Monica Bertagnolli, MD

2012-2013 BCRF Project:
(made possible by generous support from Genentech)
On behalf of Alliance for Clinical Trials in Oncology
Co-Investigators: Wendy L. Frankel, MD, Ohio State University; and Jennifer Ligibel, MD, Dana-Farber Cancer Institute, Brigham & Women's Hospital, Harvard Medical School, Boston, MA

The Cancer and Leukemia Group B, now part of the Alliance for Clinical Trials in Oncology, has a long and successful history of conducting clinical trials in the adjuvant and metastatic setting. In recent years, the Breast Committee leadership, recognizing the need to more rapidly identify effective novel treatments, has decided to pursue clinical trials in the preoperative setting. Among the organization's current initiatives, the Alliance is conducting a trial (CALGB 40903) to help determine which patients with ductal carcinoma in situ (DCIS) is likely to develop invasive breast cancer. Due to increased use of mammography in the United States, there has been an increase in diagnosis of DCIS, a noninvasive and non-metastatic, but malignant, breast disease. DCIS may progress to become invasive breast cancer, but estimates of the likelihood of progression 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 in combination with radiation, and endocrine therapy. Presently, no other less aggressive treatment option exists, even if the perceived risk of cancer progression is small. Researchers participating in this trial plan to obtain breast MRIs several times before surgery to monitor response to therapy, as well as collect breast tissue at diagnosis and following six months of hormonal therapy. Importantly, quality of life correlates will also be studied for the effect of letrozole in the neoadjuvant setting. 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.

Another clinical trial that the Alliance is undertaking in the current grant year is the application of the PAM50 assay trial examining the role of paclitaxel in adjuvant chemotherapy of women with node-positive breast cancer. While the administration of paclitaxel reduced the risk of recurrence and death, these advantages must be weighed against the toxicity and cost of therapy. Genetic analysis of breast tumors, conducted through the PAM50 assay, will be used to determine which patients are most likely to benefit from use of the drug, paclitaxel as part of adjuvant chemotherapy. A new platform for genetic tumor analysis, referred to as "nanostring" was recently selected for performing this analysis and has been validated. The Alliance plans is study tumor materials from CALGB adjuvant therapy trials using this technology, as well as create a tumor DNA bank that can be used for validation of any RNA based signature and also be used for regulatory filings.

To date, BCRF funding assisted in the development of the PAM50 assay during the phase of the project where genes were being selected on the basis of how accurately they could be assayed in degraded RNA from formalin-fixed tissues. BCRF has also supported the intrinsic subtype experiment based on IHC which has been completed.

In addition, the Alliance will initiate a multi-institutional study to explore the effect that weight loss has on insulin and other related hormones in breast cancer survivors, as well as to determine how these changes in hormone levels are related to rates of breast cancer recurrence and death. Women who are overweight or obese when they are diagnosed with breast cancer appear to be at a higher risk of cancer recurrence as compared to leaner women, but the reasons for this are not clear. Studies have suggested that obese women may have higher levels of hormones like insulin, which regulate the way that the body uses and stores energy. Many of the hormones that are affected by obesity have in turn been linked to both the risk of developing breast cancer and the risk of dying from the disease. This study will thus provide important new information about the pathways through which weight and other lifestyle factors could affect breast cancer risk and prognosis. The results of this trial will not only teach us more about the complex processes that lead to the development of breast cancer, but will also demonstrate which patients are most likely to benefit from losing weight after diagnosis.

Mid-year Progress: The Alliance has made significant progress on their multiple projects. Their evaluation of dose-dense chemotherapy using PAM50 assay has completed tissue microarray analyses. The results were presented as a poster at the San Antonio Breast Cancer Symposium in December 2012, and a manuscript is in preparation.

As part of the merger of CALGB, NCCTG, and ACOSOG into the Alliance Breast Committee, leadership and scientists meet recently and reprioritized ongoing and proposed correlative projects. As a result, the Committee's enthusiasm for investing valuable resources and funding into additional correlative projects for CALGB 49907 has diminished. The Committee's top priorities are continuing the genomic analyses of breast tumors in their preoperative trials, CALGB 40601 and 40603, in light of their recent closure and maturing data. Thus the Committee prefers to invest BCRF's valuable resources into this higher priority work that will shape the Committee's future research agenda and breast cancer trials.

The Alliance has also activated the phase 2 study of preoperative letrozole for postmenopausal ER-positive ductal carcinoma in situ. Accrual has been delayed due to sites obtaining the necessary regulatory approvals as well as undergoing mandatory radiology qualification to participate.

In addition, the Alliance study team recently submitted their concept for the proposed telephone-based weight loss intervention study to National Cancer Institute's Breast Cancer Steering Committee. Unfortunately, the submitted concept was not approved for development; however the Steering Committee and Division of Cancer Prevention supports a weight loss intervention in breast cancer and has provided recommendations for a revised concept, which includes a more substantial developmental phase. Thus, the Alliance team is working to submit a revised concept based on reviewer feedback, which will be submitted to the NCI for review in the upcoming months.

Bio:
Dr. Bertagnolli is a Professor of Surgery at Harvard University Medical School and the Chief of the Division of Surgical Oncology at Brigham and Women's Hospital and Dana-Farber Cancer Institute. Dr. Bertagnolli is a member of the Gastrointestinal Cancer and Sarcoma Disease Centers at the Brigham and Women's/Dana Farber Cancer Center, where she collaborates with colleagues in medical oncology, radiation oncology, and pathology to treat cancer patients in a tertiary care setting.

Dr. Bertagnolli maintains an active research laboratory whose work focuses upon understanding the role of the adenomatous polyposis coli (APC) gene in epithelial tumor formation. She was also one of the organizing members of gastrointestinal correlative science initiatives within the NCI-funded Cancer Cooperative Groups, where she facilitated integration of tumor-specific molecular markers of treatment outcome into nation-wide clinical cancer treatment protocols. Dr. Bertagnolli has had numerous leadership roles in multi-institutional cancer clinical research consortia, and currently serves as President of the Alliance for Clinical Trials in Oncology (ACTION), a group combining the Cancer and Leukemia Group B (CALGB), the North Central Cancer Treatment Group (NCCTG), and the American College of Surgeons Oncology Group (ACOSOG).