Does addiction last a lifetime?

I am now 11 years into recovery from my battle with opiate addiction, and I have always been fascinated with two related questions: is there truly such a thing as an “addictive personality,” and do people substitute addictions?

The myth of the addictive personality

The recently deceased writer and television personality Anthony Bourdain was criticized by some for recreationally using alcohol and cannabis, in what was seemingly a very controlled and responsible manner, decades after he quit heroin and cocaine. Was this a valid criticism? Can a person who was addicted to drugs or alcohol in their teens safely have a glass of wine with dinner in their middle age?

It depends on which model of addiction and recovery you subscribe to. If you are a traditionalist who believes that addictions last a lifetime, that people readily substitute addictions, and that people have ingrained “addictive personalities,” the answer is: absolutely not. This would be playing with fire.

During my 90 days in rehab, it was forcefully impressed upon me that addictions are routinely substituted, and that if one is ever addicted to any substance, then lifelong abstinence from all potentially addictive substances is one’s only hope of salvation. This seemed to make sense, as a person would have the same lifelong predispositions to an addiction: genetic makeup, childhood traumas, diagnoses of anxiety or depression — all of which could plausibly set them up to become addicted to, say, alcohol, once they have put in the hard work to get their heroin addiction under control. In medical terms, the concern is that different addictions can have a common final pathway in the mesolimbic dopamine system (the reward system of our brain), so it is logical that the body might try to find a second pathway to satisfy these hungry neurotransmitters if the first one is blocked, a “cross-addiction.”

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I learned early in my own recovery how critical it is to apply logic and evidence to the field of addiction, and that just because things make sense, and because we have thought about them in a certain way for an extended period of time, that doesn’t mean that they are necessarily true. While in rehab, I was actually told a lot of other things that turned out to have no basis in scientific evidence. For example, I was told on a daily basis that “a drug is a drug is a drug.” This mentality doesn’t allow for there being a difference between, for example, the powerful opiate fentanyl, which kills thousands of people every year, and buprenorphene (Suboxone) which is a widely-accepted treatment for opioid use disorder.

I have come to believe that an uncompromising “abstinence-only” model is a holdover from the very beginnings of the recovery movement, almost 100 years ago, and our understanding has greatly evolved since then. The concepts of addiction and recovery that made sense in 1935, when Alcoholics Anonymous was founded, and which have been carried on by tradition, might not still hold true in the modern age of neurochemistry and functional MRIs. That said, mutual help groups today do have a place in some people’s recovery and they can encourage the work of changing and maintaining change.

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Recovery may improve resiliency to new addictions

It seems as if no one definitively knows the answer about whether people substitute addictions. According to the National Institute on Drug Abuse in response to a request for comment from the website Tonic: “A previous substance use disorder is a risk factor for future development of substance use disorder (SUD),” but “It is also possible that someone who once had an SUD but doesn’t currently have one has a balance of risk and protective genetic and environmental factors that could allow for alcohol consumption without developing an AUD [alcohol use disorder].”

One study published in JAMA in 2014 showed that, “As compared with those who do not recover from an SUD, people who recover have less than half the risk of developing a new SUD. Contrary to clinical lore, achieving remission does not typically lead to drug substitution, but rather is associated with a lower risk of new SUD onset.”

The authors of this study suggest that factors such as “coping strategies, skills, and motivation of individuals who recover from an SUD may protect them from the onset of a new SUD.” In other words, by making the life-affirming transition from addicted to recovered, we gain a recovery “toolbox” that helps us navigate life’s challenges and stresses in a much healthier way. We learn to connect with people, push our egos aside, and to ask for help if we need it. Thus, when faced with stressful situations that formerly would trigger us to drink or drug, we might respond by exercising or calling a friend, rather than using a substance. As such, we substitute addictions with healthier activities that perform the function that the drink or drug used to, albeit in a much more fulfilling way.

This issue is also, partly, a question of semantics, and of how narrowly or widely we define addictions. Many hold that an addiction can be to either a substance or a process: gambling, eating, video game playing, Internet use, sex, work, religion, exercise, or compulsive spending. Lots of people gain weight when they quit smoking. Is that a case of substituting an addiction? I like to joke that, in my observations, the only reliable outcome from a stay at rehab was a nicotine addiction, because many people, in an attempt to cope with the trauma and dislocation of being sent away to rehab, pick up cigarettes.

Brain-based devices: How well do they work?

There are more than 10,000 patent filings for brain-based devices that claim to help people “develop muscle memory faster,” “lose weight,” “monitor and act on…sleep,” and “treat depression.” Many of the websites featuring these devices cite “science” as backing up their claims. However, a recent review by science journalist Diana Kwon concluded that the large majority of these claims are not scientifically valid. As a consumer, how can you separate hype from science when deciding to use a brain-based device?

Even when there is science, you can’t assume that a device will work for you

Many people choose to ignore scientific findings, even when there is published evidence supporting a view. While this is understandable, it makes little sense to completely ignore scientific findings when you are evaluating new technologies.

For the scientific community to believe that a device is helpful, they usually consider the following basic factors:

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  • True positive findings: There must be a statistically significant difference between the device and a placebo or sham treatment.
  • Replication: There are many different experiments by different groups that show a device has worked.
  • Control: The device should be compared to a placebo or sham treatment to show that it had a real effect.
  • Blindness: People conducting the experiment should not know what they are administering, and participants should not know what they are receiving. When both researchers and participants are blind to the intervention, this is called a double-blind study. Also, the intervention should be randomized (people should receive the placebo or control interventions at random). When trials are double-blind and randomized, bias is reduced.
  • Peer-reviewed journal: The findings should be published in a peer-reviewed journal, and not just an open online platform.

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Challenges facing neuroscience research

While scientific studies do provide one line of evidence that supports whether a device will work or not, in neuroscience research the criteria above are fraught with challenges.

False-positive findings. Many neuroscience studies are not stringent enough, and as a result, you cannot believe findings at face value. For instance, Stanford epidemiologist John Ioannidis explained that most neuroscience studies produce false alarms because they are designed poorly. The findings are blown out of proportion because the sample sizes are too small or biased. For example, one headline stated, “Brain implant ‘predicts’ epileptic seizures” but only 15 people were tested. Another study of a cognitive training program had a large sample size, but all the participants were already using the program, making this quite biased.

Can you be blind to a device? Unless researchers make a placebo device that looks and feels identical, they will not be blind to what they are administering. And unless participants cannot distinguish between an actual device and a placebo, they know what they are getting. When either researchers and participants are not blind to the intervention, this can bias study results.

Randomized, double-blind, placebo-controlled trials give you comparisons of an average effectiveness of a device in a group. As a unique individual, you can’t be certain a device will work for you because it has worked for others.

Is replication possible? Close to 50% of medical studies cannot be replicated, even once. This is especially true of neuroscience research. Also, biology changes over time, so even if you do replicate a finding on the same sample, it is essentially a new finding.

Do studies use the right control groups? Across different studies, control groups should also be comparable. Age, gender, geography, diet, and temperament can all vary, and when they do, the results are less reliable. Also, simply being in a study may make people behave differently from how they behave in their everyday lives, so you can’t assume that research findings will translate to real life.

Peer review is flawed. When a study is peer-reviewed, it means that qualified people who study a similar topic have double-checked the study for quality and accuracy. In 2006, British physician Richard Smith explained that peer review is an inherently flawed and subjective process. While peer review does ensure oversight by respected experts, peer reviewers are often doing similar research, and they may be biased if new findings oppose their own research. Also, peer reviews are dominated by men, due to gender biases that are often subtle or unconscious.

How do you assess the value of new neurotechnologies?

So, what can you do when the absence of studies gives you no information, or the validity of studies is highly questionable?

Your risk of dementia: Do lifestyle and genetics matter?

Globally, Alzheimer’s disease and other forms of dementia are a major burden on individuals and communities. To make matters worse, there are few treatments to combat these complex illnesses. Even the causes of dementia are widely debated. Sadly, clinical trials for drugs to stop or even slow its progress have come up short. Taking a different tack, some experts hope to intervene before people are diagnosed with dementia by encouraging lifestyle changes.

What is dementia and what makes it so complex?

Dementia describes groups of specific diseases characterized by symptoms such as memory loss. The most common type of dementia is Alzheimer’s disease (AD). People with AD have plaques in their brains made of up of tangled proteins, and many researchers have hypothesized that these plaques are the cause of the disease.

Another common type of dementia is vascular dementia. This is thought to be induced by damaged blood vessels in the brain, such as from a stroke.

Experts believe both genetic factors (variants of genes passed down from mom and dad) and modifiable lifestyle factors (diet, smoking, physical activity) all play a role in the development of dementia, perhaps in concert.

Protect yourself from the damage of chronic inflammation.

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What factors might affect dementia risk?

Genes — which are not considered modifiable — and lifestyle factors like physical activity and diet — which are considered modifiable — play potential roles in different forms of dementia.

A recent study in JAMA attempts to estimate how much genetic and lifestyle factors influence risk for dementia by querying individuals who pledged to be part of a UK-based “biobank.” Biobanks link large collections of biological information, such as genetics, with health and disease status gleaned from medical records. Using data in large biobanks, scientists can look at how the environment — which includes lifestyle choices — and genetics work together to increase (or decrease) risk for disease.

In the JAMA study, researchers tapped hospital records and death registries to collect diagnoses in 200,000 white British individuals age 60 or older.

But how can you measure “lifestyle” and genetic risk?

The investigators hand-picked a list of common lifestyle factors, including smoking, alcohol consumption, physical activity, and diet, and created a score. A low score denoted a “bad” lifestyle. A high score denoted a “good” lifestyle.

However, taking this approach to measure lifestyle risk has several pitfalls:

  • First, a vast number of factors comprise lifestyle and environment beyond smoking and physical activity. So any list may be arbitrary. In fact, our research team has argued that choosing a candidate list doesn’t capture our complex lifestyles and may lead to false findings. For example, what exactly constitutes a “healthy” diet?
  • Second, using a score makes the individual roles of the factors unclear.
  • Third, if connections between factors (for example, weight or history of other diseases) influence both the score and dementia, then the score might be a weak proxy for other variables that weren’t considered. In other words, if weight is associated with diet and dementia, then it is hard to untangle the association of diet.

To create the genetic risk score, the investigators used all genetic variants previously identified by a genome-wide association study (GWAS) of Alzheimer’s disease. These gene variants are strongly associated with patients who have Alzheimer’s compared with healthy controls). Using this information, the researchers constructed a polygenic risk score.

Lifestyle and genetics both play a small role in dementia

The lifestyle score was associated with dementia risk. Second, the genetic score was also associated with dementia. In other words, individuals with worse scores were at higher risk for dementia. The researchers further found that genetic risk and lifestyle appeared to act independently of each other. For example, individuals with both an unhealthy lifestyle and a high genetic risk score had almost two and a half times more risk than individuals with a low genetic score and healthy lifestyle.

Why medical research keeps changing its mind

Did you ever wonder why medical research seems to flip-flop so often? Eggs used to be terrible for your health; now they’re not so bad. Stomach ulcers were thought to be due to stress and a “type A personality” but that’s been disproven. I was taught that every postmenopausal woman should take hormone replacement therapy to prevent heart disease and bone loss; now it’s considered way too risky. It can make you question every bit of medical news you hear.

But maybe that’s not such a bad thing. Questioning what you read or hear is reasonable. And maybe medical reversals — when new research leads to a complete turnaround regarding a widespread medical practice or treatment — are not as common as they seem. Perhaps they get more attention than they deserve and drown out the consistent and “non-reversed” medical research that’s out there. For example, it seems unlikely that the health benefits of regular exercise, smoking cessation, or maintaining a healthy weight will ever be reversed.

A new study examines medical reversals

A remarkable new study explored the phenomenon of medical reversals to determine how common they are, and to identify what types of conditions were most involved.

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Researchers collected more than 3,000 randomized controlled trials; these are considered the most reliable types of research because they randomly assign otherwise similar study subjects to different treatment groups and try to account (control) for factors other than the treatments that might affect the results. For example, a trial comparing two treatments to prevent heart attacks would need to have a similar proportion of people with high cholesterol or high blood pressure, because these can affect the risk of heart attack.

In this new study, the analysis was limited to three of the top medical journals in the world: JAMA (formerly known as the Journal of the American Medical Association), The Lancet, and the New England Journal of Medicine. For each medical reversal identified, the authors searched for later studies refuting the findings and only counted those that had stood the test of time (so far!).

Here’s what they found:

  • Of 3,017 studies analyzed from the last 15 years, 396 came to conclusions that reversed prior treatments or practice recommendations. This represented about 13% of randomized controlled trials appearing in these journals and about 6% of their original research papers.
  • The most common conditions were cardiovascular disease, preventive medicine, and critical care medicine (such as care received in an intensive care unit).
  • Medications, procedures, and vitamins accounted for about two-thirds of the reversals.

Protect yourself from the damage of chronic inflammation.

Science has proven that chronic, low-grade inflammation can turn into a silent killer that contributes to cardiovas­cular disease, cancer, type 2 diabetes and other conditions. Get simple tips to fight inflammation and stay healthy — from Harvard Medical School experts.

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View Protect yourself from the damage of chronic inflammation.

Examples of medical reversals

Among the nearly 400 medical treatments or practices that were reversed during the years of this new study, here are some notable examples.

  • Wearable technology for weight loss. When fitness trackers first became widely available, recommendations to use them to help with weight loss were common. But a study in 2016 found that they were no more effective (and perhaps less so) than a standard weight-loss program that did not use an activity tracker.
  • Hormone replacement therapy (HRT). For more than 50 years, HRT was thought to prevent chronic disease, such as cardiovascular disease, in menopausal women. A number of more recent (and more powerful) studies have demonstrated that HRT provides no such benefits, and that some combinations of hormonal therapy may increase the risk of certain cancers, stroke, and blood clots. HRT may still be recommended for women with significant menopausal symptoms, such as hot flashes, but it is no longer prescribed to prevent chronic disease.
  • Surgery for a meniscal (cartilage) tear with osteoarthritis of the knee for adults ages 45 and older. This combination of problems is common among middle-aged and older adults and is frequently detected when MRI scans are performed to evaluate knee pain. While surgery was often recommended and performed to remove or repair the torn meniscus, it was uncertain whether this was truly necessary. A study in 2013 found that initial treatment with physical therapy was just as effective as immediate surgery. Guidelines soon changed to advise nonsurgical treatment as the initial approach for most middle-aged or older patients with meniscal tears and osteoarthritis of the knee.

Medical myth or medical fact?

Myth and misconception are common in matters of health and medical practice. But it’s also true that medical fact is a moving target. Things we accepted as fact years ago sometimes turn out to be wrong, as these medical reversals demonstrate. Meanwhile, certain myths could turn out to have credence if well-designed research concludes as much.

The reason this study about medical reversals is so important is that it points out how vital rigorous research is, not only for new treatments or innovative procedures, but also to evaluate older, well-established ways of doing things.

What’s next?

Hearing medical experts flip-flop on their recommendations or conclusions about medical news seems common — but is 6% of original research or 13% of all randomized controlled trials “too high”? I’d argue that it’s not. In fact, rather than casting doubt on all research, this new study about medical reversals should serve as a measure of reassurance that skepticism is alive and well in the research community, and that “low-value medical practices” will be uncovered if the right research is designed, funded, and implemented.

You can bet that there will be more head-scratching, mind-bending medical reversals in the future. Just keep in mind that most of this is simply a reflection of how researchers are continuing to clarify what works in medicine — and what doesn’t. The best they can do is to keep at it. The best we can do is to consider medical news with a critical eye and to keep an open mind.

As the pandemic drags on, when can we get back to work?

April 21, 2020By Robert H. Shmerling, MD, Senior Faculty Editor, Harvard Health Publishing; Editorial Advisory Board Member, Harvard Health Publishing

Along with widespread illness and death, the COVID-19 pandemic is also causing massive economic disruption. Stay-at-home measures and business shutdowns have prevented millions of people from working. In just four weeks, between mid-March and mid-April, 22 million Americans filed for unemployment benefits. These numbers are bound to spiral higher.

Given all the hardships — and new predictions that cases of COVID-19 will begin falling in most states in the coming weeks — when might people be able to return to work? Thus far, the answers are quite uncertain.

Although the Centers for Disease Control and Prevention (CDC) has issued some federal guidelines, you may need to follow stricter state or local regulations and employer policies. Some experts have suggested serologic (antibody) tests to determine who has had the virus and to guide decisions about returning to work. And the experiences of countries that have successfully slowed cases of COVID-19 and loosened restrictions on work will come into play, too. Below I’ve explained a bit about each approach.

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Return-to-work recommendations from the CDC

The recommendations vary depending on where you work – in healthcare or critical infrastructure, for example – whether you had symptoms of COVID-19, and whether a test confirmed that you had COVID-19. (Tests are not widely available in some areas of the country.)

  • Workers in critical infrastructure (such as emergency services, the nuclear reactor industry, or defense) who have no symptoms, but were exposed to someone with confirmed or suspected COVID-19 Recent guidelines permit continuing to work if the worker has no symptoms, no fever, wears a mask for 14 days from last exposure, maintains six-foot physical distancing from others (“as work duties permit”), and disinfects and cleans work spaces well. This relaxes previous requirements that urged such workers to remain in quarantine for 14 days before returning to work.
  • Workers in healthcare settings (such as hospitals, medical practices, or nursing homes) with suspected or confirmed COVID-19 The guidelines allow discontinuation of isolation and returning to work once fever has resolved, symptoms have improved, and swab tests for the virus are negative twice at least 24 hours apart. However, there are additional points to consider:
    • If follow-up testing is not performed Those who had COVID-19 should wait until they’ve had three or more days of improved symptoms without fever and ten days have passed since symptoms began.
    • If no symptoms were ever present but a test was positive A person can discontinue isolation if a lack of symptoms continues and it’s been 10 days since the first positive test or if two follow-up tests for the virus are negative at least 24 hours apart.
    • If testing was never performed for a person with suspected COVID-19 A person can discontinue isolation once they have had three or more days of improved symptoms without fever and ten days have passed since symptoms began.
    • If isolation was recommended following exposure to someone who had COVID-19 A person can discontinue isolation if swab testing is negative; a second test may be recommended when suspicion remains high.
  • Workers outside of these settings Currently the guidelines for people who work in healthcare settings apply here, too.

Because local regulations or employer policies may be more stringent than these recommendations, it’s important to check with your employer and primary care physician before going back to work. Return to work guidelines cannot entirely prevent the spread of COVID-19. They may change in coming months as public health officials respond to rising or falling levels of the virus.

A new Alzheimer’s drug: From advisory panel to FDA — what’s at stake here?

November 12, 2020By Andrew E. Budson, MD, Contributor; Editorial Advisory Board Member, Harvard Health Publishing

It’s been more than 17 years since the FDA last approved an Alzheimer’s drug. Will Biogen’s drug, called aducanumab, end this drought? The FDA will decide by March 2021, based on its own analysis of clinical trial data and an advisory panel’s review of the evidence.

How does the drug work?

Aducanumab is a monoclonal antibody engineered in a laboratory to stick to the amyloid molecule that forms plaques in the brains of people with Alzheimer’s. Most researchers believe that the plaques form first and damage brain cells, causing tau tangles to form inside them, killing the cells. Once aducanumab has stuck to the plaque, your body’s immune system will come in and remove the plaque, thinking it’s a foreign invader. The hope and expectation is that, once the plaques are removed, the brain cells will stop dying, and thinking, memory, function, and behavior will stop deteriorating.

Protect yourself from the damage of chronic inflammation.

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Will the FDA’s decision be important?

If aducanumab works, it would be the first drug that actually slows down the progression of Alzheimer’s. That means we could possibly turn Alzheimer’s from a fatal disease into one that people could live with for many years, in the same way that people are living with cancer, diabetes, and HIV/AIDS.

For researchers, it means that more than 20 years of scientific work, which suggests that removing amyloid from the brain can cure Alzheimer’s, may be correct. But many of us have begun to doubt this theory, because trial after trial has shown that amyloid could be cleared from the brain but clinical disease progression was not altered.

So, does the drug work?

I attended the day-long FDA hearing on November 6, 2020, and also independently reviewed all the publicly available data for aducanumab. There was one small (phase 2) clinical trial to assess efficacy and side effects, and two large (phase 3) clinical trials to assess effectiveness, side effects, safety, and how the drug might be used in clinical practice. The small phase 2 study and one of the large phase 3 studies were positive, meaning that the drug worked to slow down the decline of thinking, memory, and function that is usually impossible to stop in Alzheimer’s. The other large study was negative. Hmm… Is two out of three positive studies good enough? Biogen’s scientific team had many plausible explanations for why that one study was negative.

The advisory panel, however, was not convinced. They pointed out that phase 2 studies are always positive, because otherwise you wouldn’t move on to phase 3, so that study doesn’t count. They also pointed out that, although you can think of the positive phase 3 study as the “true” one, and try to understand why the negative one failed (which is what Biogen did), you could equally think of the negative study as the true one, and try to understand why the other one showed positive results.

The advisory council was concerned that there was “functional unblinding” in both studies, because large numbers of participants in the treatment group needed additional MRI scans and physical exams to deal with side effects, which did not occur in the placebo group. Hence, if you were asked to come in for an extra MRI scan, you knew that you were on the real drug. This knowledge may have influenced the responses subjects and their family members gave regarding how they were doing, which were the primary outcomes of the study.

Should the FDA approve it?

To determine if a drug should be approved, many factors need to be considered. First is whether it works and, as discussed above, there are questions regarding its efficacy. You also have to consider side effects and other burdens on patients, families, and society.

You first need an amyloid PET scan to be sure you have the amyloid plaques of Alzheimer’s. Then to take the drug, you need an intravenous infusion every four weeks — forever. Thirty percent of those who took the drug had a reversible swelling of the brain, and more than 10% had tiny brain bleeds. These side effects need to be watched closely by an expert neurology/radiology team who understand how to monitor for these events, and know when to pause or stop the drug.

Another factor to consider is the size of the benefit. Here, it was fairly small. Looking at the two objective measures, in the positive trial, the high dose made a 0.6-point change on the 30-point Mini-Mental State Examination (MMSE). On the 85-point Alzheimer’s Disease Assessment Scale–Cognitive Subscale-13 (ADAS-Cog-13), the high dose made a 1.4-point change. In the negative trial, the analogous results were -0.1 (worsening) for the MMSE and 0.6 for the ADAS-Cog-13.

Cost also needs to be considered; for aducanumab, this is estimated at $50,000 per year per patient. There are more than two million people with Alzheimer’s in the mild cognitive impairment and mild dementia stages. If one-quarter of those decide to take the drug, that’s $25 billion each year — not including the cost of the PET scans and the neurology/radiology teams to monitor side effects. Since most people with Alzheimer’s disease have Medicare, we will all share this cost.

Moreover, Dr. Joel Perlmutter, a neurologist at Washington University in St. Louis and member of the FDA’s advisory committee, argued that if the FDA approves aducanumab, fewer people would want to participate in a trial of a novel medication — and that would likely delay the approval of better medicines.

If it’s not approved, what other treatments are out there?

There are many other treatments for Alzheimer’s that are also being developed. Drugs that remove tau — the tangles of Alzheimer’s — are being tested. Treatments using flashing lights to induce specific brain rhythms may protect the brain. Other treatments change the microbiome of the gut or other parts of the body. Drugs are being developed which alter nitric oxide — a gas that has critical functions in brain health. Lastly, in my laboratory, we are developing strategies to help individuals with mild Alzheimer’s and mild cognitive impairment to remember things better, because, at the end of the day, that’s what matters most.

Can some postmenopausal women with breast cancer skip chemotherapy?

Breast cancer remains the most common cancer among women. In the last two decades, the treatment of breast cancers has become personalized. This has been possible due to the subtyping of breast cancers. Breast cancers have been subtyped based on the receptors on the breast cancer cell. The most clinically significant receptors — those that have targeted therapies — are the estrogen and progesterone receptors and the human epidermal growth factor receptor 2 (HER2). Cancers that have the estrogen and progesterone receptors are termed hormone receptor (HR)-positive cancers.

The development of hormone therapy for HR-positive breast cancers means that some women, for whom the risks of chemotherapy outweigh the benefits, may be able to forego chemotherapy. The development of genomic assays, tests that analyze genes expressed in cancer, have provided a way to help doctors and women decide who will obtain the most benefit from chemotherapy.

How does genomic testing help to personalize breast cancer treatment?

Increasingly detailed knowledge about breast cancers has led to the development of personalized therapy. In addition to knowing the type and stage of your cancer, genomic testing has further refined how we assess the risk of recurrence for breast cancer. One genomic test, Oncotype Dx, is a useful tool that can help predict the likelihood of benefit from chemotherapy, as well as the risk of recurrence for invasive breast cancer.

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Not all women will require chemotherapy, but for some women hormone therapy alone is not enough. Oncotype Dx analyzes the expression of 21 genes in HR-positive, HER2-negative breast cancer and assigns a recurrence score (RS) based on risk of recurrence. The Oncotype Dx test places women into three groups: low, intermediate or moderate, and high risk of recurrence. Women with a low score do not need chemotherapy and benefit the most from hormone therapy, while women who have a high recurrence score benefit the most from chemotherapy in addition to hormone therapy.

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There is new research to help women make decisions about chemotherapy

Until recently, it was unclear how much benefit women with an intermediate risk score obtained from chemotherapy. A randomized clinical controlled trial, the Tailor Rx trial, answered this question. The trial randomized women with node-negative (cancer that has not yet spread to the lymph nodes), HR-positive, HER2-negative breast cancers with an intermediate risk score to hormone therapy alone, or to chemotherapy in additional to hormone therapy. The results showed that most women with an intermediate risk of invasive cancer did not get any added benefit with chemotherapy. However, the subgroup of women who did benefit from chemotherapy were premenopausal women under age 50.

While the results of the Tailor Rx trial were practice-changing, it did lead to questions about the benefit of chemotherapy in women whose cancer has spread to their lymph nodes and who had HR-positive, HER2-negative breast cancer. The RxPonder trial answered this question.

The RxPonder trial randomized 5,015 women with stage II/III HR-positive, HER2-negative breast cancer, with one to three positive lymph nodes, and an intermediate RS (≤ 25). Patients were randomized to receive hormone therapy alone, or hormone therapy with chemotherapy. The main goal of the study was to determine how many women did not get a recurrence of the invasive breast cancer while they were being followed.

There were many ways to compare the women in the study, but the main characteristics chosen for comparison were: menopausal status, RS, and the kind of axillary surgery they received. At a median follow up of 5.1 years, there was no association between chemotherapy benefit and RS value between zero and 25 for the entire population. However, there was an association seen between chemotherapy benefit and menopausal status. This trial provided evidence that even women with cancer in their lymph nodes, if they had a low or intermediate RS, could avoid chemotherapy.

Premenopausal women responded better to hormone therapy and chemotherapy

Of the women enrolled in the RxPonder trial, 3,350 were postmenopausal and 1,665 were premenopausal. Further analysis by menopausal status revealed that there was no difference in five-year survival for postmenopausal women treated with hormone therapy alone versus hormone therapy with chemotherapy.

However, for premenopausal women there was a 46% reduction in the risk of invasive disease. For this subgroup of women, the five-year, invasive disease-free survival rates were 94.2% in women treated with hormone therapy and chemotherapy, compared to 89% in women treated with hormone therapy alone. The premenopausal women who received both chemotherapy and hormone therapy had an additional benefit of around 5%. It is unclear if the survival benefit seen in premenopausal women is primarily due to chemotherapy’s effect, or indirectly by ovarian suppression due to chemotherapy

What does this mean for breast cancer treatment decision-making?

The treatment of breast cancer has truly become personalized. It has always been important to know the stage of your caner, but now it is also important to know the type of your cancer. With this information, women can make an informed discussion with their oncologist about the risks and benefits of chemotherapy.

If you are a premenopausal woman with a HR-positive, node-positive breast cancer, chemotherapy and hormone therapy may give you the greatest chance of decreasing your risk of the cancer coming back. However, for a postmenopausal woman with HR-positive breast cancer, chemotherapy may not add many treatment benefits to hormone therapy, and it carries risks that may affect your quality of life. Studies like the TailorRx and RxPonder trials have provided more information to help you make an informed decision.

Can we slow the aging process?

Q. Is it possible that scientists will one day be able to slow down the aging of our bodies?

A. You may be dubious, but yes, it is possible. I know it seems that every living thing ages — the flowers in the garden, our pets, and us. Yet a Harvard Medical School colleague who studies aging, genetics professor David Sinclair, tells me there are certain cold-water fish that may never die natural deaths. They die from injury or being consumed by a larger animal, but it’s not clear they die naturally. Some are hundreds of years old, and still frisky.

Scientists are beginning to understand the natural biological processes that control aging, including specific genes involved, and they’ve made some truly remarkable discoveries. For example, in a laboratory dish, inserting certain genes into adult human cells can convert them into cells like the very first cells in the human embryo. Aged cells can be made young again. You can turn back the clock — all the way back to the beginning.

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That’s extraordinary, but it’s cells in a laboratory dish, not living animals. Could aging be slowed in living animals? When scientists introduced a handful of genes into worms, the worms lived five times as long. And, until nearly the very end, the worms still were as active as they had been in their youth, able even to copulate. Extending their life span extended their health span. It did not increase their period of decrepitude.

Another genetics professor here at Harvard Medical School, George Church, inserted three genes associated with longevity into mice. Mice are more complex than worms. They are mammals, like us. Many things we find to be true in mice prove to be true of us. Inserting the longevity genes into the mice protected them from becoming obese and from developing diabetes, kidney failure, and heart failure. Genes that extended life also protected against diseases of aging.

My colleague Sinclair recently used similar gene therapy techniques to insert a combination of three genes into cells in the eyes of mice going blind from aging. This fully restored vision in the aging mice — with no ill effects. Sinclair’s team had been able to reach into one aging and failing organ, and rejuvenate that organ. Could similar techniques one day rejuvenate failing organs in us? You can be sure there are scientists interested in answering that question.

If, on the day I became a doctor, you had asked me whether we could ever slow aging, my answer would have been: “Of course not, aging is an inevitable part of life on earth. What have you been smoking?” I’ve been surprised. Our investment in biological research has produced many such exciting surprises.

Should we track all breakthrough cases of COVID-19?

The vaccines currently available in the US to prevent COVID-19 have proven remarkably safe and highly effective thus far. But, since no vaccine is perfect, we expect to see occasional infections even after full vaccination.

And we have. More than 10,000 of these so-called breakthrough cases of COVID-19 have been reported in the US. Seems like a large number, right? But keep in mind that nearly 133 million people have been vaccinated, so these breakthrough cases represent less than one in 10,000. It’s safe to assume that not all breakthrough cases are being reported, of course, but so far that’s a remarkably low failure rate!

Because the vaccines help prevent severe infections, most breakthrough cases are mild or moderate. Should we keep tracking those, or should we focus only on severe cases — those that lead to hospitalizations, ICU stays, and, more rarely, deaths? That’s the question the CDC recently answered by deciding to focus only on cases that require hospitalization.

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What can all breakthrough cases tell us?

While that approach may not seem unreasonable, it certainly has disadvantages. Because COVID-19 is a new disease caused by a novel virus and the vaccines were only recently developed, studying breakthrough cases could tell us a lot. For example:

  • Are factors related to the different vaccines responsible?
    • One type of vaccine might be less effective than another.
    • Manufacturing problems might make certain lots of a vaccine less effective.
    • Problems with storage or thawing, or errors in vaccine dosing, might lead to vaccine failure.
    • The timing of the second vaccine might play a role, whether given earlier or later than recommended.
  • Are factors related to people who get vaccinated important?
    • Differences in failure rates might be based on age, gender, ethnicity, medication use, or immune function.
    • Apparent vaccine failure might occur due to a lack of mask-wearing, physical distancing, and/or exposure to an infected person just prior to full vaccination.
  • What about factors related to the virus?
    • Certain mutated versions of SARs-CoV-2 — the viral variants of concern — may be over-represented among breakthrough cases. We don’t know yet, because a genetic analysis has been done in relatively few of these cases. If correct, it would suggest that available vaccines are less effective against certain variants, a discovery that could lead vaccine makers to modify them.

Besides getting a better understanding about why breakthrough cases occur, it would be helpful to figure out why some breakthrough cases are mild while others are severe. And we need to learn whether people who develop a breakthrough infection should receive a booster shot of vaccine after they recover.

Wondering about a headline-grabbing drug? Read on

Sometimes it seems like we hear news of a “breakthrough” drug nearly every day. Yet true breakthroughs are rare.

How can you decide whether the new drug you’re hearing about is truly important? It’s not easy. For starters, be skeptical about dramatic headlines. Don’t accept terms like “breakthrough” at face value. While the early part of a story may make it sound as though a drug is amazing, later you may learn that the findings are preliminary, or that side effects are unacceptable.

Read on for ways to better understand the news you hear about the next big drug discovery.

Start with the study

What type of study is it? The most powerful drug trials are randomized controlled trials (RCTs), which randomly assign a similar pool of study subjects to receive either the new drug or a placebo. Neither the study subjects nor the researchers know what each participant is taking during the trial. Researchers then compare how the two groups fared. RCTs can provide a true sense of whether a drug works for people with similar characteristics.

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By contrast, observational studies might collect information on thousands of people to discover whether there’s a link between a treatment and a disease. For example, such a study might find that those taking vitamin C have a lower incidence of diabetes. That doesn’t mean that vitamin C caused the lowered risk. Maybe people taking the vitamin are more health-conscious, eat better, and exercise more. Perhaps those healthy habits — not vitamin C — lead to the lower rate of diabetes. Studies like these can find a link, or association, between a treatment and a desired outcome, but cannot determine that the treatment actually caused the benefit. And that makes them far less powerful than RCTs.

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Ask how the study relates to you

Do the outcomes reported really matter to you? For example, cholesterol-lowering medications should do more than just lower total cholesterol. The overall goal is to lower the risk of heart attack, stroke, or other complications of cardiovascular disease, including death. So, while lowering cholesterol may be a good thing, it’s not the only thing: look for changes in measures you care most about rather than a surrogate measure.

Are the study subjects similar to you? Heck, are the study subjects even human? It’s not rare to read about a breakthrough drug, only to realize it’s only been studied in mice, or rats, or zebrafish. Even if the subjects are human, they may be so different from you in age range, general health, and other measures that study results don’t apply to you. Some groups of people may not be well represented as participants. Studies may exclude people who do or don’t have certain conditions, take certain drugs, or are too old, too young, or too sick.

Then consider actual benefits, possible risks, and costs

How are results reported? Imagine a study that found a new drug could reduce heart attacks by 15%. Sounds great, right? But it may not be so impressive if you know the actual numbers. Let’s say heart attacks occur in 10% of study subjects taking a placebo and 8.5% of those taking a new drug. That’s a 15% reduction in relative risk. Yet the absolute reduction in heart attacks was only 1.5%, which may not be much of a benefit in real terms. It’s accurate to express changes in terms of relative risk or absolute risk, but only reporting relative rates can be misleading. The best news reports include both.

Are the findings meaningful? Studies often report changes that, while statistically significant, aren’t big enough to matter. For example, let’s say a pain medication lowered average pain by 2 points on a 0 to 100 scale. That might be statistically significant, but people taking the drug are unlikely to notice any meaningful improvement.

Are the benefits worth the risks and its cost? Even if a drug performs well in a trial, if it causes serious side effects in half the study subjects or costs $100,000 a year, it isn’t going to be a big breakthrough for most people.

A timely example

Aducanumab (Aduhelm) was approved by the FDA in June 2021 to treat Alzheimer’s disease. Here are some notable headlines just after the approval was announced:

A new day for Alzheimer’s disease treatment after FDA approval of Biogen’s Aduhelm

FDA approves Aduhelm, first new Alzheimer’s disease treatment since 2003

FDA Approves Breakthrough Drug for Alzheimer’s Disease

Yet, in the hundreds of news stories that covered the initial announcement, some important details were not always made clear:

  • The studies leading to approval did not convincingly demonstrate a benefit for the symptoms of Alzheimer’s disease. Instead, the drug was approved because it appeared to reduce the amount of a protein in the brain (called amyloid) thought to contribute to disease development.
  • The study subjects had early stages of dementia. Those with more advanced cases were excluded from participating, because it was thought they would have little chance of improving.
  • Aducanumab treatment is expensive: estimates are that it will cost $56,000 a year, plus the cost of frequent brain MRIs. In trials, it caused potentially serious side effects in more than a third of participants, such as brain swelling or bleeding into the brain.
  • The approval could soon be reversed if additional studies required by the FDA find no compelling evidence of benefit for patients’ symptoms.