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BREAST CANCER: Larry Norton Conceptual and Practical Implications of Breast Tissue Geometry: Toward a More Effective, Less Toxic Therapy Oncologist 2005; 10: 370-381 [Abstract] [Full text] [PDF]

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Is cancer self-seeding linked to IHC similarities between primary & metastatic tumors?

Sven Kurbel, Branko Dmitrovic, Jozo Kristek, Ilijan Tomas and Mario Bozac   (6 March 2009)

Is cancer self-seeding linked to IHC similarities between primary & metastatic tumors? 6 March 2009
Sven Kurbel, medical oncologist Osijek Medical Faculty, Osijek, Croatia, Branko Dmitrovic, Jozo Kristek, Ilijan Tomas and Mario Bozac Send letter to journal: Re: Is cancer self-seeding linked to IHC similarities between primary & metastatic tumors?	Larry Norton and Joan Massagué recently proposed a provocative model of cancer growth (1, 2) that is based on a unified process of growth and metastasis including self-seeding of the primary tumor by circulating tumor cells. As pointed out in the first paper (1), new insights in cancer growth can focus our therapies to mechanisms involved in metastasis, including metastasis to self. Clinicians usually require some testable prediction before accepting new interpretation of the previously defined phenomenon and cancer growth is no exception. An obvious candidate for testing is the model’s prediction that continuous exchange of malignant cells between metastatic sites and the primary tumor would make all tumor sites similar in malignant cells subpopulations. Based on this prediction, we have tried to statistically compare immunohistochemical (IHC) features of breast cancers and their metastasis on data of 60 ductal invasive breast cancer patients, as presented elsewhere (3). IHC profiles of six parameters (ER, PR, Ki-67, bcl-2, p53, and cathepsin D) for primary tumors and their node metastasis were done. Observed values were compared by the Wilcoxon matched pairs test and a p-value was calculated for the each patient. Wilcoxon p-values ranged in our patients from 0.0431 to 0.999 with median of 0.593 (eight cases), mean value of 0.571 and standard deviation of 0.297. Six cases had p-values below 0.10 and 10 cases above 0.90. If we can use the Wilcoxon p-value as a measure of similarity in IHC profiles of primary and metastatic breast cancer sites, higher values might suggest higher rates of self seeding that prevent any site-specific evolution of malignant subclones. On the contrary, the low values can be expected in patients with low rates of self seeding, thus allowing separate tumor sites to take separate routes of development. According to the described distribution of p-values, it seems that our group of patients involved both expected types. To check out whether p-values are dependent on tumor size, or on the share of the axillary node involvement (number of positive nodes divided by the number of extirpated nodes), we have performed an EM clustering of our cases based on tumor size and their node involvement (StatSoft, Inc. (2004). STATISTICA (data analysis software system), version 7; www.statsoft.com). Two clusters were identified: the first one with 39 cases and the second with 21 cases, as shown in Figure 1. The first cluster is characterized by smaller tumors and lower axillary involvement, while the contrary can be said for the second one. It turned out that the Wilcoxon p-values were significantly higher in the first cluster, tested with the Mann-Whitney U test (Z=2.378, p=0.0173). This result suggests that higher similarity in IHC profiles of breast cancer and its axillary metastasis can be expected in small aggressive tumors that, despite their small size, have already produced a regional metastasis. Larger tumors might be less continuous in self-feeding, so local evolution of subclones can take place in primary and secondary sites and this can explain the lower Wilcoxon p-values. References 1. Norton L. Conceptual and practical implications of breast tissue geometry: toward a more effective, less toxic therapy. The Oncologist 2005;10:370-381. 2. Norton L, Massagué J. Is cancer a disease of self-seeding? Nat Med. 2006;12:875-878. 3. Kristek J, Dmitrovic B, Kurbel S et al. Tumor growth fraction, expression of estrogen and progesterone receptors, p53, bcl-2 and cathepsin D activity in primary ductal invasive breast carcinoma and their axillary lymph node metastases. Coll Antropol 2007;31:1043-1047. Disclosures: No actual or potential conflicts of interest were disclosed by the authors of this eLetter.