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personalized medicine

Personalized Combination Therapies Yield Better Cancer Outcomes

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Doctor consulting with patient
Credit: NIH National Cancer Institute Visuals Online/Daniel Sone

Gratifying progress has been made recently in an emerging area of cancer medicine called precision oncology. It’s a bold attempt to target treatment to the very genes and molecules driving a cancer, aiming to slow or even halt its growth. But there’s always more to learn. Now comes evidence that, while a single well-matched drug might be good, a tailored combination of drugs that attack a cancer in multiple ways at once might be even better.

The findings come from the I-PREDICT clinical trial, which treated people with advanced cancer who hadn’t benefited from previous therapy [1]. The NIH-funded team found that analyzing a tumor’s unique genetic and molecular profile provided enough information to recommend individualized combination therapies to patients. What’s more, patients who followed their individualized combination therapies most closely lived longer, with longer periods of progression-free disease, than did those who took fewer of the recommended drugs.

In most previous clinical trials of precision oncology, researchers have relied on a tumor’s unique profile to identify a single, well-matched drug to treat each patient. But cancer is complex, and, just as with certain infectious diseases, tumors commonly develop resistance to a single drug.

In the trial reported in Nature Medicine, researchers led by Razelle Kurzrock and Jason Sicklick, University of California, San Diego, wondered if they could improve treatment responses by tailoring combinations of cancer drugs to target as many molecular and genetic changes in a person’s cancer as possible.

To test the potential for this strategy to work, the researchers enrolled 83 people with various cancers that had advanced despite previous treatment. Tumor tissue from each patient was run through a comprehensive battery of tests, and researchers sequenced hundreds of genes to look for telltale alterations in their DNA.

They also looked for evidence that a cancer had defects affecting the DNA “mismatch repair” pathway, which causes some tumors to generate larger numbers of mutations than others. Mismatch repair defects have been shown to predict better responses to immunotherapies, which are designed to harness the immune system against cancer .

With all the data in hand, a special panel of oncologists, pharmacologists, cancer biologists, geneticists, surgeons, radiologists, pathologists, and bioinformatics experts consulted to arrive at the right customized combination of drugs for each patient.

The panel’s findings were presented to the health care team working with each patient. The physician for each patient then had the final decision on whether to recommend the treatment regimen, balancing the panel’s suggestions with other real-world factors, such as a patient’s insurance coverage, availability of drugs, and his or her treatment preference.

Ten patients decided to stick with unmatched treatment. But 73 participants received a customized combination therapy. As no two molecular profiles were identical, the customized treatment regimens varied from person to person.

Many people received designer drugs targeting particular genetic alterations. Some also received checkpoint inhibitor immunotherapies to unleash the immune system against cancer. Four people also were treated with hormone therapies in combination with molecularly targeted drugs. In all, most regimens combined two to five drugs to target each cancer profile.

Participants were followed until their cancer progressed, they could no longer take treatment, or they died. For each person, the researchers calculated a “matching score,” roughly defined as the number of molecular alterations matched to administered drug(s), with some further calculations.

The evidence showed that those with matching scores greater than 50 percent, meaning more than half of a tumor’s identified aberrations had been targeted, were more likely to have stopped the progression of their cancers. Importantly, half of patients with the higher matching scores had prolonged stable disease (six months or longer) or a complete or partial remission. Similar results were attained in only 22 percent of those with low or no matching scores.

These encouraging results suggest that customized combinations of targeted treatments will help to advance precision oncology. However, there are still many challenges. For example, many of the combinations used in the study have not yet been safety tested. The researchers managed the potential risk of toxicities by starting patients on an initial low dose and having their physicians follow them closely while the dose was increased to a level well-tolerated by each individual patient.

And indeed, they saw no evidence that those receiving a greater proportion of “matched” drugs (i.e. those with a higher matching score) were more likely to experience adverse effects than those who took fewer drugs. So, that’s an encouraging sign.

The researchers are now enrolling patients in a new version of the I-PREDICT trial. Unlike the initial plan, patients are now being enrolled prior to receiving any treatment for a recently diagnosed aggressive, often-lethal form of cancer. The hope is that treating patients with well-matched, multi-drug treatment combinations early will yield even better results than waiting until standard treatment has failed. If correct, it would mark significant progress in building the future of precision oncology.

Reference:

[1] Molecular profiling of cancer patients enables personalized combination therapy: the I-PREDICT study. Sicklick JK, Kato S, Okamura R, Schwaederle M, Hahn ME, Williams CB, De P, Krie A, Piccioni DE, Miller VA, Ross JS, Benson A, Webster J, Stephens PJ, Lee JJ, Fanta PT, Lippman SM, Leyland-Jones B, Kurzrock R. Nat Med. 2019 Apr 22.

Links:

Precision Medicine in Cancer Treatment (National Cancer Institute/NIH)

Study of Molecular Profile-Related Evidence to Determine Individualized Therapy for Advanced or Poor Prognosis Cancers (I-PREDICT) (Clinicaltrials.gov)

Razelle Kurzrock (University of California, San Diego)

Jason Sicklick (University of California, San Diego)

NIH Support: National Cancer Institute


All of Us Needs All of You

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I’ve got some exciting news to share with you: as of May 6, 2018, NIH’s All of Us Research Program is open to everyone living in the United States, age 18 and older. That means that you, along with your family and friends, can join with 1 million or more Americans from all walks of life to create an unprecedented research resource that will speed biomedical breakthroughs and transform medicine.

To launch this historic undertaking, All of Us yesterday held community events at seven sites across the nation, from Alabama to Washington state. I took part in an inspiring gathering at the Abyssinian Baptist Church in New York’s Harlem neighborhood, where I listened to community members talk about how important it is for everyone to be able to take part in this research. I shared information on how All of Us will help researchers devise new ways of improving the health of everyone in this great nation.


Got a Great Research Idea? “All of Us” Wants to Hear It!

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PeopleOne of the boldest undertakings that NIH has ever attempted, the All of Us Research Program has been hard at work in a “beta” testing phase, and is now busy gearing up for full recruitment in the spring. This historic effort will enroll 1 million or more people in the United States to share information about their health, habits, and what it’s like where they live. This information will be part of a resource that scientists can use to accelerate research and improve health. How? By taking into account individual differences in lifestyle, environment, and biology, researchers will uncover paths toward realizing the full potential of precision medicine.

Before embarking on this adventure, All of Us is reaching out to prospective researchers, community organizations, and citizen scientists—including people just like you—to get their input. Imagine that the project has already enrolled 1 million participants from all over the country and from diverse backgrounds. Imagine that they have all agreed to make available their electronic health records, to put on wearable sensors that can track body physiology and environmental exposures, and to provide blood samples for lab testing, including DNA analysis. Is there a particular research question that you think All of Us could help answer? Possible topics include risks of disease, factors that promote wellness, and research on human behavior, prevention, exercise, genetics, environmental health effects, health disparities, and more. To submit an idea, just go to this special All of Us web page.


Creative Minds: Designing Personalized Clinical Trials

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Karina Davidson

Karina Davidson/Jörg Meyer

It might have been 25 years ago, but Karina Davidson remembers that day like yesterday. She was an intern in clinical psychology, and two concerned parents walked into the hospital with their troubled, seven-year-old son. The boy was severely underweight at just 37 pounds and had been acting out violently toward himself and others. It seemed as though Ritalin, a drug commonly prescribed for Attention Deficit Disorder, might help. But would it?

To find out, the clinical team did something unconventional: they designed for the boy a clinical trial to test the benefit of Ritalin versus a placebo. The boy was randomly assigned to take either the drug or placebo each day for four weeks. As a controlled study, neither clinical staff nor the family knew whether he was taking the drug or placebo at any given time. The result: Ritalin wasn’t the answer. The boy was spared any side effects from long term administration of a medication that wouldn’t help him, and his doctors could turn to other potentially more beneficial approaches to his treatment.

Davidson, now an established clinical psychologist at the Columbia University Irving Medical Center, New York, wants to take the unconventional approach that helped this boy and make it more of the norm in medicine. With support from a 2017 NIH Director’s Transformative Research Award, she and her colleagues will develop three pilot computer applications—or digital platforms—to help doctors conduct one-person studies in their offices.


Built for the Future. Study Shows Wearable Devices Can Help Detect Illness Early

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Michael Snyder wearing monitors

Caption: Stanford University’s Michael Snyder displays some of his wearable devices.
Credit: Steve Fisch/Stanford School of Medicine

Millions of Americans now head out the door each day wearing devices that count their steps, check their heart rates, and help them stay fit in general. But with further research, these “wearables” could also play an important role in the early detection of serious medical conditions. In partnership with health-care professionals, people may well use the next generation of wearables to monitor vital signs, blood oxygen levels, and a wide variety of other measures of personal health, allowing them to see in real time when something isn’t normal and, if unusual enough, to have it checked out right away.

In the latest issue of the journal PLoS Biology [1], an NIH-supported study offers an exciting glimpse of this future. Wearing a commercially available smartwatch over many months, more than 40 adults produced a continuous daily stream of accurate personal health data that researchers could access and monitor. When combined with standard laboratory blood tests, these data—totaling more than 250,000 bodily measurements a day per person—can detect early infections through changes in heart rate.


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