• Surgical Oncology

    Teaming Up for Innovative Clinical Trials

    You can compare a team that runs today's multidisciplinary breast cancer clinical trials to a musical quartet, says J. Dirk Iglehart, MD. "The musicians have to play in sync; if one misses, the melody may be lost," he says. When conducting a clinical trial, everything has to work perfectly, from the time the patient consents to participate until the data are analyzed. "We work together to get answers that will allow us to improve outcomes for patients."

    Iglehart, a member of Cancer Biology at Dana-Farber and surgical oncologist at Brigham and Women's Hospital, serves as director of the Women's Cancers Program. He oversees a team of surgeons, medical oncologists, radiologists, pathologists, epidemiologists, and basic scientists determined to find new ways to understand, prevent, and treat breast and gynecologic cancers.

    As the investigators teamed up, they recognized that the traditional course of breast cancer treatment made it difficult to fully assess the effectiveness of an innovative therapeutic drug. "When surgeons removed tumors before therapeutic drugs were given, there was no measurable disease after surgery, so we didn't know if the drug was working," says Iglehart. Since there was no data to indicate whether patients did better if the tumor was removed first, the team decided to turn things around and started administering the drug first. "A typical preoperative trial may go from two months to four months prior to surgery, a delay which doesn't appear to make a difference to the patient's outcome," he emphasizes. After surgery, the patient continues with a normal chemotherapy regimen.

    The value of this approach was demonstrated in a study led by Judy Garber, MD, MPH, of Medical Oncology. As reported in 2008, the study preoperatively treated "triple-negative" patients whose tumors were negative for estrogen receptor (ER) protein, the HER2 cell-surface receptor, and the ER-related receptor for progesterone. "Twenty percent treated only with cisplatin achieved a complete pathologically confirmed disappearance of their disease," Iglehart notes. This result was unexpected and highly significant.

    This study also highlighted the critical importance of molecular profiling when evaluating treatment outcomes. By integrating such profiles with treatment response data, Dana-Farber researchers and their colleagues were among the first to identify four distinct molecular subtypes of breast cancer, each with a different treatment response profile.

    Such studies are enabled by a set of resources available at Dana-Farber and Brigham and Women's Hospital. The cancer research information system, known internally as CRIS, stores clinical, treatment, and outcomes data for cancer patients treated through Dana-Farber/Partners Cancer Care. CRIS was started in 1997 by Jane Weeks, MD, MSc, of Medical Oncology. Complementing CRIS, surgical pathologist Andrea Richardson, MD, PhD, of Brigham and Women's Hospital, developed a tumor tissue bank. One of the largest of its kind, the bank has 3,000 frozen breast cancer specimens available for molecular analysis. A blood sample bank is yet another part of the investigative toolkit, funded by the Nancy Lurie Marks Foundation and led by Richardson and Penelope Miron, PhD, of Cancer Biology. "Getting a sample of the patient's normal DNA is critical," Iglehart points out. "And the only way you'll ever discover a blood test for breast cancer is to get serum from lots of people with cancer."

    Importantly, specimen data from the tissue and blood banks are integrated with the outcomes data in CRIS. "Now you can really ask, is there a marker in the blood that went down after the treatment?" Iglehart says. "Is there a gene in the body that predisposes a patient to a given response to the drug? Is there a gene in the tumor that was hit by the drug, and did it get inhibited? And what happened to the patient? You can put it all together, sometimes without having to conduct a new trial."

    "This really is a sea change in cancer research," Iglehart declares. "We are developing drugs that are more and more targeted to hit specific molecular pathways." He gives the example of the PI3 kinase (PI3K) pathway, which affects many cellular growth signals. Scientists at Dana-Farber, including Thomas Roberts, PhD, and Jean Zhao, PhD, have done major work in understanding this pathway, and companies are developing drugs that inhibit PI3K. Eric Winer, MD, chief of the Division of Women's Cancers in the Department of Medical Oncology, and Ian Krop, MD, PhD, also in the Division, are conducting trials of PI3K-inhibiting drugs in women with advanced breast cancer and, preoperatively, in women with earlier stages of breast cancer, including tumors that are HER2-positive and appear to rely on PI3K for their growth. Winer and Krop will test PI3K inhibitors in women whose breast cancers have become resistant to the HER2-targeting drug trastuzumab (Herceptin) and will combine PI3K inhibitors with trastuzumab in women prior to surgical excision. Now, the basic scientists will learn whether their results in the laboratory and in animals actually predict efficacy in people.

    "In the next 20 or 30 years, we will cure or significantly reduce the burden of several subtypes of breast cancer," Iglehart sums up. "We'll be able to identify the subtypes and treat them selectively, improving outcomes, and reducing toxic effects. It won't be easy, but it will be an exciting time in clinical research."

  • Email
  • Print
  • Share
  • Text
Highlight Glossary Terms