Matching Therapy to a Tumor’s Faulty Genes
It’s hard to imagine a walk to raise funds for BRAF-positive cancers. But in the future, cancer may no longer be a disease known primarily by its tissue of origin – breast cancer, colon cancer, lung cancer. Instead, it may be classified by the genetic mutations that drive it.
As the view of cancer shifts, so will cancer therapy.
“Cancers of the same genetic abnormalities should be treated the same whether they come from the skin or the colon or the lung,” says Jeffrey Sosman, M.D., director of the Melanoma Program at the Vanderbilt-Ingram Cancer Center. “I think that’s a concept that is really going to change our approach to treatment.”Increasingly, physicians will “look at the genetic makeup of a patient’s tumor and use that information to select therapy,” says William Pao, M.D., Ph.D., who is leading the new Personalized Cancer Medicine Initiative at Vanderbilt-Ingram. Pao is putting into place the systems that will make personalized cancer medicine – matching targeted cancer drugs to a tumor’s genetic changes – a routine part of clinical care.
How will this new view of cancer change treatment?
Right now, oncologists consider both the patient’s characteristics and the cancer’s characteristics (tissue type, stage) to plan therapy.
But it’s not an exact science. Chemotherapy treatments are often a one-size-fits-all approach – sometimes they work, and sometimes they don’t.
In general, patients receive a course of chemotherapy and then wait – up to six weeks or longer – to find out if the drug is having an effect. If it doesn’t appear to be killing the cancer cells, the doctor and patient will decide on another treatment option. In the meantime, the patient may have suffered the unpleasant side effects of chemotherapy, without any benefit.
Rita Quigley knows this approach first-hand.
In the summer of 2007, she noticed a mosquito bite-sized bump under the skin on her upper arm. She mentioned it to the dermatologist she was routinely seeing because of a malignant melanoma (skin cancer) that had been removed from her back 17 years earlier. There was nothing visible on the skin, and the dermatologist had trouble even feeling the bump, Quigley recalls.
She requested that the mass be removed. The pathology report came back with ominous news: melanoma.
CT and PET imaging scans revealed that she had tumors in her lungs, and Quigley’s Huntsville, Ala., oncologist referred her to Sosman at Vanderbilt-Ingram.
Malignant melanoma that has metastasized to distant sites in the body is notoriously difficult to treat.
“Melanoma has been the most frustrating of solid tumors,” Sosman says. “There have been some positive results with various therapies in a small minority of patients, but the great majority of patients do not respond to the chemotherapy or immunotherapy treatments that we have.”
Sosman opted to treat Quigley with the chemotherapy drug dacarbazine. Quigley says she was fortunate to suffer only mild discomfort – achiness and flu-like symptoms – during the three months of chemotherapy (an intravenous infusion once every three weeks). The lung tumors didn’t shrink.
At the end of October 2007, thoracic surgeon Eric Lambright, M.D., at Vanderbilt-Ingram removed her lung tumors. The surgery was successful.
But a follow-up scan several months later showed new tumors in Quigley’s pelvic area, and Sosman decided to treat her with interleukin-2, an immunotherapy aimed at stimulating the patient’s immune system to kill the cancer. For the interleukin-2 treatment, Quigley was hospitalized for five days while the medicine was administered every eight hours around-the-clock through a central venous catheter. After one week of rest at home, the treatment was repeated. Hospitalization is required because the side effects of interleukin-2 treatment can be severe.
“Interleukin-2 is a different ballgame. It was several weeks after the second treatment before I felt like myself again,” Quigley says.
Six weeks after the treatment, imaging scans showed no tumor shrinkage.
A year had passed since Quigley first noticed the bump on her arm. She had been through two surgeries, two grueling treatments, and still the cancer persisted.
At this point, a door opened for Quigley – Sosman and his Vanderbilt-Ingram colleague Igor Puzanov, M.D., were studying a new drug in patients with metastatic melanoma. The drug, a “targeted cancer therapy” called PLX4032, had been shown in cell and animal testing to be effective against tumors that contained a particular genetic change in a gene called BRAF.
In 2002, investigators reported that about 60 percent of melanomas contained a BRAF gene mutation. The BRAF protein normally functions in a cell growth signaling pathway, and the mutation activated the pathway and caused cells in culture to behave like tumor cells.
“Everyone who read that paper said, this is a target for melanoma – if we can target BRAF, we’re going to see responses in melanoma,” Sosman recalls.
PLX4032, produced by Plexxikon and Roche Pharmaceuticals, not only targets BRAF, it specifically blocks the BRAF mutant most commonly found in melanoma.
Quigley’s melanoma had the mutation, and she enrolled in the Phase I clinical trial being led at Vanderbilt by Puzanov. Six centers participated in the trial.
Initial results were not stellar, Sosman recalls, but a reformulation of the drug allowed the investigators to achieve higher doses and “all of a sudden, everybody started seeing responses.” He remembers the striking images that investigators at the various centers shared electronically.
“It was really stunning. Some of the patients were responding incredibly quickly, and we even saw symptomatic improvement – patients who were sick when they started, got the drug, and felt much better. That’s something I’ve never seen in treating patients with melanoma,” Sosman says.Quigley started taking PLX4032 in August 2008. Her tumors have shrunk, and she continues to take the pills daily, with minimal side effects. She felt well enough to return to work as a part-time nurse in a pediatrics practice, after seeing her second of three daughters off to college.
She has the highest praise for Sosman and his colleagues and finds it “amazing that it’s a possibility” to have a medicine selected to fit her tumor.
“I feel very blessed; I’m very thankful,” Quigley says.
Puzanov presented initial findings from the Phase I trial at last year’s annual American Society of Clinical Oncology conference. Of 16 patients with BRAF-positive melanoma, more than half had their cancer shrink by at least 30 percent. Patients without the mutation had no response to the drug. The investigators extended the Phase I trial to include additional patients, and they have launched Phase II studies, which will treat between 90 and 150 patients at 12 centers. Sosman is leading the Phase II trial.
“The world of melanoma treatment has changed,” Sosman says. “It’s really very exciting to treat patients whose tumors have the right genetic profile with this drug and expect them to respond, and for the most part they do.”
The BRAF mutation targeted by the PLX drug also is present in other cancers, Sosman points out. It’s present in almost half of thyroid cancers, about 10 percent of colon cancers, and up to 6 percent of lung cancers. A trial under way in colon cancer patients with the mutation is showing response rates similar to the melanoma studies.
Pao, whose research has focused on tailoring therapies for lung cancer, is working to make personalized cancer medicine a routine part of clinical care. At Vanderbilt-Ingram, which he joined last year, he says he has found a culture of collaboration and “an openness to new ideas and trying new things that might improve patient care.”
With the aid of Cindy Vnencak-Jones, Ph.D., and colleagues in the Department of Pathology’s Clinical Molecular Genetics program, Pao is developing a platform to test for multiple genetic mutations at the same time.
The goal is to develop tests for between 30 and 50 mutations. Pao and colleagues are “mining” databases of reported mutations, in order to build melanoma and lung cancer-specific panels. The mutations they select for testing will have relevance with respect to existing or emerging targeted therapies. Later, they will develop panels to detect mutations specific to other cancer types.
The results of the tests will need to be integrated into the electronic medical record with algorithms that aid physicians in assigning therapies. Vanderbilt is a world leader in medical informatics, and Dan Masys, M.D., professor and chair of Biomedical Informatics at Vanderbilt, and his colleagues are working on the informatics needs.
“Many cancer centers are trying to move this kind of tumor genotyping and therapy planning forward, but the big question is how to do that in the most efficient manner,” Pao says. “I think that Vanderbilt has the right strengths to really make this happen.”
The initiative is being supported by the Robert J. Kleberg, Jr. and Helen C. Kleberg Foundation and an anonymous foundation. Foundation support is especially important, Pao says, because it is difficult to gain National Institutes of Health funding for “nuts and bolts” implementation efforts like this.
Ultimately, Pao thinks that using genetic measurements to guide therapy decisions will become routine, something that we won’t even call “personalized” anymore.
But he is quick to acknowledge that we’re not there yet.
We still need the results of ongoing efforts that are defining the genetic mutations in cancers – particularly those mutations that drive tumors, Pao says. We need more and better drugs to hit those targets. We need to understand how tumors that initially respond to targeted medicines become resistant – something Pao and his colleagues have done for lung cancers that become resistant to the targeted therapies Iressa and Tarceva – and use that information to identify new targets and new drugs. Despite the hurdles, Pao is excited.
“The pace of discovery is increasing and we’re going to be able in the next five to 10 years to routinely assign therapies based on the genetic makeup of patients’ tumors.
And we’ll head out to the park to walk in support of our friends living with BRAF-positive cancers.