The Lucky Years: How to Thrive in the Brave New World of Health (9 page)

The tumor gene sequencing report of a patient with advanced lung cancer.

This shows the results of tumor sequencing for a patient with lung cancer. These are the reports I get when I send a piece of cancerous tissue to be examined and genetically sequenced. Don’t bother trying to understand the gibberish of the coding that we use to label the genes. Focus on the results: a total of five genomic mutations, or alterations in four target genes, are found related to the lung cancer in this patient.

The piece of the cancer that was used for the sequencing comes from what’s called a paraffin block of tumor; it’s basically a very small sliver of the cancer that was extracted from the patient and placed into a waxy material (paraffin) where it can be stored after surgery and reviewed by the pathologist before going on for genetic testing.

A group of paraffin (wax) blocks with pieces of tumor embedded within them.

Every cancer patient has one of these—samples of the tumor upon which the diagnosis is made. The following image is of a lung biopsy being performed. In this case, a needle is placed into the tumor to retrieve the biopsy.

This is a CT scan image of a lung biopsy in a case of suspected lung cancer. The needle is seen on the right entering the lung mass. The small image on the lower right shows where the larger image was taken from the patient (where the line intersects the patient).

DNA is then isolated from this piece and sequenced. When DNA from the biopsied cells is compared with DNA in the patient’s noncancerous cells, we can identify the changes of DNA that made it a cancer. These are the “on” switches. Now, let’s go back to the sequencing results.

For one of the targets, ALK, an FDA-approved drug is available. This drug has tremendous benefit, but only in patients that have this gene altered. The good news also for the cancer sequenced here is that
in addition to having at least one potential therapy to try, there are ten clinical trials this patient can also consider—opportunities to try other drugs whose effects on this type of cancer are still being tested.

Anyone can find out about all the clinical trials taking place today by going to clinicaltrial.gov and learning about which ones are still open to new patients and how to become involved if possible. Clinical trials are nothing to be afraid of; they are important in our quest to find new solutions and identify which drugs might help which individuals, even if the number of people helped is small. In the future, of course, we will get better at running trials, so that their outcomes are more meaningful for more people, and we will improve the success rate for drug development and new treatment plans. It’s important to note that clinical trials of new drugs or approaches to care are done only after we’ve tested them in a laboratory setting using cells and animal models. The most promising treatments seen in these early experiments are then studied in people via a carefully controlled trial that follows a strict protocol over the course of multiple phases. Guidelines called eligibility criteria exist for every clinical trial; they spell out who can and cannot participate. This ensures the most reliable results, as participants must be alike in key ways—age, gender, type of condition, previous treatments, and health status. The goals of the trial’s phases, depending on the questions that we’re trying to answer, could be to show that a new treatment is safe, works better than an established one, or has fewer side effects than the standard therapy.

All clinical trials in the US must be reviewed by what’s called an IRB, or an institutional review board. This is an independent committee of professionals including physicians, researchers, statisticians, and patient advocates whose job is to protect the rights, safety, and well-being of the subjects in the clinical trial and minimize its risks. Patients who join the trial must be fully informed and protected.

The best trials are those that are “randomized,” meaning that one group receives the experimental drug and another group receives the current standard treatment. This allows us to have a way of comparing the new therapy to the usual kind. Randomization also verifies that everyone in the trial has an opportunity to get either the new treatment or the
usual one. In a “double-blind study,” neither the patient nor the doctor knows which treatment the patient is getting; this helps strengthen the credibility of the results by reducing the researchers’ biases when they make their evaluations. If you enter a clinical trial that is randomized and double-blind, you are notified during the informed consent process, and you can then decide whether you want to participate or not.

I often get asked about placebos, as many patients who fantasize about receiving a blockbuster new drug in a clinical trial fear that they’ll be allocated to the placebo group and miss out. Placebos are “dummy pills”—drugs that look exactly like the real ones being studied, but have no effect (and placebos can come in any form, including liquid and powder, so long as they mimic the experimental drug). In fact, we don’t use placebos in most cancer-related clinical trials. But some trials use a placebo for a good reason: it’s often the only way to know whether a new approach or drug works. In these cases, participants are told before they decide to join, during the informed consent process. And any trial can be halted at any point if one group appears to be doing significantly better than the other. This is what happened with a trial for the breast cancer drug tamoxifen in April of 1998. When doctors documented that the high-risk women in the National Cancer Institute–sponsored Breast Cancer Prevention Trial who took tamoxifen showed a 45 percent reduction in breast cancer, those who had been taking a placebo were immediately invited to switch to the active drug.

Let’s go back to the genetic profile of this individual with lung cancer. It is not from a patient of mine, but I have a great many examples from my own case files that show not just the power of drugs to squash cancer cells, but the power of dosage. The following story is true, but I changed the name of the patient, whom we’ll call Rick. I briefly mentioned this story in the introduction.

Rick has lung cancer—a tumor that exhibits the same altered gene called ALK, which the drug ceritinib (Zykadia) and several others can target. Initially, the tumor, which had metastasized throughout the body, responded beautifully to treatment with one of the ALK-targeting drugs. But over time, as with so many stealthy cancers, some of the cells
dodged the treatments and traveled to his brain, where the cancer was growing. The cancer in the rest of the body wasn’t growing and was still responding to treatment.

While discussing his case with colleagues, I wondered what I could do now to attack the cancer. My weapon wasn’t reaching Rick’s brain because of the blood-brain barrier, which shields the organ from outside, foreign molecules. While this “fence” was supposed to insulate the brain, in this case, it was harming the patient: it was letting cancer in while preventing the cancer drug from following it to attack. Some colleagues suggested I go from giving the drug every day to every
other
day but at a much higher dose, hoping that extra punch would overcome the blood-brain barrier and penetrate inside. Once again, I was flying blind, but I had nothing to lose. So I tried it, and it worked. At this writing, Rick is still one of the leaders of an enormous company, and he’s working every day—nearly four years after his lung cancer was first diagnosed. The right drug at the right dosage can be life-saving.

Let me show you one more molecular test result from an individual with bladder cancer:

The tumor gene sequencing report of a patient with advanced bladder cancer.

This person has some hope from the molecular test: there are four genetic defects identified as being associated with the cancer, and for one of the mutations, four FDA-approved therapies exist that may help target it, though these drugs are FDA-approved for other types of cancer. And even though there aren’t any known therapies to target three of the patient’s mutations, there are clinical trials underway that he or she can investigate and potentially enter. I should point out that when a drug isn’t approved by the FDA to treat one specific disease or condition, that doesn’t mean a doctor cannot prescribe it and use it “off-label.” To be clear, if a drug is used off-label, that doesn’t necessarily mean that it’s dangerous or unproven. Certain drugs are off-label only because the pharmaceutical company chose not to go through the expense and work the FDA requires to approve a drug for a specific condition or disease—especially when it comes to rare conditions that afflict only a few people.

Many of the treatments we use in cancer are in fact off-label uses of FDA-approved drugs. For example, many of the combination therapies we use to treat lymphoma, breast cancer, and colon cancer aren’t FDA approved for these specific cancers. While off-label drug use can bring benefits to many patients, it isn’t always paid for by insurance companies. Imagine if this person with bladder cancer got this result back from the lab and his doctor recommended a drug to treat the cancer based on the profile, but the insurance company said it won’t pay, and the drug costs $100,000 or more per year. This is a common scenario in the cancer world today.

It used to be that only a small handful of new drugs for diseases emerged each year, but now new drugs are coming out routinely, even in my domain. Targeted therapies like imatinib (Gleevec) and trastuzumab (Herceptin), for example, have emerged over the past decade as standard treatments for several different types of cancer. These drugs fire at cancer cells by homing in on specific molecular changes seen primarily in those cells. And as immunotherapies also come into the picture—buying people months or sometimes years—we’ll begin to see medicine enter a new phase in which cells become living drugs.
This has been called the third pillar of medicine.
¹¹
The pharmaceuticals that arose from synthetic chemistry made up the first pillar. Then, after Genentech produced insulin in a bacterium in 1978, there was the revolution of protein drugs. Now drug companies are hoping to use our own cells as the treatment. In the case of T cells, there is tantalizing evidence that some cancers could be treated with few side effects other than a fever. And if early results hold, tests of engineered T cells in blood cancers may lead to a relatively quick FDA approval for the treatment of cancer. It could take as little as seven years, whereas the average drug takes closer to fourteen.