Trial Information

Estrogen Priming to Increase the Efficacy of Standard Adjuvant Chemotherapy in Operable Breast Cancer.

Results from a recent clinical study (1) show that tamoxifen administered concurrently with
chemotherapy reduces the efficacy of the latter in patients with estrogen and/or
progesterone receptor positive breast cancer. Tamoxifen exerts its anti-tumour efficacy in
breast cancer primarily by its anti-estrogenic effect on the breast tissue. Anti-estrogenic
effects of tamoxifen are mediated by competitive inhibition of the estrogen receptor,
resulting in reduced transcription of estrogen-regulated genes (2). This results in blockade
of cell cycle transit in G1 phase and inhibition of tumour growth. This mechanism of action
might be the theoretical basis of the negative effect of concomitantly administered
tamoxifen on the efficacy of adjuvant chemotherapy and could be explained thus: Most human
solid tumours grow (and regress) following Gompertzian kinetics rather than the exponential
one (3). The fundamental difference between Gompertzian and exponential models is that the
growth fraction of the tumour (the fraction of cells in cell cycle) decreases with tumour
growth in the former whereas in the latter it remains constant. Since many chemotherapeutic
agents cause cell kill only in the fraction that is in cell cycle, this is used to explain
(partly) the failure of chemotherapy in large tumours. Since tamoxifen also causes cell
cycle arrest (in G1) and decreases the growth fraction, it could also impair the effects of
chemotherapy in an analogous fashion. This is the result seen in this randomized trial.

The fraction of cells in cycle in breast cancer is low (5 to 10%) as determined by thymidine
labeling index (4). Since most chemotherapeutic agents act preferentially or exclusively on
cycling tumor cells, it is theoretically and intuitively appealing to increase the fraction
of cycling cells to enhance the efficacy of chemotherapy. One way to do it in breast cancer
would be to administer estrogen, which is known to enhance the proliferation of breast
cancer cells. Weichselbaum et al (5) demonstrated that low concentrations of estradiol (10-9
M) increased the fraction of cells in S-phase and enhanced the rate of cell proliferation in
estrogen receptor positive MCF-7 breast cancer cell line. The cell kill of this cell line on
exposure to cytosine arabinoside was enhanced. Others have shown that even estrogen receptor
negative tumors have increased cell proliferation in response to estrogenic stimuli (6).
This has been explained partly as a result of modulation of the kinetic response of cancer
cells to other growth factors (7,8). There have been a number of randomized studies in
literature to test the concept of kinetic recruitment of breast cancer cells by estrogens to
increase the efficacy of chemotherapy (9-14). All these studies have used
diethylstilbesterol (DES) for few days before standard chemotherapy for breast cancer to
recruit cells into cycle and all these studies have been in patients with locally advanced
(LABC) or metastatic breast cancer (MBC). The results of these studies have largely been
negative. In the trial by Baldine et al (14) in LABC patients there was no difference in the
response rates between DES-CAF and CAF arms (56% Vs 63%) and no difference in the overall
(47 Vs 49 months) and progression free (21 Vs 24 months) survival. DES-CAF was found to be
more myelotoxic compared to CAF alone, which resulted in reduced dose intensity in the
former. In the trial by Conte et al (13) patients of MBC were randomized to DES-CEF versus
CEF alone. Again, there was no difference in the response rages (49% Vs 57%) and overall
survival (20 Vs 17 months) in between DES-CEF and CEF, the former being more myelotoxic. In
the trial by Ingle et al (12) in MBC patients, the response to DES-CMF was higher (39% Vs
25%, p=0.06) compared to CMF alone but there was no difference in time to disease
progression or survival. In the study by Paridaens et al (11) in LABC and MBC patients,
ethinyl-estradiol plus CAF was compared to CAF. There was no difference in response rates,
time to progression or survival in the two groups. Toxicities were also similar.

To summarize, the results of estrogenic recruitment in patients with LABC or MBC have been
negative with respect to survival but some studies have shown a trend towards higher
response rates in the recruitment arm. There are two possible explanations for these
negative results. All these studies have been in metastatic or locally advance breast cancer
patients. It is possible that the fraction of cells with inherent chemoresistance is higher
in these patients compared to early stage patients and this would negate any beneficial
effect of cell recruitment into cycle. Secondly, the total trial size has been small (less
than 260) in all these studies and therefore they were grossly underpowered to detect
meaningful differences between the two groups.

As a direct corollary of the negative effect of tamoxifen administered concomitantly with
chemotherapy and the proven ability of estrogens to increase the proliferating fraction in
breast cancer cells, we hypothesize a beneficial effect of estrogen priming on the efficacy
of standard adjuvant chemotherapy in operable breast cancer. Since the effect is
hypothesized on micrometastasis, it is likely that chemoresistance will be a lesser or no
impediment.

Thus in a manner that is inverse to tamoxifen, estradiol could `prime’ the tumour for
subsequent chemotherapy. Since only operable breast cancer patients who have undergone
surgery and need adjuvant chemotherapy will be the test population, the estradiol priming
will theoretically act on micrometastases that chemotherapy seeks to eradicate.