The long-term objectives of this proposal are to develop and refine methods of breast cancer staging in patients that are substantially less morbid than current methods, yet still provide the same diagnostic and therapeutic benefits. For the past nine years we have partnered with the National Surgical Adjuvant Breast and Bowel cooperative group (NSABP) to conduct a large, multi-center, randomized, Phase III prospective trial that compares sentinel lymph node (SLN) resection to conventional axillary dissection in clinically node-negative breast cancer patients (NSABP trial B-32). During the last grant period we have also launched a multi-center study to investigate whether detection of the presence of bone marrow micrometastases provides enhanced and early prediction for survival of breast cancer patients (NSABP study BP-59). Several tasks have been shared between UVM and NSABP, such as final trial design and protocol development. UVM has had non-overlapping primary responsibility for the following: (1) training and quality control of all aspects of SLN surgery and bone marrow sample procurement;(2) processing and interpretation of SLNs for occult metastases;(3) processing and interpretation of bone marrow samples for disseminated tumor cells;and (4) statistical analysis of the following three relationships: firstly, the relationship of training to surgical outcomes and quality of reported data;secondly, the relationship of occult metastases in SLNs to survival and other patient variables, and thirdly, the relationship of bone marrow micrometastases to survival. During the time period of this proposal the first 6 Aims will be fully completed and the 7th Aim will result in complete specimen accrual and interpretation.
The Specific Aims of the current active grant are:
Specific Aims #1 and #2: Determine whether SLN resection alone, when compared to ALN dissection plus SLN resection, results in equivalent long-term control of regional disease (Aim 1) and disease-free and overall survival (Aim 2).
Aim #3 : Determine the magnitude of morbidity reduction of SLN surgery versus ALN resection.
Aim #4 : Determine the magnitude of quality of life improvement by SLN surgery versus ALN resection.
Aim #5 : Determine whether standardized immunohistochemistry analysis of hematoxylin and eosin- negative SLNs identifies patients at risk for decreased overall and disease-free survival.
Aim #6 : Establish a standardized method of SLN surgery in a large number of centers for procedural consistency.
Aim #7 : Determine the relative risk of death associated with the presence of tumor cells in the bone marrow of breast cancer patients and investigate the relationship between 2 tumor cell detection methods, brightfield and immunoflourescence cytochemistry, in detecting bone marrow micrometastases.

Public Health Relevance

Successful outcome of the B-32 trial will mean that 75% of breast cancer patients can safely have only a few axillary lymph nodes removed (sentinel node dissection) rather than the majority of axillary nodes (axillary dissection). Successful outcome of the BP-59 study will result in a method that, at the time of initial treatment, will detect disseminated tumor cells in the bone marrow of those breast cancer patients most likely to develop serious systemic cancer recurrence.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Clinical Oncology Study Section (CONC)
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Song, Min-Kyung H
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University of Vermont & St Agric College
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United States
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Weaver, Donald L; Ashikaga, Takamaru; Krag, David N et al. (2011) Effect of occult metastases on survival in node-negative breast cancer. N Engl J Med 364:412-21
Krag, David N; Anderson, Stewart J; Julian, Thomas B et al. (2010) Sentinel-lymph-node resection compared with conventional axillary-lymph-node dissection in clinically node-negative patients with breast cancer: overall survival findings from the NSABP B-32 randomised phase 3 trial. Lancet Oncol 11:927-33
Land, Stephanie R; Kopec, Jacek A; Julian, Thomas B et al. (2010) Patient-reported outcomes in sentinel node-negative adjuvant breast cancer patients receiving sentinel-node biopsy or axillary dissection: National Surgical Adjuvant Breast and Bowel Project phase III protocol B-32. J Clin Oncol 28:3929-36
Ashikaga, Takamaru; Krag, David N; Land, Stephanie R et al. (2010) Morbidity results from the NSABP B-32 trial comparing sentinel lymph node dissection versus axillary dissection. J Surg Oncol 102:111-8
Krag, David N; Kusminsky, Roberto; Manna, Edward et al. (2009) Cytokeratin-positive cells in the bone marrow of breast cancer patients and noncancer donors. Appl Immunohistochem Mol Morphol 17:403-8
Krag, David N; Ashikaga, Takamaru; Harlow, Seth P et al. (2009) Surgeon training, protocol compliance, and technical outcomes from breast cancer sentinel lymph node randomized trial. J Natl Cancer Inst 101:1356-62
Krag, David N; Kusminsky, Roberto; Manna, Edward et al. (2005) The detection of isolated tumor cells in bone marrow comparing bright-field immunocytochemistry and multicolor immunofluorescence. Ann Surg Oncol 12:753-60
Harlow, S P; Krag, D N (2001) Sentinel lymph node--why study it: implications of the B-32 study. Semin Surg Oncol 20:224-9