer after an informed discussion with patient regarding risks, benefits, and evidence," Dr. Khorana toldMedscape Medical News. He recommended low-dose aspirin (81 mg/day).

Both Dr. Pasche and the investigators warn that the study sample was small.

There were 964 patients with rectal or colon cancer in the 2 cohorts, but only 152 of those carried aPIK3CA mutation. Still, the effect of aspirin on survival among patients was considerable.

Of the 90 patients with PIK3CA-mutated tumors who did not use aspirin after diagnosis, 23 (26%) died within 5 years. However, of the 62 who used aspirin regularly after diagnosis, only 2 (3%) died within 5 years (P < .001).

In contrast, aspirin appeared to have no effect on patients with wild-type tumors. The 5-year cumulative colorectal-cancer-specific mortality was the same (15%) for users and nonusers of aspirin after diagnosis (P = .92).

Contradictory Finding Explained

In both cohorts, documentation of the use of standard-dose (325 mg) aspirin began in the 1980s. After 1992, to reflect the increasing use of low-dose aspirin, participants were asked to convert 4 low-dose tablets to 1 standard-dose tablet in their response, the investigators explain. Ultimately, "aspirin use" was defined as the regular use of aspirin during most weeks, and "nonuse" was defined as no regular use of aspirin during most weeks.

These data allowed the investigators to determine whether patients diagnosed with colorectal cancer used aspirin before and after diagnosis.

They found that the same proportion of patients with wild-type and mutant PIK3CA used aspirin before their diagnosis; thus, before-diagnosis use was not skewed between the 2 subgroups.

However, in what appears to be a contradictory result, the proportion of PIK3CA-mutated tumors was the same (17%) among users and nonusers of aspirin before diagnosis.

If aspirin provides an antitumor effect in PIK3CA-mutated tumors, logic would dictate that there would be fewer cases of the mutated colorectal cancers in aspirin users than in nonusers. In other words, aspirin should also have a preventive effect.

The investigators note that this "apparent discrepancy" might be related to "tumor evolution." The tumor microenvironment might evolve in such a way that there is a "differential interaction of aspirin use andPIK3CA mutation in the early phase of evolution (before diagnosis) versus the late phase (after diagnosis)."

Study Findings Not Entirely Novel

Previously, in a prospective study involving 1239 patients with a diagnosis of stage I, II, or III disease, researchers found that regular aspirin use after a diagnosis of colorectal cancer was associated with a 21% reduction in overall mortality and a 29% reduction in colorectal-cancer-specific mortality (JAMA. 2009;302:649-658).

A subgroup analysis from that study showed that the reduction in overall mortality and colorectal-cancer-specific mortality was observed exclusively in patients with primary tumors that overexpressed the enzyme known as prostaglandin-endoperoxide synthase 2 (PTGS2, formerly known as cyclooxygenase-2).

These findings on the postdiagnosis use of aspirin and PTGS2 were recently replicated in a large Dutch study (Br J Cancer. 2012;106:1564-1570).

However, as Dr. Liao and his colleagues point out, PTGS2 is not an ideal biomarker because it cannot be easily assessed with commonplace immunohistochemistry. "Considering the challenges in standardizing PTGS2 immunohistochemical assays across pathology laboratories, other molecular biomarkers...are needed to better identify patients with colorectal cancer who will derive a benefit from aspirin," they write.

PIK3CA, which is detectable with standard immunohistochemical methods, might be their sought-after biomarker.

This study was supported by the National Institutes of Health, the Bennett Family Fund for Targeted Therapies Research, and the Entertainment Industry Foundation through the National Colorectal Cancer Research Alliance. Some of the study authors and Dr. Pasche report financial relationships with nonprofit companies or industry, as detailed in the papers. Dr. Khorana reports being a consultant to Bayer.

HRT DECREASE SUBSTANTIALLY CVD RISK IN WOMEN

Hormone-replacement therapy (HRT) in postmenopausal women with a mean age of 50 significantly reduced the risk of the combined end point of mortality, MI, or heart failure in a new randomized Danish study published online October 9, 2012 in BMJ [1]. The participants, who used HRT for more than 10 years, were not at significantly increased risk of breast cancer or stroke either, report Dr Louise Schierbeck (Hvidovre Hospital, Denmark) and colleagues.

"This is the longest randomized trial with hard end points, and we found a 50% reduction in cardiovascular end points for the women who took HRT, and there was no increased risk of cancer," Schierbeck told heartwire . The women were also followed for a further six years after discontinuation of randomized treatment, she noted.

Schierbeck says the findings, in 1000 women, confirm the "timing hypothesis." In 2002, primary results from the Women's Health Initiative (WHI) showed no cardiovascular benefit from HRT--something that had been suggested by numerous observational trials--and even an indication there may be harm; this led to the widespread abandonment of this therapy. But subsequent analyses of WHI, and data from other studies, have suggested that the time at which HRT is first prescribed is key. The women in this Danish study were 13 years younger, on average, than the women in WHI (mean age 63 years). "It doesn't make much sense to start treating women 13 years after menopause for menopausal symptoms. It's important to initiate the treatment at menopause and not many years later," she observes.

Asked to comment on the new findings, Dr Howard N Hodis (UCLA) told heartwire , "Until this came out there had been no trial to directly study the estrogen cardioprotective hypothesis. This is unique, because it is the only study to have looked at women, a priori, randomized basically at the time of or just a little beyond menopause. And that's a really important point that I think some of the detractors have glossed over. The women averaged 50 years old, just like the women that we treat who come in close to the menopause and say, 'I want hormones,' because they are having symptoms. So scientifically, this is a very important trial."

Ob/gyn Dr James Liu (Case Western Reserve University School of Medicine, Cleveland, OH) said: "This paper adds to the evolving data on HRT for newly menopausal women in the under-age-60 category. The study conclusions are worth noting and are statistically significant and congruent with older observational studies such as the Nurses' Health Study and the subgroup-stratified analyses of the WHI cohort from 50 to 60. Thus, there are two randomized trials that have congruent data." Among the "surprising points," says Liu, are no increase in breast cancer risk for the 16 years of follow-up and the fact that stroke risk was not increased.

Hodis also addressed criticisms that the new Danish trial is too small to yield any meaningful results. "Although the sample size is small, there are 16 years and 20 000 women-years of follow-up." Schierbeck concurs. "We had a very long study, so there are 10 000 person-years of randomized treatment, and we do have a significant outcome in 1000 women, so it's clinically relevant."

Greater-Than-50% Reduction in CV Events Without Increasing Cancer Risk

The 1006 healthy women aged 45 to 58 who were recently postmenopausal or had perimenopausal symptoms were participants in the Danish Osteoporosis Prevention Study and were randomized to receive HRT (n=502) or no treatment (control, n=504).

The primary end point was a composite of death, hospitalization for heart failure, and MI. Secondary end points were the individual components of the primary end point and admission to the hospital for stroke. Safety end points included death or a diagnosis of breast cancer or other cancer grouped together and admission to the hospital for pulmonary embolism or deep venous thrombosis (DVT).

The women in the treated group with an intact uterus received 2-mg synthetic 17-{:beta:}-estradiol for 12 days, 2 mg 17-{:beta:}-estradiol plus 1 mg  norethindrone acetate for 10 days, and 1 mg 17-{:beta:}-estradiol for six days (Trisekvens, Novo Nordisk, Denmark). In women who had undergone hysterectomy, first-line treatment was 2 mg 17-{:beta:}-estradiol a day (Estrofem, Novo Nordisk, Denmark). Other treatment modalities were offered to those who experienced side effects or insufficient relief of symptoms.

The planned duration of the study was 20 years. However, as the WHI data--which came out in 2002 around the time of the 10-year visit--indicated that use of HRT might result in more harm than benefit, the participants were advised to stop treatment. But they were followed for death, cardiovascular disease, and cancer for up to 16 years.

After 10 years of intervention, there was a 52% reduction in the primary composite end point of death, MI, or heart failure, and this was not associated with an increase in any cancer. Schierbeck said numbers were too small to draw any meaningful conclusions on venous thromboembolism (VTE), although she acknowledges that HRT is known to increase the risk of VTE but pointed out, "This is a less serious event than a CV event."

After 16 years, the reduction in the primary composite outcome was still present and still not associated with an increase in any cancer, something both Schierbeck and Hodis say is "reassuring," particularly in terms of breast cancer.

Results After 10 Years of Intervention in Danish Osteoporosis Prevention Study

End point	HRT group (n=502), n	Control group (n=504), n	Hazard ratio	95% CI	p
Primarya	16	33	0.48	0.26– 0.87	0.015
Mortality	15	26	0.57	0.30–1.08	0.084
Cancer	36	39	0.92	0.58–1.45	0.71
Breast cancer	10	17	0.58	0.27–1.27	0.17
DVT	2	1	2.01	0.18– 22.16	--b
Stroke	11	14	0.77	0.35–1.70	0.70

a. Composite end point of death, MI, or heart failure

b. Numbers too low to calculate p

Emotion Has Overtaken the Evidence in Discussions About HRT

Hodis says emotion has long overtaken reason in the HRT debate. "We have had observational studies for the past 50 years in this field, at least 40 of them, and they are all consistent--and you just don't see that in medicine--across two very important outcomes: they reduced cardiovascular disease and they reduced mortality" in women around the time of menopause, he asserts. "But when WHI was conducted, it was done in women who were 12 years or more past menopause. These are two completely different populations of women.

"In all of the emotions after WHI, that 'hormones are killing women'--which is absolutely ridiculous--nobody sat back and said, 'Where is the evidence to support that?' The guidance that unfortunately came out of the results of WHI was 'lowest dose for shortest period of time possible.' Now what we have is a well-conducted, 10-year randomized trial that clearly shows that short-term usage of these products is not going to derive maximum benefits for women."

And other "important" data have come out recently in support of HRT, he notes, including the KEEPSstudy, reported just last week. "This was the largest trial ever done to assess mood, and it showed positive effects in terms of anxiety, depression, and tension, and no adverse effects."

Schierbeck says: "It is a shame that so many women are anxious about HRT, because it's so important for life quality around the time of menopause." She agrees the current mantra seems to be that if a woman wants to use HRT to "go with the lowest dose for the shortest time," but she hopes that this study will have a major impact and influence international societies working on new guidelines.

Asked what she thinks the optimal duration of HRT should be, she said: "I don't think we can set a time limit on it. At least for 10 years, we didn't find any serious side effects."

Hodis says he does not believe there will be a seismic shift in recommendations, because doctors and women have lived in fear of HRT for so long, but "people will look at this and say we can feel comfortable going longer with therapy." Personally, he says, "I'm neither a proponent nor an opponent of HRT: I use these products in women, with or without symptoms, who want to be put on them, with caveats--for example, not if they have had blood clots. They do have risks, but they are so low, and certainly no higher than many other drugs we use."

Where Next? HRT and Chronic Disease Prevention

Hodis also believes there is a role for HRT in chronic disease prevention. "The data strongly indicate that hormones are an excellent prevention for chronic diseases, including bone fractures and heart disease." And although the reduction in deaths in the Danish study was not significant, Hodis says the totality of evidence points to HRT adding "almost two years" to the life of a woman, with the additional benefit that hormones "are cost-effective, coming in at around $2300 per quality-adjusted life-year [QALY]. There's nothing else in women that does that. Statins do not extend life and they cost $50 000 $100 000 per QALY."

But not everyone agrees. KEEPS and WHI trialist Dr JoAnn E Manson (Brigham and Women's Hospital, Boston, MA) maintained last week that HRT should be used only for the treatment of menopausal symptoms.

"We certainly would not say at this point in time to initiate hormone therapy for the express purpose of trying to prevent heart disease or cognitive decline; the evidence is not to that point," she said in an interview. "But for women who have menopausal symptoms and who are considering HRT to reduce their symptoms and improve their quality of life related to these symptoms, there were many favorable effects seen of taking HRT for four years."

Differences in Doses of Hormones, Medication Schedules

Liu says there are also some limitations to the Danish study that are pointed out by the authors, but others that are not. The latter include the fact that the medication used was lower dose than the 0.625-mg conjugated equine estrogen traditionally used [in the US] and in the WHI, although "there are some who may state that the 2-mg estradiol dose is similar," he observes. And the progestinused is different.

In addition, the type of dosing is different: "The Danish study used cycle estrogen and progestin in a 28-day dose-pack form, and the pattern of estrogen-progestin administration is somewhat unique in that the last six days used a lower estradiol dose of 1 mg.  Thus, the estrogen exposure is not uniform across the 28 days. This dose is also different from women with hysterectomy who received 2-mg estradiol continuously. This contrasts with WHI, which used continuous combined estrogen/progestin daily for those women with a uterus."

And the data end points for the Danish study--due to its small size--are combined for women on estrogen alone (due to hysterectomy) and cyclic estrogen-progestin. "This analyses is different from the WHI approach, where there were two separate studies (those with a uterus were in a separate study from those with a hysterectomy) with larger cohort sizes."