Hormone replacement therapy is beneficial and safe, it turns out

 

A new study that just appeared in the Journal of the American Medical Association has some good news for women who take estrogen replacement therapy.

To jump to the punch line: estrogen therapy helps to alleviate hot flashes and other symptoms of menopause, and it carries little risk. And even better news: the study also reported that estrogen-only therapy might actually decrease the risk of breast cancer.

Why does this matter? Because about 20 years ago, millions of women stopped taking estrogen, even if it was helping them, because of a report that hormone replacement therapy might increase (not decrease) the risk of breast cancer.

These latest results come from the long-running Women’s Health Initiative, a National Institutes of Health-funded study of more than 160,000 women who were given various hormone therapies and then followed for up to 20 years. The WHI was responsible, somewhat notoriously, for the cancer scare in 2002, when the NIH reported–without consulting many of the scientists leading the study–that hormone replacement therapy increased the risk of breast cancer. This was wrong, as I explained in this column a few years ago, but as a result, many women stopped taking estrogen, and physicians stopped recommending it.

The confusion stemmed from the use of two different types of hormone therapy: (1) estrogen alone, or (2) estrogen plus progestin. The increased risk occurred solely in the combination therapy group (estrogen plus progestin), and not in the estrogen-only group. Despite this crucial difference, the WHI halted the studies of both treatments in 2002, and their press releases didn’t fully explain the difference.

And yet, as Dr. Robert Langer explained in 2017, the WHI trial of estrogen alone (without progestin) continued to track its subjects, and in 2004 that study reported that estrogen-only therapy led to a reduction in breast cancer, and a reduction in coronary heart disease as well.

(Aside: the Women’s Health Initiative website boasts that their 2002 report contains “revolutionary findings about combined hormone therapy,” emphasizing only the harm. I couldn’t find any comparable highlight describing the benefits of estrogen-only therapy.)

The new study, which appeared in JAMA on May 1, confirms several earlier studies that have reported a cancer benefit for estrogen therapy. In addition to its beneficial effects on menopause symptoms (which are widely acknowledged), the new study found that, after an average of 10.7 years, “rates of breast cancer were significantly lower in the CEE group [estrogen only] compared with the placebo group (HR, 0.77).” That HR value means that women who took estrogen had a 23% reduction in their risk of breast cancer.

Further supporting these findings is a 2022 study from NIH, available as a preprint in medRxiv here, which found that women taking estrogen only, compared to no hormones at all, had “significant risk reductions for all study cancers, breast, lung, endometrial, colorectal and ovarian” as well as a 20% reduction in mortality. The 2022 NIH study also found, similarly to the 2002 findings from WHI, that when estrogen was combined with progestin, the risk of breast cancer increased.

And there’s more. This 2012 study out of Denmark studied women who received estrogen-only therapy for 10 years starting in the early 1990s. They then followed these women for another 16 years, and found that women taking estrogen had a lower risk of heart attack, heart failure, or death–and no increased risk of cancer.

(As another aside: the new JAMA paper also reported results on a completely separate study of calcium plus vitamin D. They found that taking supplemental calcium+D didn’t provide any benefit in reducing the risk of bone fractures, confirming what I wrote in a recent column, here.)

So what’s the bottom line? We now have a raft of evidence showing that for post-menopausal women, estrogen therapy can offer significant benefits not only in treating hot flashes and other “bothersome menopausal symptoms” (to quote JAMA), but also in reducing the risk of some types of cancer. In contrast, hormone replacement therapies that use progestin, which is commonly used in birth control pills, might increase the risk of cancer and should be avoided.

As with most medical treatments, the true picture is complicated, but millions of women today might benefit from estrogen therapy. If you think you might be one of them, talk to your physician.

An aspirin a day keeps the grim reaper away

Low-dose aspirin is good for you. Any brand of aspirin 

will do, Bayer or otherwise.

Should you take an aspirin every day to prevent some types of cancer? The evidence is growing, and it all points to the same answer: yes.

In 2016, the US Preventive Services Task Force, a science-guided panel that reviews the evidence for a wide range of treatments, recommended regular low-dose aspirin use for people between the ages of 50 and 69 as a way to prevent heart attacks, strokes, and some types of cancer. For people younger than 50 or older than 69, the USPSTF said that the evidence was inconclusive.

The 2016 recommendations came with a caveat: long-term aspirin use carries a slightly increased risk of bleeding in the stomach and intestinal tract, and a small increase in the risk of a hemorrhagic stroke–although it reduces the risk of ischemic strokes. (Ischemic strokes are caused by blood clots in the brain, while hemorrhagic strokes are caused by bleeding. Aspirins reduces the blood's ability to clot, so this tradeoff makes sense physiologically.)

Later in 2016, a study by Yin Cao and colleagues at Harvard found that aspirin use reduced the risk of cancers, especially colon cancer. To be specific, they found a benefit from taking 0.5 to 1.5 aspirin tablets per week for at least 6 years (a standard tablet is 325 mg). For people who followed this regimen, the risk of colon cancer was about 19% lower.

Now, a new study also led by Yin Cao and others at Harvard, just reported in the annual meeting of the American Association for Cancer Research, shows even clearer benefit. They looked at long-term results in a group of 130,000 women (mostly nurses) and men (doctors and other health professionals) who have been followed since the 1980s. Overall, woman had a 7% reduction in the relative risk of dying from any cause and men had a 11% reduction.

Most of the reduction in mortality was due to the reduced risk in dying from colon cancer, breast cancer, and prostate cancer. Just as with the previous study, the benefit appeared in people who took 0.5 to 1.5 aspirin tablets per week for at least six years.

A decrease in the risk of dying by 7-11% seems like a mighty nice benefit from such a simple treatment. For those (like me) whose stomach is upset by aspirin, a low-dose aspirin tablet taken with food may be easier to tolerate. The low-dose pill contains 81mg, one-fourth of a standard tablet, so 2-6 of these per week is equivalent to the 0.5-1.5 tablets that provided a benefit in the latest study.

It's very encouraging when the evidence for a simple, low-cost treatment consistently shows the same benefit. An important caveat is that that if you have any bleeding problems, you should consult your doctor before taking aspirin.

As for me, I've already stocked up on low-dose aspirin. I'm trying the chewable ones first.

Should we test all women for breast cancer-causing mutations?

In this week’s Journal of the American Medical Association, famed geneticist Mary-Claire King argues that all women over age 30 should be tested for cancer-causing mutations in the BRCA1 and BRCA2 genes. King, who made the original discovery of the link between BRCA1 and breast cancer, is one of the world’s leading experts on how mutations in these genes cause cancer.

But her proposed new universal testing policy, which fellow Forbes contributor David Shaywitz calls “audacious,” goes far beyond what other experts recommend. Earlier this year, the highly regarded U.S. Preventative Services Task Force (USPSTF) recommended testing BRCA genes only in women with a family history of breast or ovarian cancer. 

Although there’s no question that King is an expert on BRCA gene testing, I think she’s gone much too far with her latest proposal. She has the science right, but she is far too optimistic about how her recommendation would actually play out. The policy might save some lives, but it would also cause a great deal of pain.

First, it’s worth explaining why King thinks universal BRCA testing is a good idea. In her JAMA article, King and colleagues describe a new study they conducted in Ashkenazy Jews that showed, somewhat surprisingly, that 

“50% of families found to harbor BRCA1 or BRCA2 mutations had no history of breast or ovarian cancer that would have triggered clinical attention." 

In other words, under current policy guidelines, 50% of people who have a damaging mutation in one of these genes will not have their genes tested. Many of them will eventually get breast or ovarian cancer—as King explains, women with harmful BRCA1 mutations have a 60% risk of cancer by age 60, and for BRCA2 the risk is 33% by age 60. That’s a very high risk, though it’s important to keep in mind that many women with these mutations will never get cancer.

With modern DNA sequencing technology, any large-scale genetic BRCA testing program is likely to uncover thousands of mutations that have no harmful effects, and thousands more whose effects are simply unknown. (Aside: each BRCA gene spans about 80-90 thousand nucleotides of DNA, and each of those letters can mutate in 4 ways, changing into one of the other 3 bases or just being deleted. This means there are at least 400,000 mutations possible in each gene, not counting larger deletions. A colleague and I published an article in 2010 describing one such BRCA test.) King is clearly aware that such reporting these mutations to patients would only sow confusion, and she recommends that:

“Testing for BRCA1 and BRCA2 should focus solely on unambiguously loss-of-function mutations with definitive effect on cancer risk…. A VUS [variant of unknown significance] can increase confusion and compromise clinical management; for population-based screening, these variants should not be reported.”

Herein lies one of the biggest problems with King’s idea. We don’t have universal agreement on which mutations have no significance, and even if we did, most physicians are not experts on cancer genetics. In our lawsuit-prone medical culture, there exists an unfortunate tendency to over-treat and over-report everything. 

Thus I fear that if we had wider BRCA testing, clinical labs would report all mutations back to physicians (how could they not?), and physicians in turn would report everything to the patients. The result would be that millions of women would be told "you have a mutation in BRCA1, and we don't know what it means." What's a patient supposed to do with that?

The other problem is that the only treatment to prevent breast and ovarian cancer is surgery to remove a woman’s breasts and ovaries. We don’t have a pill you can take, or lifestyle changes you can adopt, that will dramatically reduce your risk of hereditary cancer. But unlike a cancer diagnosis, the discovery of a BRCA mutation does not mean you have cancer. It simply means you have a risk, possibly a high risk, of getting cancer at a young age. We know from decades of research that people are not very good at evaluating risk. We tend to over-estimate the danger of events that seem very dramatic or visible to us, as cancer is to many people. 

By King’s own estimates, widespread BRCA testing would detect cancer-causing mutations in 250,000 to 415,000 women in the U.S. This estimate assumes the test doesn’t have false positives, which it almost certainly would. All of these women would then be faced with an extremely difficult dilemma: should they have both their breasts removed, or live the rest of their lives in fear of breast cancer? 

This dilemma was famously on display last year, when actress Angelina Jolie revealed in a New York Times article that she’d had a double mastectomy, after discovering that she carried high-risk BRCA mutations. Jolie’s mother died from cancer at the age of 56, and she explained in her article that as a result of the surgery, “ I can tell my children that they don’t need to fear they will lose me to breast cancer.”

King’s proposal is audacious, and it’s well worth debating. But without a better treatment option, telling hundreds of thousands of women that they have a high risk of breast and ovarian cancer carries a potentially enormous cost, both physical and emotional, for these women. Rather than putting huge numbers of women under the surgeon’s knife, we should instead double or triple our investments in research on treatments that may eventually make surgery unnecessary. 

Myriad Genetics CEO Claims He Owns Your DNA

With the Supreme Court about to hear a landmark case on gene patents, Myriad Genetics, the company that owns the patents under scrutiny, is going on the offensive.  I've written about this case before, when the patents were first thrown out by one court, and then restored by another.  Now the Supremes will have the final say.

Just last week, geneticists Jeffrey Rosenfeld and Chris Mason wrote a commentary for the Washington Post that warned about the consequences of companies owning the rights to our gene sequences.

Today, in a letter filled with non sequiturs and distortions, Myriad Genetics' CEO Peter Meldrum, worried about whether his company will be able to maintain their monopoly on a test for which they charge $4000, responded.  Let's look at his claims.

First, though, let me remind readers that the genes in question, BRCA1 and BRCA2, are linked to an increased risk of breast and ovarian cancer, a risk that was first discovered in 1994 by scientists at the University of Utah.  Myriad Genetics owns a patent on these genes, and as I wrote last year:

"Thanks to these patents, you can’t look these genes in your own body without paying a fee to Myriad. Sounds ridiculous, right? Well, that was the state of gene patents until last May [2011], when judge Robert Sweet ruled that the Myriad’s patents were invalid."

Myriad appealed the decision, and the appeals court overturned Judge Sweet, buying into the argument by Myriad's lawyers that "isolated DNA" is not the same as the natural DNA, and that this distinction allows companies to patent it.  This is scientific nonsense for many reasons: for one thing, the process of isolating DNA does not create an artificial molecule. The body's own cells isolate DNA all the time, in the process of turning it into proteins.  But the appeals court accepted the argument, perhaps just because they wanted to uphold the patents.  So now the Supreme Court will re-examine this scientifically ridiculous claim.

Now let's look at CEO Meldrum's letter.  He first claims that Myriad's patents

"were essential to developing diagnostic tools that have been used by more than 1 million women to understand their hereditary risks of breast cancer and ovarian cancer."

This claim is simply false.  Myriad's patents made no contribution at all (and certainly weren't "essential") to the diagnostic tools used to detect mutations.  I know something about these tools, which I've been using in my own research for over 15 years.  Furthermore, academic medical centers were offering their own diagnostic tests on the BRCA genes, at a lower cost than Myriad, until Myriad's lawyers forced them to stop.  So Myriad's patents have increased costs to patients and, if anything, slowed down progress on making the tests faster and cheaper.

Second, Meldrum writes:

"Were these molecules derived in part from natural material? Sure. But that is true of many patents. Labs routinely turn naturally found molecules into innovative medicines and get patent protection."

One's jaw drops at this irrelevant non sequitur.  Myriad has never created "innovative medicine" or any other sort of medicine.  And the BRCA gene tests are not medicine: they are a diagnostic test that reads your DNA and tells you if you have harmful mutations in two specific genes.  Myriad's patents have nothing to do with medicines that treat breast and ovarian cancer - although it's clear that Meldrum would like us to think otherwise.

Third, Meldrum claims:

"Our tests are also accessible; some 95 percent of patients get insurance coverage, and we offer the test for free to those who cannot afford it."

This too is irrelevant, and also untrue.  The fact that 95% of patients have insurance, even if true, has nothing to do with whether or not genes should be patented.  And this merely hides the fact that Myriad's test is outrageously overpriced, at $4000 per patient.  The actual costs of testing for this gene should be far lower: we can now sequence an entire genome for $4000, and this test only looks at 2 genes out of more than 20,000.

Meldrum also throws out the unproven claim that Myriad offers it for free to those who cannot afford it.  Really?  Who decides if someone can afford it? If a woman can scrape together the $4000 with great hardship, does Myriad give her a break on the price?  I doubt it.  And what does this have to do with Myriad's supposed right to own your genes?

Fourth, Meldrum makes the remarkable claim that

"Our patents have also promoted additional research; 18,000 scientists have studied the genes, resulting in 10,000 published papers."  

This is just unfounded bragging.  Even the most wildly successful scientists would be very careful about claiming that that 10,000 papers have been based on their work.  In the case of Myriad, this is just false.  If you do a PubMed search for BRCA1, you can indeed find over 9,600 papers, as I did today.  However, there is no evidence whatsoever that these papers were even remotely supported by Myriad's patents.  It is far more likely that the patents prevented additional research on the BRCA genes.  The vast majority of research on these genes was supported by the public, which in the U.S. means by the National Institutes of Health.  Meldrum's boastful claim is absurd.

It's worth noting that the original paper describing the link between BRCA1 and breast cancer was published by a multi-institutional team from the University of Utah and other places, who were supported by multiple grants from the NIH and from the Canadian government.  Myriad Genetics subsequently licensed the patent rights from Utah, and has used them ever since to maintain its monopoly and prevent others from developing tests on the BRCA genes.  To claim that its patents promote innovation is pure nonsense.

The bottom line is that no one invented your genes, and no private company should be able to tell you that you can't even read your own DNA.  Today, you can get your DNA sequenced for less than the cost of the Myriad test.  Using free software (developed by my lab), you can scan that DNA for mutations in BRCA1 and BRCA2. And no company should be able to tell you not to.

Peter Meldrum's letter reveals that he doesn't care very much about the truth.  Meldrum made $4.87 million in 2011 as CEO of Myriad, so it's pretty clear what motivates him. Myriad's use of its patents to charge exhorbitant prices to women at risk for breast and ovarian cancer does not demonstrate innovation. It just demonstrates greed.