Shelley Hwang, MD, MPH

2009-2010 BCRF Project
On behalf of Cancer and Leukemia Group B
Co-investigator: Richard L. Schilsky, MD, President, CALGB Foundation; Group Chair, CALGB; Professor of Medicine, Cancer and Leukemia Group B, Chicago, IL

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. Shelley Hwang is Chief of Breast Surgery at the UCSF Helen Diller Family Comprehensive Cancer Center. She received her medical training at UCLA Medical School, and completed her surgical residency at Cornell University's New York Hospital. She completed a fellowship in breast oncology at Memorial Sloan-Kettering Cancer Center as well as a Surgical Oncology fellowship at the National Cancer Centre in Singapore.

Dr. Hwang has a long-standing interest in the early detection of breast cancer, especially of ductal carcinoma in situ. Her research focus includes exploring less invasive treatment options for preinvasive breast cancers, and identifying genomic and stromal determinants of cancer progression. She has contributed to the genomic characterization of DCIS, LCIS, as well as subtypes of invasive cancer. Her translational research interest is to study radiographic and biologic changes in DCIS induced by preoperative treatment with hormonal therapy as well as novel agents in the window trial setting. She has received support from The Breast Cancer Research Foundation to characterize the MRI changes that accompany treatment of DCIS with hormone-targeted therapy.