References [1] Mackenzie TC, Flake AW. Multilineage differentiation of human MSC after in utero transplantation. Cytotherapy 2001;3(5):403–5. [2] Wang JS, Shum-Tim D, Chedrawy E, Chiu RC. The coronary delivery of marrow stromal cells for myocardialregenera- tion: pathophysiologic and therapeutic implications. J Tho- rac Cardiovasc Surg 2001;122(4):699–705. [3] Yoon YS, Park JS, Tkebuchava T, Luedeman C, Losordo DW. Unexpected severe calcification aftertransplantation of bone marrow cells in acute myocardial infarction. Circula- tion 2004;109(25):3154–7. [4] Jensen CH, Jauho EI, Santoni-Rugiu E, Holmskov U, Teisner N, Tygstrup N et al. Transit-amplifying ductular (oval) cells and their hepatocytic progeny are characterized by a novel and distinctive expression ofdelta-like protein/preadipo- cyte factor 1/fetal antigen 1. Am J Pathol 2004; 164(4):1347–59. [5] Turksen K, Troy TC. Epidermal cell lineage. Biochem Cell Biol 1998;76(6):889–98. Boon Chin Heng Tong Cao Stem Cell Laboratory Faculty of Dentistry National University of Singapore 5 Lower Kent Ridge Road 119074 Singapore Singapore Tel.: +65 6874 4630; fax: +65 6774 5701 (T. Cao) E-mail address: dencaot@nus.edu.sg (T. Cao) doi:10.1016/j.mehy.2005.01.024 Are all prognostic factors changing with time in breast cancer? – New proposal for classification of prognostic factors as time-dependent and time-independent To The Editor, Currently, it is not known that whether standard prognosticfactors such as tumor size, axillary lymph nodes, grade, lymho-vascularinvasion, S-phase fraction, estrogen receptor (ER) status at the initial diagnosis of breast cancer would be dif- ferent if breast cancer were diagnosed at an earlier time. While we can predict that tumor size would be smaller, number of involved lymph nodes lesser and possibly the presence of lympho-vascular inva- sion would be less frequent.Grade and S-phase fraction may not change as the tumor progresses. Millis et al. [1] showed that tumor grade does not change between primary and recurrent mammary carcinoma and also found that the type of the duc- tal carcinoma in situ (DCIS)component was also significantly associated with the grade of the infil- trating component. ER status also may not change. In the case of ER-positive DCIS breast,if cells change into breast cancer, most of them will be ER-positive cells. Diab [2] determined the concor- dance between ER status of DCIS and invasive dis- ease in the same patient. They identified 187 patients with known ER status ofboth DCIS and the invasive disease.In general, there was high concordance between ER status in DCIS and subse- quent invasive breastcancer (83%).ER-negative DCIS yielded ER-negative invasive disease in 60% of the cases. It is known that another prognostic factor, status of HER-2, may change with time. Small studies of HER-2 in DCIS have typically demonstrated expres- sion in more than 40% of DCIS patients overall, with a much higher percentage of patients with comedo/ high-grade DCIS expressing HER-2 than of patients with non-comedo/low-grade-DCIS[3]. HER-2 expression is found in more cases of DCIS than in invasive cancer. The incidence of HER2 expression in invasive disease may reflect the fact reduced expression when DCIS progresses to invasive cancer, or it may reflect the fact that most invasive cancers develop from DCIS tumors that have low expression of HER-2 but high proliferative rates [3]. Although recently published data show that HER-2 could be acquired during the progression of disease [4], we cannot say whether this population is related to change of HER-2 negative cell to HER-2 positive cell or proliferation of scarce HER-2 cells present at the time of diagnosis. In summary, we propose that tumor size, axillary lymph nodes, HER-2 are the prognostic factors Correspondence 413