• Paths of Progress Fall/Winter 2013

    Profiling the Future of Cancer Medicine

    by Richard Saltus

    Dana-Farber's Gene Display 

    In the past two years, around 20,000 new cancer patients coming to Dana-Farber Cancer Institute, Brigham and Women's Hospital (BWH), and Boston Children's Hospital have volunteered for an ambitious study called Profile that embodies the future of cancer care.

    Cancer samples from more than 5,000 of these patients have been scanned for oncogenic mutations — flaws in the genetic code of certain cells that disrupt normal programming and cause cancer to form.

    Every patient's cancer has a distinctive group of mutations and other DNA changes, its genetic profile, that potentially can be targeted by precisely aimed drugs. The genetic mutation data on each patient's tumor are included in a Profile database — a growing storehouse of knowledge that will fuel research for years to come.

    Barrett Rollins and Neal LindemanProfile is led in part by Barrett Rollins, MD (left), Dana-Farber's Chief Scientific Officer, and Neal Lindeman, MD (right), head of the Center for Advanced Molecular Diagnostics at Brigham and Women's Hospital.  

    This is the kind of information needed to advance the goals of "personalized" cancer treatment. Personalized or precision medicine can be many things, but in cancer therapy it means selecting targeted drugs that match up with the specific genetic aberrations that drive a patient's cancer.

    Profile, which entered a new phase last summer using a more powerful gene analysis technology, is a large scale effort to discover and catalog cancers by their distinctive DNA mutations and other alterations. A major goal is to speed the development of precision therapies that home in on molecular targets — flaws in a tumor's DNA code — found in cancer cells but not in normal cells.

    Until recently, Profile has enrolled adult patients, but since early 2013 it has been expanding gradually to include pediatric patients from Boston Children's. By early 2014, the program will include samples from all pediatric oncology treatment centers, according to Katherine Janeway, MD, of pediatric oncology.

    "Twenty thousand patients [agreeing to be genotyped] is a huge number of patients; it represents 75 percent of all those we ask," says Profile scientist Nikhil Wagle, MD.

    The power of Profile lies in the sheer volume of the data it is amassing on the genetics of cancer, and the potential to correlate distinctive DNA abnormalities in a specific person's cancer with its behavior and how it responds to treatment, explains Barrett Rollins, MD, PhD, Dana-Farber's chief scientific officer.

    Even in the study's early stages, the results of a few patients' tests have given them new options for clinical drug trials.

    Now, as Profile gets more powerful and takes advantage of "massively parallel" or "next-generation" sequencing that digs deeper and more broadly into a tumor's DNA, researchers expect these clinical connections to increase.

    The initial platform was limited to detecting 471 known mutations in 41 genes. The new phase of Profile, known as OncoPanel, can rapidly read out the entire genetic code of 305 cancer-related genes in a DNA sample – potentially detecting millions of mutations. Thus OncoPanel gives scientists a more comprehensive blueprint of the cancer's altered genetic wiring.

    "Next-generation sequencing tells us a lot more of what could potentially be driving a person's cancer," says Rollins. "It reveals a lot more about what might be treatable by personalized medicine in the future."

    Philip Kantoff, MDPhilip Kantoff, MD, principal investigator for Profile, says scientists are tapping the project's databanks to pursue new leads in cancer research.  

    In addition to hunting for small mutations, which are single "typos" in a segment of genetic code, the latest test can spot other important types of alterations in the DNA of cancers, explains Neal Lindeman, MD, who heads the Center for Advanced Molecular Diagnostics (CAMD) lab in the BWH Department of Pathology, where the Profile genotyping analysis is performed. Such abnormalities include copy-number changes — where a section of genetic code has been deleted, duplicated, or amplified many-fold — and structural rearrangements caused by broken and incorrectly repaired chromosomes, which contain the genes.

    The genetic profile of a tumor may suggest which drugs are likely to shrink or slow the cancer, and which compounds are unlikely to be effective. In addition, mutations found to be typically associated with better or poorer outcomes can help predict the course of a patient's specific cancer.

    The entire human genome contains about 20,000 genes — called the exome — that tell cells how to make the proteins that make up and operate the body. Using "whole-exome sequencing," it's possible to decipher all of these genes at once, but it's a time-consuming and expensive process. Instead, OncoPanel will focus on a group of 305 genes selected by Dana-Farber and Brigham and Women's investigators — genes in which abnormalities are suspected of being linked to cancer.

    Genetic Testing to Guide Treatment

    Personalized cancer genetic testing has long been an important tool in care of patients with certain cancers at Dana-Farber/Brigham and Women's Cancer Center (DF/BWCC). Tests for known mutations in melanoma, breast, lung, and colon cancers, among others, help physicians and patients understand their risks and guide therapy. "We test thousands of patients and those results make a difference and cause patients to live longer," says Philip Kantoff, MD, principal investigator of the Profile research project.

    Laura MacConaillLaura MacConaill, PhD, scientific director, says Profile represents "a long-term investment" in advancing understanding about the causes of cancer.  

    However, "testing one gene at a time in a disease isn't cost-effective, takes too long, and uses up too much of the precious DNA in a tumor sample," says Laura MacConaill, PhD, Profile's scientific director. A huge advantage of OncoPanel is its ability to rapidly catalog all detectable DNA abnormalities in the 305 genes at one time. MacConaill notes that Profile is "a long-term investment that will contribute to our understanding of all the different types of cancer."

    Indeed, Profile's leaders say the project has the potential to be as important as landmark population health research studies such as the long-running Nurses' Health Study and the Framingham Heart Study, which accumulated vast information on patients' characteristics and lifestyle habits and how they influence disease risks.

    Being a research study, Profile isn't a clinical service at present and the molecular profile obtained by OncoPanel isn't being entered into a patient's medical record. However, a physician can request a report on a patient's cancer sample, and view the results with a special software program.

    Profile "really gets exciting when it finds unexpected mutations," says Wagle, a postdoctoral fellow who co-developed the sequencing method used by OncoPanel. "It can offer an opportunity to a patient for whom other options have failed, or a therapy you never would have thought of in that cancer," he says.

    A case in point: A Connecticut woman, Gaye Zukauskas, was referred to DF/BWCC in 2012 after she had run out of options to treat recurring abdominal cancer — a type of ovarian cancer — she had battled since 2004. "The tumor was the size of a softball," says Zukauskas. "It was pinching nerves in my back and causing tremendous pain in my legs and buttocks."

    Gynecologic oncologists Joyce Liu, MD, suggested Profile testing of the tumor. It turned up a combination of two mutations — PIK3CA and KRAS — that are not often found together in that type of cancer. "Dr. Liu called me at 6 p.m. on a Friday, and offered me a clinical trial of two oral drugs for my cancer," recalls Zukauskas. "I dropped everything and went on the study."

    Researcher John Hilton, MD, in Dana-Farber's Early Drug Development Center (EDDC), cared for her during the trial. "She was extremely sick — very symptomatic," says Hilton. "She tried a clinical trial of drugs targeted to those mutations, and she had a tremendous response. Her symptoms improved and her CA125 level [a biomarker of ovarian cancer], which was 163, dropped to 20 in three months."

    Once the tumor began to shrink "it got rid of all of the pain in my legs," Zukauskas remembers. "It was wonderful." The clinical trial not only gave her months of improved symptoms, but enabled her to spend time with her daughter, who is stationed at Hanscom Air Force Base near Boston, and her two-year-old grandchild. "She is my life," Zukauskas says simply.

    Tapping Profile's Data Trove

    Now that Profile has accumulated a critical mass of data, researchers are beginning to sift through the genetic snapshots of different kinds of tumors, looking for leads to new cancer discoveries.

    The first two studies are being done by Dana-Farber research fellows — Natalie Collins, MD, PhD, of Pediatric Oncology, and Elizabeth O'Donnell, MD, of Medical Oncology. Collins is looking for mutations in melanoma tumors that may affect how the immune system responds to cancer. O'Donnell's study aims to find a link between mutations in aggressive testicular cancers and patients' response to treatment.

    For all of its breadth, at its roots, the potential of Profile lies in the power of individual patients. Every patient has a role to play "in pushing back the frontiers," says Rollins. "Agreeing to be part of this Profile project is your personal contribution to the most exciting cancer project we can think of."

    Paths of Progress Fall/Winter 2013 Table of Contents 

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  • Personalized Medicine Research

    • Barrett Rollins, MD, PhD and Neil Lindeman, MDLearn about Profile, a comprehensive somatic genotyping study that focuses on the development of targeted treatments for every person with cancer.
  • Personalized Medicine