and tumor growth
Tamoxifen and tumor growth
Tissues are composed of tissue units. The tissue unit consists of a stem cell (DS) whose progeny are dividing progenitors, which mature to non dividing end cells. Progenitors and end cells are collectively called transitional cells. A tumor is initiated in a single tissue unit when a normal stem cell is transformed into a neoplastic. Obviously this transformed cell has to be a stem cell (DS), since transformed transitional cells are short lived. Tumor initiation is a stem cell event.
During the initial stages of tumor development the tissue unit elongates and is populated mainly by progenitors. The ratio end cells / progenitors declines until all end cells disappear and the entire unit proliferates.
During the subsequent phase neoplastic stem cells populate the entire unit. The gradual loss of end cells is known as maturation arrest. Each stem cell creates its own neoplastic unit. Together they form a growing tumor. These are the earliest changes in neoplastic (or tumor) evolution. They are called also precursor lesions, exhibiting the salient features of a tumor. Progenitor amplification and neoplastic stem cell accumulation.
As neoplastic cells evolve they lose their original stem cell attributes, acquire new gene mutations which endow them with new neoplastic properties. This process is called de-differentiation.
Mammary tumor evolution
The mammary gland unit proceeds through the same stages. Initially it is well differentiated, populated with end cells containing estrogen receptors which make it sensitive to estrogen. The hormone promotes its growth while castration retards it. During this period the tumor is estrogen dependent. As it evolves it gradually loses its end cells with their receptors, and becomes estrogen receptor negative. Now it grows even in the absence of estrogen. This process is known as de-differentiation.
Tamoxifen selectively inhibits the effects of estrogen on breast tissue, provided it has estrogen receptors, otherwise it is much less effective. Khoshnoud et al (1) studied the long-term pattern of disease recurrence among in pre- and post-menopausal patients with primary breast cancer according to estrogen receptor status. The study was based on patients with an operable, invasive breast cancer entered in one of three controlled clinical trials conducted by the Stockholm Breast Cancer Group. They selected those 2,562 patients who had been randomly allocated between adjuvant tamoxifen and no adjuvant systemic therapy. These patients had a known estrogen receptor status. The following figures are reproduced from the published paper and will be interpreted in terms of breast tumor kinetics.
Fig.1 Cumulative incidence of events among all 2,562 patients according to ER status and randomized treatment allocation (tamoxifen or no tamoxifen)
ER positive and negative tumors represent two stages in breast tumor evolution. ER-negative tumors are less differentiated and more advanced, and do not respond to tamoxifen (Panel A). Thus the response to tamoxifen (Panel C) indicates which patients carry a more differentiated tumor.
Initially the recurrence rate of ER-positive tumors is lower than that of ER-negative (Panel B), and later on their recurrence rates coincide.
Cumulative incidence of ER-negative tumors (panel A) proceeds through two periods. An accelerated when the incidence curve is steep, and a decelerated when its slope becomes more moderate. The slope is proportional to the rate of tumor recurrence. The steeper the curve the faster tumors recur. More tumors recur during the first three years than later on. This phenomenon is known as bi-modal hazard (BMH). The cumulative incidence is a manifestation of the bi-modal hazard (BMH) and is explained elsewhere.
BMH is most pronounced in ER-negative tumors (panel A) and less in ER-positive tumors (panel B). Panel C illustrates that tamoxifen lowers the recurrence rate only in ER-positive tumors and does not affect ER-negative tumors (panel A).
Tumor growth rate
Tumor incidence is defined as recurrence of a previously hidden tumor which depends on two factors: Resolution power of tumor detecting means, and tumor growth rate. During the accelerated phase tumor grows faster and following the third year its growth rate declines. Tamoxifen slows down ER- positive tumor growth and does not affect the growth of ER-negative tumors
The tumor incidence curve indicates that treatment did not remove all tumor cells, and they continue growing. Initially faster and later on slower. Yet what about a tumor that recurs after 10 years? Did it grow that slow? Or might it rest there in a dormant state, known in cell kinetics as G-0 phase? What kept it dormant so long? It is our belief that tumor dormancy was sustained by the organism, which is discussed in other chapters of this site
In summary: Tumor recurrence rate is proportional to tumor growth rate.
1. Mahmoud R. Khoshnoud , Tommy Fornander , Hemming Johansson and Lars-Erik Rutqvist
Long-term pattern of disease recurrence among patients with early-stage breast cancer according to estrogen receptor status and use of adjuvant tamoxifen
Breast Cancer Research and Treatment Volume 107, Number 1 / January, 2008