Precision Medicine: Gene Sequencing Saves Cancer Patients

New directions

If Yale Medicine physicians find a mutation or other kind of abnormality in a tumor, it provides clues that might predict how a patient could respond to a therapy.

At Yale Medicine, new diagnostic techniques are turning dead ends into new opportunities.

5 things you should know about precision medicine
  • Precision medicine allows pathologists to identify a tumor’s genetic abnormalities, which might suggest more specific and effective treatment.
  • Precision medicine can offer new hope, via targeted treatments, for patients who have not had success with traditional treatments.
  • “Personalized medicine” is the catch-all term that refers to the process of studying a patient’s genome to find ways to optimize his or her health.
  • The gene sequencer used in the Tumor Profiling lab at Yale Medicine processes DNA samples in just a few hours.
  • The pathologists at the Tumor Profiling lab have knowledge of the latest research, which informs their analysis and suggests effective treatments.

Possibly more difficult than receiving a cancer diagnosis is learning, after months or even years of treatment, that a drug regimen has stopped working. That recently happened to a Yale Medicine patient, a 60-year-old man with an aggressive type of prostate cancer. Seemingly healthy after a three-year battle, which included a prostatectomy and chemotherapy, he learned that his cancer had suddenly returned.

With no tools left in the treatment kit, his oncologist referred the case to the Tumor Profiling Laboratory at Yale Medicine’s Departments of Pathology and Laboratory Medicine. There, experts searched the patient’s DNA for clues that might offer hope for a new approach. This is the basis of what is known as precision medicine.

“Genetic abnormalities can indicate whether certain newer therapeutic agents will be more or less likely to work,” says Yale Medicine’s Zenta Walther, MD, PhD, a professor of pathology who specializes in molecular diagnosis of surgical specimens. “These new therapies are like a finer tool that can be used to specifically target cancer cells in their vulnerabilities.”

Laboratories may seem like impersonal places far removed from patient care. Yet they are where the deep analysis behind precision medicine occurs. Although the pathologists almost never meet their patients, they are focused on using the best tools modern medicine has devised to help people, including this prostate cancer patient, fight for their lives.

“The majority of our patients have already had standard therapies, and their disease has progressed anyway and they’re looking for advanced therapies,” Dr. Walther says. “If we find a mutation or other kind of abnormality in a tumor, it may not tell us for sure that the patient will be helped by a particular drug, but it lets us know that he or she is more likely to respond. Often it makes the patient eligible to go on a clinical trial, where they are testing new therapies.”

Studying the genome

Every person is born with a genetic blueprint imprinted with information that will affect their health throughout their lives, including their risk for specific diseases and the strength of their immune system in fighting off those illnesses. “Personalized medicine” refers to the process of studying a patient’s genome to find ways to optimize his or her health. For cancer patients, this means identifying genetic vulnerabilities that are specific to an individual tumor. That way, clinicians can tailor treatment in a way that is most effective.

Lofty as all that sounds, the process of analyzing a patient’s tumor is fairly straightforward. In the case of the prostate cancer patient, the initial diagnosis had been made at Yale Medicine, so the team examined the original slides, looking for regions that displayed the highest concentration of tumor cells.

From there, DNA was extracted and prepared by lab technicians for analysis. Typically, and in this case, a panel of about 150 genes—those with the highest likelihood of being altered by cancer— is prepared for sequencing. “The last step is to put the prepared DNA into the sequencer,” Dr. Walther says.

There are many types of sequencers. The one used in Yale Medicine’s Tumor Profiling Laboratory is about the size of a small refrigerator. Once the sample is put in place, the sequencer analyzes all the genes at once. “It’s massively parallel sequencing, and it happens very fast, much faster than it used to,” Dr. Walther says. “The whole process occurs in hours, rather than days, which is what it used to take.”

The information is output from the sequencing machines into a computer that processes the data. The Tumor Profiling Laboratory has a dedicated bioinformatician who sets up and maintains this “bioinformatics pipeline.” In this pipeline, the patient’s DNA sequence is compared to a “normal” human genome to identify abnormalities and mutations.

“Sometimes we will find abnormalities that are either unique or have only been seen a few times before or that only occur within a particular type of cancer, and often we see abnormalities in several genes,” says Dr. Walther. Treating oncologists receive the pathologists’ interpretations as to which mutations are driving tumor growth, which might identify a potential target for therapy.

How this patient’s life was saved

The team did not locate many mutations in the tumor of the 60-year-old prostate cancer patient, but Dr. Walther says they identified an important one. “What we found was a mutation in a gene that is involved in DNA repair,” she says.
The timing was fortunate. Says Dr. Walther: “We knew that there was brand-new research, published within the month, showing that a particular class of drugs can work with this particular mutation. So we were really excited!”

The next step was to interpret the data. “After we write up a report, we very often will contact the oncologist to discuss the case,” Dr. Walther says. “The interpretations are complicated, and we often find that it is best to talk directly.”

The findings are also presented and discussed at the biweekly Precision Medicine Tumor Board, a forum for open discussion of these studies, the results and how the findings might be used to help a patient. Typically, Dr. Walther says, there are multiple presentations, including by the surgical pathologist and the molecular pathologist, along with the oncologist who has been caring for the patient.

“As a group we discuss what clinical trials might be open for a patient or what drugs might be available to try,” Dr. Walther says. “In this instance, we presented the case and also the relatively recent papers, of which the oncologist was already aware. Several weeks later the oncologist reported that he had, in fact, put the patient on the new drug and he was responding beautifully.”

In addition to offering hope, targeted therapies have other advantages, most notably fewer side effects.
Six months after the patient’s turnaround, Dr. Walther could report that the patient was still doing well. Dr. Walther says: “My favorite line in the chart is: ‘He notes no pain and runs eight-minute miles.’”