Research Summary Our Gillette Center for Breast Cancer clinical research program has increased significantly and continues to grow at a rate of approximately 20% additional new patient consults per annum. In 2004, with the generous support of the Avon Foundation Paul, Goss MD, PhD, an internationally recognized breast cancer leader, was recruited to direct the Massachusetts General Hospital breast research program and co-direct the DF/HCC clinical breast program. Since his arrival recruitments to our program have included three medical oncologists, one radiation oncologist, one surgical oncologist, one pathologist, two nurse practitioners, one research nurse practitioner and a physical therapist. Most recently John K Erban, MD a widely recognized researcher and clinical program chief from NEMC, has been recruited to coordinate the clinical aspects of our breast program. Dianne Finkelstein, PhD an internationally prominent Massachusetts General Hospital Cancer Center biostatistician, has also joined the breast cancer research program.
Since 2004, multiple research initiatives have been have been launched under the leadership of our investigators: five international endocrine trials and one HER2 positive trial in early stage breast cancer; one international breast cancer prevention trial and two international breast cancer prevention pilot trials; one international neoadjuvant endocrine trial and two local trials in triple negative disease; four proof-of-principle metastatic trials; five international tissue repositories have been established for correlative science; two local radiation trials; and one lymphedema trial.
In addition an MGH-Avon International Breast Cancer Research Program has been established with three projects planned, a metastatic endocrine tumor signature project and two proof-of-principle metastatic clinical trials.
Our program leads two international breast cancer prevention pilot clinical trials (NCIC CTG MAP1and 2) regarding evaluation of the effects of steroidal and non-steroidal aromatase inhibitors on breast density and bone and lipid metabolism in healthy postmenopausal women. Results are being presented at the 2007 San Antonio International Breast Cancer Symposium. These studies compliment our ongoing MA27D mammographic density trial and our published data on breast density in the MA17 trial.
Breast Cancer Prevention and Risk Assessment
We are conducting the leading breast cancer prevention trial in the world, the ExCel Trial (n=4650). This is the first trial of an aromatase inhibitor for the prevention of breast cancer. The study is e=being coordinated by the National Cancer Institute of Canada Clinical Trials Group, an NCI funded academic group. Correlative sub-studies which we are leading include MAP3B1, a study of bone metabolism and MAP3B2, a study of bone quality. Dr. Goss is leading a consortium of NCI PGRN (Pharmacogenomic Research Network) including the Mayo Clinic, the University of Washington, the University of Michigan, Duke and Georgetown University to study the pharmacogenomics of mammographic density, pathways of estrogen metabolism and other end-organ functions and toxicities. Serum for proteomics is also being analyzed in this regard.
Dr. Kevin Hughes has initiated a series of studies to optimize identification of high risk women among those presenting for routine breast screening in an office or mammography center setting. Identification of such high risk women would allow use of appropriate screening and prevention approaches to reduce risk of breast cancer morbidity and mortality. MGH surgical oncology and mammography databases have been used to design a tablet PC system that allows assessment of patient risk and to facilitate appropriate management of high risk women and their family members is a cost-effective manner. Dr. Hughes is piloting this system in the Avon Foundation Comprehensive Breast Evaluation Center and at our affiliate Newton-Wellesley Hospital.
Early Stage Breast Cancer Trials
Our program has established international leadership in endocrine therapy of early stage breast cancer. Following publication of the landmark NCIC CTG MA17 trial we have initiated the MA17R trial (n=1800) randomizing women completing five years of adjuvant AI therapy to five further years or no treatment. We are leading the NCIC CTG MA27 international trial (n=7400) of the steroidal aromatase inhibitor exemestane versus anastrozole, including a second randomization of celecoxib or placebo in a proportion of patients. The MA27B bone sub-study (n=400) and the MA27D breast density study (n=500) are separate studies under our leadership. These trials promise to change the treatment of breast cancer. Recently MGH proposed and launched a 32 country trial (n=3000) of Lapatinib versus placebo (TEACH) trial in HER2 + early stage breast cancer patients. Positive results will have a substantial impact on clinical practice world-wide.
Our group has focused on neoadjuvant trials and leads an international endocrine trial of faslodex (n=~300). Two further trials in patients with locally advanced triple negative tumors are completed or underway. Dr. Paula Ryan co-led a trial of cisplatin and is leading the ongoing Cisplatin Avastin® trial. These trials strive to find a way to treat the most aggressive form of breast cancer for which there is currently no effective treatment. Biomarker correlation is ongoing (see below).
With our leadership in endocrine sensitive breast cancer we are interested in mechanisms of resistance to these therapies and ways to overcome them. Toshi Shioda has developed a single cell clone library to isolate and investigate this SCC library for biomarkers of resistance. Paula Ryan is leading a randomized Phase 2 international trial of an IGF1R antibody plus aromatase inhibitor in metastatic breast cancer as well as a personalized therapy intermittent aromatase inhibitor trial in advanced ER+ disease. A trial determining whether responses occur when aromatase inhibitors are withdrawn at a point of disease progression is also ongoing.
In non-endocrine responsive triple negative disease Drs. Leif Ellisen and Steve Isakoff are leading a trial in metastatic disease of cisplatin. Ellisen is building upon his discovery that tumors over expressing p63/73 are specifically vulnerable to cisplatin chemotherapy. This observation is being studied among the tumors from both triple negative neoadjuvant trials.
Correlative Science Studies
We are conducting biomarker and tumor signature studies on two large tissue repositories from the MA17 (aromatase inhibitor versus placebo) and MA14 (tamoxifen versus tamoxifen + octreotide) clinical trials. We plan to confirm the prognostic value of our MGH (Sgroi) two-gene signature and compare this to both a semi-quantitative IHC test and to a quantitative aqua-based immunofluorescent assay as both prognostic and predictive factors within these trials. In collaboration with the MAYO clinic and the NCI pharmacogenomic Research Network (PGRN) we are planning a detailed pharmacoanalysis of germ-line DNA and tumors within the MA27 trial. Dr. Dennis Sgroi also holds the tissue repository for the faslodex neoadjuvant clinical trial and the TEACH triple negative trials. Correlative science studies to identify women most likely to benefit from these therapies or to develop toxicities are underway.
Locoregional Studies in Early Stage Breast Cancer
Our group is conducting several studies that could result in a change in clinical practice. Dr. Alphonse Taghian has led to a series of studies related to partial breast irradiation for breast cancer. Forty-eight breast cancer patients were treated with partial breast irradiation via brachytherapy catheters from 1997 to 2001. The outcome for these patients is being updated with respect to recurrence rates and long-term cosmetic outcome.
A prospective study of external beam partial breast radiation is under way, with more than 200 patients accrued in the past 3 years in a dose escalation protocol with a 300 patient goal. The Mass General breast radiation oncology group has also reported the first use of proton beam irradiation for breast cancer and is refining technical aspects of this approach draped.
Our group is also studying axillary radiation as an alternative to dissection in women with positive sentinel node biopsies. More than 540 of the planned 560 patients have been accrued in the approximately three years the trial has been open (PI: Dr. Michele Gadd, Surgical Oncology).
Dr. Angela Katz has created and published a nomogram to predict the risk of additional positive axillary nodes in a breast cancer patient with a positive sentinel node. This nomogram will serve as the basis for additional studies of radiation rather than axillary dissection for positive sentinel nodes, allowing the ability to stratify patient risk and adjust the extent of radiation treatment accordingly.
Our group has also reported on some of the world's largest series of sentinel node biopsies in patients undergoing mastectomy, patients being treated for ductal carcinoma in situ, and patients undergoing neoadjuvant systemic therapy. These results have provided guidance for modification of clinical practice. The report on the timing of sentinel node biopsy with respect to neoadjuvant chemotherapy received the "Scientific Impact" award at the American Society of Breast Surgeons meeting at which it was presented.
The Division of Surgical Oncology has had assembled a database for more than 23,000 women treated for breast cancer at the MGH and Brigham and Womens Hospital (BWH) since 1960, containing detailed and surgical information about patient factors, pathology results, survival and cause of death (PIs James Michaelson, PhD and Barbara Smith, MD, PhD). This is one of the largest databases in the world and has been used for numerous retrospective and hypothesis generating studies related to breast cancer screening, treatment options and in designing models of breast cancer behavior.
The Department of Radiation Oncology has also maintained a database of breast cancer patients treated at the MGH that has been used to review treatment options and outcomes. This data set was recently used to demonstrate differences in local recurrence rates related to breast cancer subtypes (Luminal A and B., HER-2 and Basal like).
Management of Breast Cancer in the Elderly
Dr. Kevin Hughes served as the overall PI for CALGB trial 9343, Lumpectomy plus Tamoxifen with or without Irradiation in Women 70 Years of Age or Older with Early Breast Cancer, which demonstrated a excellent local control and survival with lumpectomy and tamoxifen without radiation for her elderly women with ER positive breast cancer. He is currently preparing an update of this data and will the completion of 10-year follow-up results.
Dr. Alphonse Taghian has initiated a large prospective study of the incidence and time course of arm edema in patients receiving surgery and/or radiation for breast cancer. Patient arm volume is measured with a laser perometer, a device that accurately calculates arm volume, at initial diagnosis and over time after surgical and radiation treatments. Even small percentage increases in breast volume can be identified and a prospective trial is being designed in collaboration with Dr. Michelle Specht of Surgical Oncology to study early predictors of long-term lymphedema and assess the utility of physical therapy, complex, decongestive therapy, compression garments and other interventions.
Sub-macroscopic Breast Anatomy Studies Nipple Sparing Mastectomy Techniques
Drs. Rusby, Smith and Michaelson of Surgical Oncology and Drs. Koerner and Brachtel of Breast Pathology assembled a series of 320 consecutive mastectomy specimens that were utilized to study rates of nipple involvement by tumor in therapeutic and prophylactic mastectomies. Detailed 3-dimensional reconstructions of nipple duct, nipple vessel and nipple surface anatomy were created. These results were used to identify predictors of nipple involvement by tumor for patients being considered for nipple sparing mastectomy, and to design appropriate surgical techniques for thorough nipple duct resection while maintaining nipple skin viability through preservation of nipple vessels. The surface anatomy studies yielded previously unrecognized anatomic details with significant implications for ductal lavage and breast ductoscopy techniques. These studies received awards at both the American Society of Breast Surgeons and the American Society of Breast Disease in 2007.
As part of the Eighth Annual Avon Walk Boston, the Avon Foundation awarded a generous research and patient care grant to Mass General's breast cancer program.
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