What's Sauce for the Goose May Not Be Sauce for the Gander

Avastin has been in the news a lot lately, and most of the press has been negative.  In November, the FDA revoked its approval of Avastin to treat newly diagnosed metastatic breast cancer.  Then, in December, Genentech, who manufactures Avastin, announced it would not seek FDA approval for the treatment of ovarian cancer, based on studies showing an improvement in progression-free survival but not overall survival.  Of course, whether Avastin helps women with ovarian cancer remains a controversial question, depending how you value progression-free survival. Compare this report with this one, for example. 

In tomorrow's New England Journal of Medicine, there are two reports of clinical trials evaluating Avastin for patients with newly diagnosed HER2-negative breast cancer.  In both this study and this one, women with newly diagnosed breast cancer were given chemotherapy with or without Avastin.  The women with HER2-negative tumors had a higher rate of "pathological complete response" if they received Avastin.  "Pathologic complete response" means that when it was time for surgery, not living tumor could be found.  Women with a "pathologic complete response" tend to live longer than women who do not respond as well.

What does all this mean?  Will these studies "reignite the debate" about Avastin in breast cancer?  I guess that depends on who is doing the debating.  I think the role of Avastin in breast cancer, indeed the role of Avastin in treating any cancer, remains unclear.  In the end, I believe it will be shown that Avastin helps some cancer patients and not others, and it will all depend on the biology of each tumor type.  Clearly, not all breast cancer is the same, and breast cancer is not the same as ovarian cancer, let alone osteosarcoma or lymphoma.  Today's studies simply reinforce the fallacy of extrapolating from one tumor type to another.  A drug may be very helpful for one type of cancer, and useless for another.


That's why we do clinical trials like this one, sponsored by St. Jude Children's Research Hospital, in which we are participating, trying to see if Avastin helps osteosarcoma patients.

These studies do raise another important point, which I will discuss very soon.  These studies relied on a "surrogate end point."  That is, the studies were designed to see an effect on "pathologic complete response," but only because that is thought to correspond with improved overall survival.  Only time will tell whether the women who received Avastin do actually live longer.

More to come...

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Yoga – Not Just for Skinny, Pretty Women Anymore?

This post is dedicated to a close friend of mine, a budding scientist with an aversion to yoga.

The benefits of yoga for cancer patients were plastered throughout the popular press recently, in anticipation of a presentation by Dr. Karen Mustian from the University of Rochester Medical Center at this year’s meeting of the American Society for Clinical Oncology in Chicago. This study enrolled 410 cancer survivors (96% female, 75% had breast cancer) suffering from moderate or worse sleep disturbance. The participants were randomized to standard monitoring versus a 4 week yoga intervention. Participants in the yoga program had improvements in sleep quality, fatigue, and various measures of Quality of Life compared with the control arm (no intervention). The benefit was significant enough to be covered by mainstream media outlets like CNN as well as web-based media like Breastcancer.org. ASCO president Douglas Blayney, MD, stated that the results are “readily applicable” for a huge patient population.

But wait. As we scientists often ask, do the results support the conclusions?

I think the answer is a resounding “Maybe.”

There is mounting evidence that cancer survivors benefit from participating in yoga programs. Although this study is the largest thus far reported, it is certainly not the first to show a benefit to yoga. Back in 2003 a study presented at the ASCO meeting showed that participation in a yoga intervention improved the Quality of Life of women newly diagnosed with breast cancer.

But is it yoga, per se, that helps? So far none of the studies have compared participation in yoga with any other exercise program. This study, for example, published in 2001, demonstrated that a home-based walking exercise program improved fatigue and other Quality of Life measures in women being treated for breast cancer. The studies cited on this page of the American Cancer Society’s website demonstrate a benefit to using a treadmill or an outpatient wellness program involving aerobic exercise, strength training, flexibility and relaxation. So maybe it’s exercise in general, and not specifically yoga, that helps cancer survivors live better.

Are the results of the yoga study “readily applicable” to a huge patient population, as suggested by Dr. Blayney? Again, I think the answer is “Maybe.” It depends on how you define “a huge patient population.” Dr. Mustian’s study is certainly applicable to the very large number of women diagnosed with breast cancer every year, but her study involved essentially only women with breast cancer. Given the variety of ways various cancers are treated, it may be premature to conclude that because yoga helped these women, that it would make a difference for young adults being treated with intensive chemotherapy for leukemia.

So what can we conclude? I think it is safe to conclude that some degree of exercise is beneficial for cancer patients, probably regardless of where they are in the course of their therapy. But before we can state that yoga is the best form of exercise, the right study has to be performed: patients need to be randomized to various forms of exercise, and research participants need to include men as well. Perhaps for a relatively inflexible man like me, the frustration of not being able to do “downward dog” will make yoga a poor choice, while the feeling of accomplishment associated with being able to last 5 more minutes on the treadmill will make that form of exercise a much better choice. Only a well-designed experiment can tell us for sure.

 
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More What You'd Call "Guidelines" than Actual Rules

Of course, Captain Barbossa was referring to The Pirate Code, but he could just as easily have been referring to documents released last month by the US Preventive Services Task Force or the American Congress of Obstetricians and Gynecologists (ACOG).

In an unanticipated coincidence, these two groups, operating independently, reached similar conclusions about commonly utilized screening tests: mammograms and Pap smears. Both groups reviewed the data and concluded that routine use of these screening tests, as currently recommended, may not be warranted.

Much newsprint has been expended since then discussing the political implications of these new recommendations. As this is not a political blog, I will leave that discussion to others.

What I want to talk about is how guidelines (should) influence patient care.


I think a lot of the worry surrounding these guidelines stems from concerns that they will be interpreted by those who pay the bills in our system (meaning the Federal Government, through Medicare reimbursement regulations, and the private insurance industry) as “Actual Rules” rather than “Guidelines,” meaning that if you get a mammogram or a Pap smear but don’t meet the “Guidelines” your service won’t be covered. In the current environment, this may be true, but it shouldn’t be.

The key to my argument is the highlighted words above: “routine use” and “as currently recommended.”

The key to understanding why both groups reviewed the published data and reached similar conclusions is an understanding of the nature of screening tests as well as a bit on biostatistics. My work colleagues who read this will laugh at the idea that I am trying to teach anyone statistics, but that’s what I’m going to do.

To start, the accuracy and usefulness of any medical test can be described by the terms “sensitivity” and “specificity.” Sensitivity refers to how likely the test is to be positive if the condition is present. So a sensitive test will pick up every case. Specificity is the mirror image – if the test is positive, how likely is it that the condition is present. Screening tests are designed to be very sensitive, even if they are not very specific – that way, no cases are missed (very sensitive), but sometimes the test is positive even if the patient does not have the disease (not very specific).

The other statistical consideration is the concept of positive- and negative-predictive value. This means, how likely is a positive test to mean the disease is there, or how likely is a negative test to mean the disease is absent? Two concepts factor into the positive- and negative-predictive values of a test: the sensitivity and specificity AND how common the condition is in the population being tested.

These considerations underlie the new recommendations. Mammograms save lives. No one disputes that. Early detection of breast cancer saves lives. No one disputes that. But mammograms are not very specific, and the positive-predictive value of a positive mammogram is MUCH more if the woman is at risk of developing breast cancer than if the woman is at relatively low risk. Since a woman with a strong family history of breast or ovarian cancer is at higher risk of developing breast cancer in her 40’s than a woman with no such history. Thus, the positive-predictive value of a mammogram in a 40 year old woman is higher if the woman is at higher risk. This is why the Task Force no longer recommended ROUTINE mammograms for women under 50.


This is where the practice of medicine comes in. As the doctor treating a 40 year old woman, it is important to remember that a mammogram will be valuable if the woman is at risk, but far less valuable if the woman is NOT at high risk. So blindly refusing to order a mammogram simply because the patient is 40 makes no sense (and an insurance company refusing to pay for it based solely on age makes equally little sense). A 40 year old woman whose mother had breast cancer should have a mammogram and it should be covered. A 40 year old woman with no relatives who have ever had cancer may not need a mammogram. Determining whether a screening test is needed is a decision for the doctor and the patient to make together.

This isn’t rationing care, this is good medicine.


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As Breast Cancer Awareness Month Draws to a Close

As breast cancer awareness month draws to a close, I wanted to highlight a few breast cancer posts from other medical bloggers:

Suture For a Living asks: "Is Breast Cancer Over-Diagnosed?"

Bayblab writes about research on a diabetes medication killing breast cancer stem cells.

Science Update Blog discusses claims that we are "Two years from breast cancer cure".

Highlight Health's Allison Bland says "The Review is in: Lifestyle Changes Prevent Breast Cancer
and Healthcare Hacks discuss the benefits of weightlifting in breast cancer survivors.

If you've found any interesting breast cancer blogs or posts, link to them in the comments!

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Does Vitamin D Help Prevent Breast Cancer?

Back in March I discussed an ad campaign sponsored by the Indoor Tanning Association promoting the supposed health benefits of tanning. Their message, in part, touted the benefits of Vitamin D, which is made in your body in a multi-step process that begins with exposure of your skin to ultraviolet light. I argued that with vitamin fortification of foods, vitamin D deficiency was rare in this country. One of my readers astutely pointed out that low vitamin D levels can cause problems even in patients who do not have an absolute deficiency.

A recent study from Mount Sinai Hospital in Toronto supports this idea. The researchers measured vitamin D levels in the blood of 512 women at the time of their breast cancer diagnosis (between 1989 and 1995). In 2006, distant disease-free survival (the percentage of women alive with no evidence of spread of their disease) was 83% for the women with adequate vitamin D levels, compared with 79% for those with insufficient levels and 69% for those who were deficient.

Considering the large number of women diagnosed with breast cancer each year, these differences are huge.

What does this mean? It means a healthy level of vitamin D is probably important for a lot more than just maintaining strong bones.

It is important to note, though, that this study does NOT show that vitamin D helps treat breast cancer, so if you already have breast cancer, supplementation may not help. Also, the study showed that the women with the very highest vitamin D levels seemed to have worse survival, so mega-doses of vitamin D may not be such a good idea, either.

So how much is enough? That varies with age, gender, and whether you are pregnant or nursing a baby. As a general rule of thumb, between 400-600 international units (IU) appears to be a healthy amount. For your specific case, you can consult the Vitamin D Fact Sheet from the Office of Dietary Supplements of the National Institutes of Health here.

Where do you get vitamin D? Your body will make it as long as you get some sun – experts recommend 15 minutes or so a few times a week (without sunscreen, so longer if you have sunscreen on) – but this will depend on where you live (the sun is stronger the closer you are to the equator). Some foods naturally contain vitamin D, like fish (especially salmon, tuna, and mackerel), beef liver, and egg yolks. The major source of dietary vitamin D in the US is fortified dairy foods.

This study was released in advance of the 2008 annual meeting of the American Society of Clinical Oncology (ASCO), which will be held at the end of the month in Chicago. The study has gotten a lot of media attention so far and as I will be at ASCO I will share what I learn.

Check out the study abstract here.

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Breast Cancer Risk & Alcohol: Isn’t Red Wine (in moderation) Good for You?

We’ve all read the articles in the newspaper. Moderate consumption of red wine is good for you. It lowers the risk of heart disease, and helps you live longer.

Doesn’t it?

A report from this week’s meeting of the American Association for Cancer Research questions that. Yesterday, Dr. Jasmine Lew presented the results of a study of 184,000 women in the US looking at the relationship between alcohol consumption and breast cancer. What they found may surprise you.

Dr. Lew’s group from the National Cancer Institute found that post-menopausal women who drank an average of 1-2 drinks a day were 32% more likely to develop hormone-sensitive breast cancer. Women who averaged 3 or more drinks a day were 51% more likely than nondrinkers to develop hormone-sensitive breast cancer.

So does that mean women should stop drinking? Not so fast…

An article written by Dr. James O’Keefe in the Journal of the American College of Cardiology last year reviewed the literature on health effects of alcohol. They reported on associations between alcohol consumption and a variety of conditions, including myocardial infarction (heart attack) in middle aged men, stroke, and the risk of type II diabetes. Their report shows that small amounts of daily alcohol consumption improves many health outcomes, while large intake makes them worse (see graph).


From O'Keefe et al., 2007.

In a related study published in The American Journal of Clinical Nutrition in 2007, Dr. Pamela Mink and her colleagues reported results from the Iowa Women’s Health Study. Study participants were 34,489 postmenopausal women who were free of cardiovascular disease. They found an inverse relationship between dietary flavonoids and coronary heart disease, cardiovascular disease, and total mortality. Flavonoids are chemicals found in fruits, vegetables, and red wine that act as antioxidants. Because flavonoids in the diet can come from several sources, these doctors looked at the relationship between consumption of various specific foods and health outcomes, and found that red wine specifically was associated with decreased mortality from coronary heart disease and cardiovascular disease.

A major weakness of all of these studies is that they are population-based comparisons, meaning that they show a correlation between wine consumption and a particular disease process, but cannot prove a causal relationship. So we assume that because red wine is correlated with decreased heart disease, the red wine causes the drinker to have less heart disease. But maybe it’s not the wine, maybe it’s alcohol. Maybe it’s the cheese that gets eaten with the wine. Maybe it’s truffles in the sauce on the red meat that goes so well with the cabernet sauvignon. Studies like these just can’t tell.



So what’s a woman to do? There is no easy answer. Like all medical decisions, the reality is more complex than the headlines. Maybe if you have a strong family history of breast cancer but have no relatives with heart disease, abstinence from wine would be beneficial. Maybe if you had your first heart attack at 35 and don’t know anyone with breast cancer, a glass of red wine a day might not be a bad idea. For most women, however, the answer is unclear. So if you drink moderately, I’m not sure the report from the AACR meeting is a valid reason to stop. However, if breast cancer runs in your family, it certainly should prompt you to discuss your alcohol consumption with your doctor.

Cancer Stem Cells and Familial Cancer Risk for Breast Cancer

One of the most important current trends in cancer biology is the study of cancer stem cells. The cancer stem cell model holds that cancer originates in tissue stem cells, and that dysregulation of these cells underlies the development of the tumor. Also, the cancer stem cell model suggests that tumors contain a small population of cells with stem cell properties (self-renewal and limitless proliferation), that these cells are resistant to chemotherapy, and that these are the cells that cause the majority of relapses.

Another important concept in oncology is hereditary cancer. Although 1 in 8 women will develop breast cancer, it has long been known that women with a family history of breast cancer are more likely to develop breast cancer themselves than are women with no such history. This observation led to the discovery of breast cancer predisposition genes such as BRCA1. Women who inherit a mutated form of this gene from a parent have a lifetime risk of breast cancer that is greater than 90% and are also at increased risk of ovarian cancer.

An interesting paper published recently in Proceedings of the National Academy of Sciences shows how these two concepts are linked. This group, led by Max Wicha from University of Michigan, wanted to investigate whether BRCA1 plays a role in the biology of mammary stem cells. Their first step was to treat normal mammary cells in a way that dramatically reduces how much BRCA1 they make (by using small interfering RNA, siRNA, a tool to inhibit the activity of a specific gene). They found that decreasing the amount of BRCA1 substantially increases the number of cells with stem-cell-like properties. This shows that one role of BRCA1 is to limit the proliferation of mammary stem cells. Because mammary stem cells are the cells that give rise to breast cancer, limiting their proliferation is protective against developing breast cancer, and loss of this protection increases the risk of developing a tumor.

The scientists were able to examine breast tissue from 13 women who were known to have a mutation in BRCA1 and from 22 women with no family history of breast cancer. 5 of the 13 samples from the women with BRCA1 mutations contained “lobules” (clusters) of cells composed almost entirely of mammary stem cells, and none of the samples from the 22 control women had such lobules. 4 of the 5 women (80%) with these “stem cell lobules” went on to develop cancer in the 9 years after the samples were obtained, compared with only 2 of the 8 women (25%) with a BRCA1 mutation but no “stem cell lobules.” Although the number of women studied was small, this difference (80% vs. 25%) was statistically significant. This result supports the idea that the increased number of mammary stem cells seen in women with a BRCA1 mutation is an early step in breast cancer development.

Normal mammary stem cells can give rise to one of two cell types, called myoepithelial cells and luminal epithelial cells. The breast ducts are lined with luminal epithelial cells, and these are surrounded by a layer of myoepithelial cells. Both can give rise to breast cancer, and women with a mutation in BRCA1 are much more likely to develop a cancer of the myoepithelial cells. Interestingly, Wicha and his colleagues showed that loss of BRCA1 function (as would happen in a woman with a BRCA1 mutation) interferes with the ability of the mammary stem cells to develop into luminal epithelial cells, but still allows the generation of normal myoepithelial cells.

One of the other functions of BRCA1 is to help maintain the integrity of cellular DNA. Loss of BRCA1 function impairs the ability of cells to correct DNA damage and leads to the accumulation of mutations. These two functions of BRCA1 together go a long way toward explaining why women with a mutation in this gene are at such high risk of developing breast cancer in particular. Loss of BRCA1 function leads to an accumulation of mammary stem cells and of myoepithelial cells that are both impaired in their ability to correct DNA damage, resulting in an extraordinarily high risk of developing breast cancer.

These findings support the cancer stem cell hypothesis by suggesting that dysregulation of stem cell self-renewal and differentiation is important for both sporadic and inherited breast cancer. What remains is to determine the role of BRCA1 in normal ovarian function, because women with mutations in this gene are prone to ovarian cancer as well.