Hypothesis: Induced angiogenesis after surgery in premenopausal node-positive breast cancer patients is a major underlying reason why adjuvant chemotherapy works particularly well for those patients

Breast Cancer Research

Pinuccia Valagussa²  William Hrushesky¹  Judah Folkman³  Romano Demicheli²  Gianni Bonadonna²  Michael Retsky³ 

[1] Dorn Veterans Affairs Medical Center and University of South Carolina School of Medicine, Columbia, SC, USA;Department of Medical Oncology, Milan National Cancer Institute, Milan, Italy;Department of Surgical Research, Children's Hospital and Harvard Medical School, Boston, MA, USA

关键词: surgery;    mammography controversy;    breast cancer dormancy;    angiogenesis;    adjuvant chemotherapy;   

Others  :  1118744
DOI  :  10.1186/bcr804

 received in 2003-12-15, accepted in 2004-04-28,  发布年份 2004

【 摘 要 】

Background

We suggest that surgical extirpation of primary breast cancer among other effects accelerates relapse for some premenopausal node-positive patients. These accelerated relapses occur within 10 months of surgery for untreated patients. The mechanism proposed is a stimulation of angiogenesis for distant dormant micrometastases. This has been suggested as one of the mechanisms to explain the mammography paradox for women aged 40–49 years. We could imagine that it also plays a role in adjuvant chemotherapy effectiveness since, perhaps not coincidentally, this is most beneficial for premenopausal node-positive patients.

Hypothesis

We speculate that there is a burst of angiogenesis of distant dormant micrometastases after surgery in approximately 20% of premenopausal node-positive patients. We also speculate that this synchronizes them into a temporal highly chemosensitive state and is the underlying reason why adjuvant chemotherapy works particularly well for that patient category. Furthermore, this may explain why cancer in younger patients is more often 'aggressive'.

Testing the hypothesis

Stimulation of dormant micrometastases by primary tumor removal is known to occur in animal models. However, we need to determine whether it happens in breast cancer. Transient circulating levels of angioactive molecules and serial high-resolution imaging studies of focal angiogenesis might help.

Implications

Short-course cytotoxic chemotherapy after surgery has probably reached its zenith, and other strategies, perhaps antiangiogenic methods, are needed to successfully treat more patients. In addition, the hypothesis predicts that early detection, which is designed to find more patients without involved lymph nodes, may not be a synergistic strategy with adjuvant chemotherapy, which works best with positive lymph node patients.

【 授权许可】

   
2004 Retsky et al.; licensee BioMed Central Ltd. This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original URL.

【 图 表 】

Figure 1.

【 参考文献 】

• [1]Retsky M, Demicheli R, Hrushesky W: Premenopausal status accelerates relapse in node positive breast cancer: hypothesis links angiogenesis, screening controversy. Breast Cancer Res Treat 2001, 65:217-224.
• [2]Baum M, Chaplain MAJ, Anderson ARA, Douek M, Vaidya JS: Does breast cancer exist in a state of chaos? Eur J Cancer 1999, 35:886-891.
• [3]O'Reilly MS, Holmgren L, Shing Y, Chen C, Rosenthal RA, Moses M, Lane WS, Cao Y, Sage EH, Folkman J: Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Cell 1994, 79:315-328.
• [4]Hofer SO, Molema G, Hermens RA, Wanebo HJ, Reichner JS, Hoekstra HJ: The effect of surgical wounding on tumour development. Eur J Surg Oncol 1999, 25:231-243.
• [5]Retsky M, Demicheli R, Hrushesky W: Breast cancer screening: controversies and future directions. Curr Opin Obstet Gynecol 2003, 15:1-8.
• [6]Demicheli R, Bonadonna G, Hrushesky WJM, Retsky MW, Valagussa P: Menopausal status dependence of the early mortality reduction due to diagnosing smaller breast cancers (T1 versus T2-T3): relevance to screening. J Clin Oncol 2004, 22:102-107.
• [7]Baines C: Mammography screening: are women really giving informed consent? J Natl Cancer Inst 2003, 95:1508-1511.
• [8]Naumov GN, MacDonald IC, Weinmeister PM, Kerkvliet N, Nadkarni KV, Wilson SM, Morris VL, Groom AC, Chambers AF: Persistence of solitary mammary carcinoma cells in a secondary site: a possible contributor to dormancy. Cancer Res 2002, 62:2162-2168.
• [9]Bonadonna G, Valagussa P, Moliterni A, Zambetti M, Brambilla C: Adjuvant cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer: the results of 20 years of follow-up. N Engl J Med 1995, 332:901-906.
• [10]NIH consensus conference: Adjuvant chemotherapy for breast cancer. JAMA 1985, 254:3461-3463.
• [11]Early Breast Cancer Trialists' Collaborative Group: Polychemotherapy for early breast cancer: an overview of the randomised trials. Lancet 1998, 352:930-942.
• [12]Miller AB, To T, Baines CJ, Wall C: The Canadian National Breast Screening Study-1: breast cancer mortality after 11 to 16 years of follow-up. A randomized screening trial of mammography in women age 40 to 49 years. Ann Intern Med 2002, 137:305-312.
• [13]Demicheli R, Miceli R, Brambilla C, Ferrari L, Moliterni A, Zambetti M, Valagussa P, Bonadonna G: Comparative analysis of breast cancer recurrence risk for patients receiving or not receiving adjuvant cyclophosphamide, methotrexate, fluorouracil (CMF). Data supporting the occurrence of 'cures'. Breast Cancer Res Treat 1999, 53:209-215.