Last Updated: 7/13/2006

Clinical Interests

Breast Surgical Oncologist

Research Interests
Despite apparent curative surgery in the treatment of breast cancer, 21% of node-negative patients still develop lymph node and distant metastatic disease at 18 years. It is likely that this group of patients has occult micrometastatic disease at the time of initial surgery, and that they are understaged. Recent studies have established that current routine histological assessment of regional lymph nodes underestimates breast cancer metastases. Use of serial sectioning and immunohistochemistry for the evaluation of routine histology-negative lymph nodes in patients with breast cancer has been performed in multiple studies and been shown to increase the detection rate of micrometastatic disease by 9% to 31%. However, the growth properties and of human breast cancer micrometastases remain unknown and their significance obscure.

The commonly accepted theroy of breast cancer metastatic development, Gompertzian growth kinetics, assumes that neoplastic growth begins with tumor seeding and continues until clinical recurrence is documented. This theory postulates that near-regular exponential growth occurs at small cell numbers than larger tumors, but also have more cells in their mitotic cycle and are thus more susceptible to chemotherapy. This model has been the basis of conventional chemotherapy.

An alternate way to explain breast cancer metastatic development is the tumor dormancy hypotheses. This hypothesis assumes that, for some patients during the pre-clinical phase, micrometastases do not grow for a given period of time, depending on tumor and/or host factors. The immune system and suppression of angiogenesis are the most likely of various possible causes of this phenomenon. Micrometastases may eventually escape dormancy when a subset of tumor cells within the micrometastases switching to an angiogenic occurs, dormancy is broken, tumor proliferation increases, and clinically evident metastatic disease develops.

Tumor dormancy has been documented in animal tumor models where micrometastatic foci have been directly observed and studied. These studies have shown that inhibition of vascularization of these micrometastases might explain how some tumor cells remain dormant. Animal studies have demonstrated that micrometastatic cells are dependent on passive diffusion for oxygen and nutrient supply, and this may limit their growth to 2 to 3 mm. To grow larger than a few cubic millimeters, solid tumors must generate new vasculature through the process of angiogenesis. In mice, lung metastases, dormant during angiogenesis suppression with angiostatin, exhibited rapid growth when the inhibition of angiogenesis was removed.

We previously developed a model of the angiogenic switch by sequential introductions of simian virus 40(SV40) large T (tumor) antigen and H-ras into murine endothelial cells. When endothelial cells expressing the SV40 large T antigen were injected into mice, they formed hemangiomas with low proliferative and apoptotic indices and had low production of VEGF. Whe H-ras was introduced into these cells, they formed rapidly proliferating angiosarcomas in vivo, and had high VEGF-production levels. This study demonstrated that introduction of a single gene resulted in a switch to the angiogenic phenotype and broke tumor dormancy.

In humans, Barnhill et a 7 demonstrated that melanoma micrometastases lack significant tumor vascularity and have low rates of proliferation and apoptosis when compared to melanoma macrometastases. This biological study of human micrometastases, although limited in terms of the number of specimens, supports the tumor-dormancy theory and is inconsistent with the Gompertzian hypothesis.

In the past decade, our ability to detect occult breast cancer micrometastases has been enhanced by the advent of sentinel lymph node biopsy, and therefore breast cancer micrometastatases are more readily available to study. The sentinel lymph node technique focuses on the first node in the lymphatic basin, the 'sentinel' node, which, as the first node to receive drainage from the tumor site, is the regional node most likely to harbor metastatic disease. The use of serial sectioning and immunohistochemistry for the evaluation of routine histologically negative lymph nodes in patients with breast cancer has been the subject of multiple studies and increases the detection rate of micrometastatic disease by 9%-31%. Therefore, sentinel lymphadenectomy with serial sectioning and immunohistochemistry provides a novel way to obtain specimens of breast micrometastases for laboratory investigation.

We have recently shown, using immunohistochemistry, that breast cancer micrometastases (obtained from sentinel lymph nodes) have lower proliferation rates, decreased angiogenesis, and no difference in apoptosis, when compared to macroscopic axillary lymph node metastases (obtained from patients with greater than 15 positive axillary nodes). In the current proposal we will take two approaches to characterize the molecular profiles of micrometastases.

The first approach is hypothesis driven: Since immunohistochemistry has shown us that breast cancer micrometastases have decreased proliferation and angiogenesis, we hypothesize that there will be a difference in expression of genes involved in angiogenesis and cell-cycle regulation. We will therefore use laser capture microdissection, amplification, and RT-PCR to look for differences in expression of important genes known to be related to angiogenesis (VEGF, b-FGF, angioprotein, thrombospondin, matrix metalloprotteinases, and TGF-beta) and cell cycle regulaiton (P53, H-RAS, cyclin D1, and c-myc).

The second approach is an inductive approach to look for genes we might not anticipate, or that might not be previously characterized. This approach will use laser capture microdissection of lymph node micro- and macrometastases, amplificaiton, and tumor genetic profiling using cDNA microarrays. This second approach, although risky, is innovative with a potential high impact for discovering new paradigms. The genetic regulation of human micrometastases is not known, and this would be the first characterization of human micrometastases of its sort.

This current research will elucidate whether differences in biologic outcome between patients with micrometastic disease versus macrometastatic disease can be explained by differences in gene expression. Understanding the biological mechanisms of micrometastases will contribute significantly to the design of treatment strategies for patients with micrometastatic disease.

This current research will elucidate whether differences in biologic outcome between patients with micrometastatic disease versus macrometastatic disease can be explained by differences in gene expression. Understanding the biological mechanisms of micrometastases will contribute significantly to the design of treatment strategies for patients with micrometastatic disease.

Recent Accomplishments and Honors
2004 Department of Defense Physician-Scientist Training Award for Breast Cancer Research

2003 NIH BIRWCH Scholar Award

2003 The Kimmel Scholar Award for Translational Research

2002 American Society of Clinical Oncology, The Breast Cancer Research Foundation Clinical Research Career Development Award

2000 Society of Surgical Oncology/ Aztrazeneca Oncology Fellowship Award for Clinical Research

Training

1999 - 2001 Fellowship in Surgical Oncology
Memorial Sloan-Kettering Cancer Center and
Cornell University Medical Center New York, NY

1996 - 1999 Residency in General Surgery
Boston University Medical Center, Boston, MA

1993 - 1996 Surgical Research Fellowship
Children's Hospital, Harvard Medical School
Boston, MA Preceptor: Judah Folkman, M.D.

1991 - 1993 Residency in General Surgery
Boston University Medical Center, Boston, MA

1987 - 1991 University of Health Sciences, The Chicago Medical School, North Chicago, IL Degree: Doctor of Medicine

1984 - 1987 Wheaton College, Norton, MA
Degree: Bachelor of Arts
Major: Biology

Publications
Klauber N, Brown F, Anand-Apte B, D'Amato RG: New activity of spironolactone: Inhibition of angiogenesis in vitro and in vivo. Circulation 94:2566-2571, 1996.

Klauber N, Parangi S, Flynn E, Hamel E, D'Amato RJ: Inhibition of angiogenesis and breast cancer in mice by the microtubule inhibitors 2-methoxyestradiol and Taxo. Cancer Res 57:81-86, 1997.

Arbiser JL, Moses MA, Fernandez CA, Ghiso N, Cao Y, Klauber N, Frank D, Brownlee M, Flynn E, Parangi S, Byers HR, Folkman J: Oncogenic H-ras stimulates tumor angiogenesis by two distinct pathways. Proc Natl Acad Sci USA 94:861-866, 1997.

Klauber N, Rohan RM, Flynn E, D'Amato RJ: Critical components of the female reproductive system are suppressed by the angiogenesis inhibitor AGM-1470. Nature Med 3:443-446, 1997.

Arbiser JL, Klauber N, Rohn R, Van Leeuwen R, Huang MT, Fisher C, Flynn E, Byers HR: Curcumin is an in vivo inhibitor of angiogenesis. Molec Med 4:376-383, 1998.

Arbiser JL, Panigrathy D, Klauber N, Rupnick M, Flynn E, Udagawa T, D'Amato RJ: The antiangiogenic agents TNP-470 and 2-methoxyestradiol inhibit the growth of the angiosarcoma in mice. J Am Acad Dermatol 40:925-929,1999.

Klauber-DeMore N, Kaptain S, Tan L, Borgen P, Fey J, Heerdt A, Paglia M, Petrek J, Cody H, Van Zee K: Sentinel lymph node biopsy: Is it indicated in patients with high-risk DCIS and DCIS with microinvasion? Ann Surg Onc 7:636-642, 2000.
Klauber-DeMore N, Van Zee KJ, Borgen P, Gerald W: Biological behavior of human breast cancer micrometastases. Clin Cancer Res 8:2434-2439, 2001.

Cody H, Klauber-DeMore N, Borgen P, Van Zee K: Is it really ductal carcinoma in situ? Ann Surg Onc 8:617-619, 2001.
Klauber-DeMore N, Van Zee KJ, Borgen P, Cody HS: Comprehensive review of the management of internal mammary lymph node metastases in breast cancer. J Am Coll Surg 193(5):547-555, 2001

Klauber-DeMore N, Boolbol SK, Derossis AM, Ruo L, Bernik S, Borgen PI: Randomized trials in breast cancer. Surg Onc Clinics NA 11:1,53-88, 2002.

Carey CA, Dees EC, Dressler L, Metzger R, Moore DJ, Livasy C, Iacocca M, Cowan D, Harden A, Miller A, Little D, Collichio F, Ollila D, Klauber-DeMore N, Sartor C, Tsui A, Graham M: Response to Trastuzumeb (Herceptin) given with paclitaxel (Taxol) immediately following 4 AC as initial therapy for breast cancer. Breast Cancer Res Treat 76 (suppl 1):4292, 2002

Stitzenberg KB, Meyer AA, Stern SL, Cance WG, Calvo BJ, Klauber-DeMore N, Kim HJ, Sansbury L, Ollila DW: Extracapsular extension of the sentinel lymph node metastases: A predictor of nonsentinel node tumor burden. Annals of Surgery; 237(5):607-12, May 2003

Klauber-DeMore, N, Ogunrinde, OB, Kuzmiak, C, Rager, E, , Ollila, D, Calvo, B, Kim, HJ, Dees, C, Graham, M, Collichio, F, Sartor, C, Metzger, R, Carey, LA. High-Resolution Axillary Ultrasound is a Poor Prognostic test for Determining Pathologic lymph Node Status in Patients Undergoing Neoadjuvant Chemotherapy for Locally Advanced Breast Cancer. American Journal of Surgery, 188 (2004)386-389.

Carey, L.A., Metzger, R., Dees, C.E, Collichio, f., Sartor, C.I., Ollila, D.W., Klauber-DeMore, N., Halle, J., Sawyer, L., Moore, D.T., Graham, M. AJCC TNM stage after neoadjuvant chemotherapy predicts breast cancer outcome. J Natl Cancer Inst. 2005 Aug 3;97(15):1137-42.

Klauber-DeMore, N., Calvo, B., Hultman, C., Kim, H.J., Meyers, M., Damitz, L., Staged Sentinel Lymph Node Biopsy Prior to Mastectomy Facilitates Surgical Planning for Breast Cancer Patients. American Journal of Surgery Frank, J., Sartor, C., Ollila, D.W., 190 (2005) 595-597.

Ollila, DW, Neuman, HB, Sartor, C, Carey, LA, and Klauber-DeMore, N. Lymphatic mapping and sentinel lymphadenectomy prior to neoadjuvant chemotherapy in patients with large breast cancers. American Journal of Surgery 188 (2005) 371-375.

Neuman, H., Carey, L.A, Ollila D.W., Livasy, C., Calvo, B.F., Meyer, A., Kim, H.J., Meyers, M., Dees, C.E., Collichio, F.A, Sartor, C.I.., Moore, D.T., Sawyer, L.R., Frank, J., Klauber-DeMore, N. Axillary Lymph Node Count is Lower After Neoadjuvant Chemotherapy. American Journal of Surgery,191(2006)827-829.

Klauber-DeMore, N., Ollila, DW, Moore, DT, Calvo, BF, Kim, HJ, Dees, EC, Sawyer, LR , Sartor, CI, Graham, M II, Carey, LA. Size of Residual Lymph Node Metastasis Following Neoadjuvant Chemotherapy in Locally Advanced Breast Cancer is Prognostic. Ann Surg Onc, 13(5):685-691, 2006.

Ollila, DW, Klauber-DeMore, N, Tesche, LJ, Kuzmiak, CM, Pavic, D, Goyal, LV, Lian, J, Chang, S, Livasy, CA4, Sartor, CI. Feasibility of Breast Preserving Therapy with Single Fraction In Situ Radiotherapy Delivered Intraoperatively. Ann Surg Onc, in press.

Klauber-DeMore, N and Peppercorn, J. An Overview of Small-Molecule Inhibitors of Angiogenesis in Clinical Trials., Angiogenesis in Oncology, 2006, in press.

Editor: Nancy Klauber-DeMore. Breast Cancer in Young Women. Breast Dis., Vol. 23, No. 1, IOS Press. 2005, 2006.

Klauber-DeMore, N, Tumor Biology of Breast Cancer in Young Women. Breast Dis., Breast Dis., Vol. 23, No. 1, pp.9-15, IOS Press. 2005, 2006.

Klauber-DeMore, N, Preface: A Comprehensive Review of Breast Cancer in Young Women. Breast Dis., Breast Dis., Vol. 23, No. 1, pp.1,2, IOS Press. 2005, 2006.

E-mail: nancy_demore@med.unc.edu
Telephone: 919-966-8007
FAX: 919-966-8806
Address: 3010 Old Clinic Building Chapel Hill, NC 27599

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