Richard L. Schilsky, MD

2009-2010 BCRF Project:
On behalf of Cancer and Leukemia Group B
Study Chair: Shelley Hwang, MD, MPH, University of California, San Francisco

The widespread use of mammography in the United States has led to an increase in diagnosis of ductal carcinoma in situ (DCIS), a noninvasive, but malignant, breast disease. DCIS may progress to become invasive breast cancer, but estimates of this event vary widely. Because physicians do not have tools to predict which patient with DCIS is at high risk for future development of invasive breast cancer, the only treatment options for patients with DCIS are surgery or a combination of surgery, radiation, and endocrine therapy. Presently, no other less aggressive treatment option exists, even if the perceived risk of cancer progression is small. Additionally, physicians do not have reliable imaging techniques to monitor DCIS.

In the proposed study chaired by Dr. Hwang, CALGB researchers will investigate the role of endocrine therapy on DCIS prior to surgery to determine whether DCIS responds to short-term non-surgical therapy. Also, they plan to develop breast MRI, specifically as a method to monitor DCIS, as the majority of breast MRI studies have been conducted in the setting of invasive breast cancer. In this clinical trial, postmenopausal women with DCIS that is dependent on estrogen, will receive six months of letrozole (Femara®), an aromatase inhibitor which blocks estrogen production, prior to surgery. In the proposed study, the researchers plan to obtain breast MRIs several times before surgery to monitor response to therapy, as well as collect breast tissue.

This study represents one of the first opportunities to see the effect of endocrine therapy and imaging diagnostics on DCIS before surgery. With support from BCRF, CALGB will be able to obtain breast MRIs for analysis and storage in an imaging bank. In this setting, breast MRI is not considered a standard of care test and therefore insurers and patients cannot be billed for the test. The results should improve understanding of endocrine therapies and breast imaging with MRI in preinvasive breast disease, and will establish a foundation to test less aggressive, non-surgical treatments for patients with preinvasive breast disease.

In ongoing CALGB projects supported by BCRF:
1) Genetic analysis of breast tumors is being used to determine which patients are most likely to benefit from use of paclitaxel as part of adjuvant chemotherapy;
2) Genetic analysis of breast tumors is being used to determine which patients are most likely to benefit from use of paclitaxel as part of adjuvant chemotherapy;
3) new technology is being utilized to generate genetic profiles of breast cancer tumors and to identify which genetic markers are associated with response to paclitaxel chemotherapy. The identification of these markers may make it possible to predict which patients are most likely to respond to paclitaxel treatment;
4) in a randomized trial of adjuvant chemotherapy with standard regimens versus capecitabine in older women, a companion to recently completed clinical trial studying adjuvant chemotherapy in older women with breast cancer, will also examine the molecular markers that predict treatment toxicity and outcome;
5) studies are evaluating magnetic resonance imaging (MRI) and spectroscopy (MRS) and various molecular markers as predictors of clinical response in women receiving chemotherapy and radiation for locally advanced breast cancer;
6) tumor epidermal growth factor receptor and Her2 expression are being correlated with the clinical outcomes of women receiving fulvestrant with or without lapatinib, a novel drug that inhibits EGFR and Her2. The goal of the project is to develop markers to guide patient selection for future therapies targeting the epidermal growth factor receptor; and
7) recent clinical trials have shown that the preoperative administration of systemic therapy (e.g. chemotherapy, hormonal therapy, targeted therapy) is safe and effective. In addition, from a research standpoint, it has two major benefits: a) researchers can quickly see whether drugs shrink the cancer and b) they can study the cancer cell before and after treatment to assess the impact of our therapies. In the CALGB, researchers are going to test two new targeted therapies using this approach. In patients with tumors that are dependent on HER2, we will compare trastuzumab (Herceptin®) versus lapatinib (Tykerb®) versus both. In patients with HER2 normal tumors ("HER2 negative") they will test the addition of an antibody that shuts off new blood vessel formation (Avastin® or bevacizumab). These studies represent a unique opportunity for the CALGB to see the effects of these treatments on tumors before surgery and this knowledge will inform future treatment trials in breast cancer.

Mid-Year Progress Report:
A number of CALGB trials are ongoing with BCRF support. 1) One CALGB project is using new technology to generate genetic profiles of breast cancer tumors and to identify which genetic markers are associated with response to paclitaxel chemotherapy. The identification of these markers may make it possible to predict which patients are most likely to respond to paclitaxel treatment.

2) The CALGB 150007 (I-SPY) is a national trial of imaging and molecular markers to rapidly assess response to chemotherapy in locally advanced cancers. Women with tumors of at least 3 cm in size who are treated with chemotherapy prior to surgery undergo Magnetic Resonance Imaging (MRI), Magnetic Resonance Spectroscopy (MRS) and tissue sampling at four time points during therapy. This project is evaluating magnetic resonance imaging (MRI) and spectroscopy (MRS) and various molecular markers as predictors of clinical response in women receiving chemotherapy and radiation for locally advanced breast cancer.

3) Genetic analysis of breast tumors is being used to determine which patients are most likely to benefit from use of paclitaxel as part of adjuvant chemotherapy.

4) Biomarker and genetic analyses of breast tumors are being used to determine which patients are most likely to benefit from use of dose dense chemotherapy.

5) Another BCRF-funded project is studying the unique biological characteristics of breast cancer that occurs in older women. This work, a companion to recently completed clinical trial studying adjuvant chemotherapy in older women with breast cancer, will also examine the molecular markers that predict treatment toxicity and outcome.

6) Another project will correlate tumor epidermal growth factor receptor and Her2 expression with the clinical outcomes of women receiving fulvestrant with or without lapatinib, a novel drug that inhibits EGFR and Her2. The goal of the project is to develop markers to guide patient selection for future therapies targeting the epidermal growth factor receptor.

7) Recent clinical trials have shown that the preoperative administration of systemic therapy (e.g. chemotherapy, hormonal therapy, targeted therapy) is safe and effective. In addition, from a research standpoint, it has two major benefits: a) to quickly see whether drugs shrink the cancer and b) to study the cancer cell before and after treatment to assess the impact of our therapies. In the CALGB, researchers will test two new targeted therapies using this approach. In patients with tumors that are dependent on HER2, they will compare trastuzumab (Herceptin®) versus lapatinib (Tykerb®) versus both. In patients with HER2 normal tumors ("HER2 negative") they will test the addition of an antibody that shuts off new blood vessel formation (Avastin® or bevacizumab). These studies represent a unique opportunity for the CALGB to gain the ability to see the effects of treatments on tumors before surgery; this knowledge will inform future treatment trials in breast cancer.

8) The widespread use of mammography in the US has led to an increase in diagnosis of DCIS, a noninvasive, but malignant, breast disease. DCIS may progress to become invasive breast cancer, but estimates of this event vary widely. Because physicians do not have tools to predict which patient with DCIS is at high risk for future development of invasive breast cancer, the only treatment options for patients with DCIS are surgery or a combination of surgery, radiation, and endocrine therapy. Presently, no other less aggressive treatment option exists, even if the perceived risk of cancer progression is small. In the proposed study, CALGB researchers will obtain breast MRIs several times before surgery to monitor response to therapy, as well as collect breast tissue. This study represents one of the first opportunities to see the effect of endocrine therapy and imaging diagnostics on DCIS before surgery. The results of this study should improve our understanding of endocrine therapies and breast imaging with MRI in preinvasive breast disease.

Bio:
Dr. Schilsky earned his M.D. at the University of Chicago Pritzker School of Medicine in 1975. Following a residency in Internal Medicine at the University of Texas Southwestern Medical Center and Parkland Memorial Hospital, he received training in Medical Oncology and Clinical Pharmacology at the National Cancer Institute from 1977 to 1981. He then served as Assistant Professor of Medicine at the University of Missouri-Columbia School of Medicine from 1981-1984 when he returned to the University of Chicago.

An international expert in gastrointestinal malignancies and cancer pharmacology, he has served on a number of peer review and advisory committees for the NCI and previously served as Chair of the Oncologic Drugs Advisory Committee for the FDA. Dr. Schilsky currently serves as a member of the NCI Board of Scientific Advisors and recently completed a term as a member of the Board of Directors of the American Society of Clinical Oncology. Since 1995, Dr. Schilsky has served as Chairman of the Cancer and Leukemia Group B.

He is a member of the external advisory committees of several comprehensive cancer centers including the Roswell Park Cancer Center, the Mayo Cancer Center, the MD Anderson Cancer Center and the Fred Hutchinson Cancer Research Center. He has also served as a member of the Selection Committee for the Bristol-Myers Squibb Award for Distinguished Achievement in Cancer Research. Dr. Schilsky is an Associate Editor of Clinical Cancer Research and Cancer and a member of the editorial board of Seminars in Oncology, the Journal of Cancer Research and Clinical Oncology and several other journals. He has published more than 225 articles and book chapters in the medical literature and is the editor of 4 books.

Cancer and Leukemia Group B (CALGB) is a national clinical research group sponsored by the National Cancer Institute, with its headquarters at the University of Chicago, and its Statistical Center at Duke University. The CALGB was founded in 1955, with the goal of bringing together clinical oncologists and laboratory investigators to develop better treatments for cancer. Since then, CALGB has grown into a national network of 30 university medical centers, over 200 community hospitals and physician practices, and 3,000 physicians who collaborate in clinical research studies aimed at reducing the mortality from cancer, relating the biological characteristics of cancer to clinical outcomes, and developing new strategies for early detection and prevention of cancer.