Download Tumor response and estrogen suppression in breast cancer patients

Annals of Oncology 11: 1017-1022. 2000.
© 2000 Kluwer Academic Publishers. Printed in the Netherlands
Original article
Tumor response and estrogen suppression in breast cancer patients
treated with aromatase inhibitors
E. Bajetta,1 N. Zilembo,1 E. Bichisao,2 A. Martinetti,1 R. Buzzoni,1 P. Pozzi,1 P. Bidoli,1
L. Ferrari1 & L. Celio1
'Division of Medical Oncology Unit B, Istituto Nazionale per lo Studio e la Cura det Tumori; 2Italian Trials in Medical Oncology (1TM0) Group,
Milan, Italy
levels, with a decrease in the levels of both hormones irrespective of any antitumor response. In particular, the degree of
Background: The rationale for the hormonal treatment of breast plasma estrogen suppression was similar in the patients who
cancer (BC) is based on depriving tumor cells of estrogenic experienced a complete remission and those with progressive
stimulation. Aromatase inhibitors (AIs) block the conversion disease (PD).
of peripheral tissue androgens to estrogens with different levels
Conclusions: The plasma estrogen suppression induced by
of potency. In an attempt to investigate the relationship be- aromatase inhibition is not the only mechanism accounting for
tween tumor response and estrogen suppression, we reviewed its clinical activity. Many clinical trials have demonstrated that
the hormonal and clinical data of two previous studies with all AIs induce a similar antitumor response regardless of their
formestane (250 and 500 mg i.m. fortnightly) in advanced BC potency, and further investigations are warranted in order to
patients.
improve our understanding as to why the patients with PD also
Patients and methods: Two hundred four BC patients were show a significant plasma estrogen suppression. It is possible
selected on the basis of the availability of records concerning that intratumoral aromatase activity may be a marker for
their plasma estrone (El) and estradiol (E2) levels assessed at selecting the BC patients most likely to respond to AI treatscheduled times. The degree of estrogen suppression and the ment.
best clinical response of each patient during the trials were
considered.
Results: There was a positive and significant (P < 0.05) Key words: aromatase inhibitors, tumour response, plasma
correlation between baseline and post-formestane El and E2 estrogen suppression
Summary
Introduction
Although the ovarian production of steroids declines
in postmenopausal women, the peripheral synthesis of
estrogens increases in fat, muscle and liver tissues, and
thus becomes the major contributor to circulating
estrogen levels.
It is widely accepted that at least one-third of breast
cancer tumors in women is induced and sustained by
estrogens, and so the rationale for hormonal treatment
is based on depriving tumor cells of estrogenic stimulation. There are currently two main pharmacological
approaches towards reducing the effects of estrogens on
tumor cells: the administration of antiestrogens (such as
tamoxifen) that interact with estrogen receptors inside
the tumor, or the use of aromatase inhibitors that block
the conversion of androgens to estrogens in peripheral
tissues [1, 2].
The aromatase inhibitors have varying degrees of
potency in inhibiting in vivo aromatisation [3, 4]. Jones
et al. [5] demonstrated that formestane inhibits peripheral
aromatase activity by 85%-92%, but Geisier et al. [6]
have more recently shown that exemestane suppresses
aromatisation by 98%, which is the same level of suppression induced by anastrozole and letrozole [7, 8].
Furthermore, it is known that there is a consistency
between the degree of aromatisation and plasma estrogen suppression, although the detection limits of the
assay make it difficult to assess plasma estrogen levels
in postmenopausal women [9].
In any case, no direct relationship between clinical
response and plasma estrogen levels during aromatase
inhibitor treatment has yet been demonstrated [4], and
there is no evidence that greater potency leads to a better
clinical response in breast cancer patients. In fact, the
clinical results of recent multicentre clinical trials of
steroidal and non-steroidal aromatase inhibitors have
shown that both are more active than megestrol acetate,
but there is no difference between them in terms of
antitumor activity and tolerability [10-14]; consequently
no aromatase inhibitor can be considered the drug of
choice [15, 16]. There are no published data directly
comparing the activity of the new aromatase inhibitors
with each other, and only letrozole [17] and vorozole [18]
1018
have been shown to be more active than aminoglutethimide (AG). No difference in the response rate between
letrozole and AG or in the overall response rate between
vorozole and AG has been observed, and it is difficult to
understand whether the more powerful effects of letrozole on time to progression, time to treatment failure
or overall survival, or of vorozole in terms of clinical
benefit, are actually due to the fact that they are more
potent than AG.
In an attempt to investigate the relationship between
tumor response and plasma estrogen suppression, we
reviewed the hormonal and clinical data of two previous
studies with formestane in breast cancer patients.
Table 1. Antitumor response rates to aromatase inhibitors observed in
trials versus megestrol acetate (patients unassessable for antitumor
response have not been considered in this table).
CR,
Non-steroidal aromatase inhibitors
11(4)
Anastrozole 1 mg
Letrozole 2.5 mg
12(7)
Vorozole 2.5 mg
5(2)
Steroidal aromatase inhibitors
Formestane 250 mg
5(6)
8(2)
Exemestane 25 mg
PR,
SD,
PD.
22(8)
29(17)
15(7)
79(30) 151(58)
19(11) 93(53)
40(19) 130(63)
10(11)
47(13)
41(45)
149(41)
34(37)
128(35)
Abbreviations: CR - complete response; PR - partial response; SD stable disease; PD - progressive disease.
Patients and methods
In 1994 and 1997, we published two papers reporting the endocnnological and clinical results of two formestane doses (250 and 500 mg
i.m. fortnightly) randomly given to postmenopausal advanced breast
cancer patients.
Patient selection
The first study [19] involved 143 patients pre-treated for advanced
disease (72 receiving 250 mg; and 71 receiving 500 mg), and the second
study [20] 152 patients at first relapse (73 on 250 mg and 79 on 500 mg)
Briefly, the eligibility criteria of each study were an age of < 80
years, postmenopausal status, measurable disease, a positive or unknown estrogen receptor status (in the latter case, a disease-free
interval of more than 2 years was required), and a performance status
<2 (ECOG scale). In agreement with the guidelines of the local
Bio-Ethics Committee, all of the patients gave their informed consent
before starting treatment according to the rules in force at the time.
Detailed information concerning all of the patients is available in the
original publications.
For the present analysis, the patients were selected on the following
basis:
• clinical response (patients were not considered if they had
progressed before the first evaluation);
• the availability of estrogen values (E2 levels in the first study; E2
and El levels in the second).
Hormonal measurements
The plasma estrogen levels were considered separately and not pooled,
because each study used a different analytical method.
In the first study, plasma E2 levels were measured by means of
RI A, in the second plasma E2 and El levels were evaluated using a new
method consisting of solid phase extraction followed by RIA. The
estrogen assays in each study were repeated in order to confirm the
results. Detailed information concerning the analytical methods is
available in the original publications.
As both studies demonstrated that the maximum suppression of
plasma estrogens induced by formestane was reached after an average
of 15 days of treatment, and that there was no significant decrease
thereafter, we have here considered only the baseline levels and those
measured after 12 (first study) or 10 weeks (second study), when the
first tumor response evaluations were made.
Tumor response
Tumor response was evaluated in both trials according to UICC
criteria by means of physical examinations, bone scans, chest and
skeletal X-rays, and liver echography or computed tomography. These
examinations were performed at the beginning of each study, after 12
(first study) or 10 weeks (second study), and then every 12 weeks.
Statistical analysis
Spearman's correlation coefficient (r) between the baseline and posttreatment plasma E2 and El levels was calculated. The plasma estrogen suppression and best clinical response of each patient during the
trials were considered, strictly following the response criteria used in
each trial.
The data are reported as median or mean values (±SD or SEM),
together with their 95% confidence limits (95% CI). A /"-value of 0.05
was considered significant for evaluating differences.
Results
This analysis involved a total 204 breast cancer patients.
Ninety-one patients with a median age offifty-nineyears
(range 45-75) were selected from the first study on the
basis of the availability of plasma E2 levels: forty-eight
patients received formestane 250 mg and forty-three
formestane 500 mg.
In the case of the second study, 113 patients with a
median age of 62 years (range 38-80), were selected on
the basis of the availability of plasma E2 levels (51
patients received formestane 250 mg and 62 formestane
500 mg), and 110 patients with a median age of 62 years
(range 38-80) were selected on the basis of the availability
of plasma El levels (53 patients received formestane
250 mg and 57 formestane 500 mg).
Plasma estrogen suppression
A significant (P < 0.05) positive correlation was found
between the baseline and post-treatment El and E2
levels (first study: E2 r - 0.73 and 0.62 for 250 and 500
mg, respectively; second study: E2 r - 0.34 and 0.54 for
250 and 500 mg, respectively, El /• = 0.40 and 0.69).
Although the correlation coefficients are not very high,
they confirm the pharmacological efficacy of formestane
and are in agreement with the previously reported results
analysed by means of ANOVA for repeated measure-
1019
Table 2 First study: E2 (pg/ml) suppression (mean values ± SD and
95% CI) and clinical response, by formestane dose.
500 mg
250 mg
No.
CR
6
PR
8
SD
4
PD
30
Baseline
250 mg group
Twelve
weeks
7.3 ±3.5 4.3 ± 2.4
(4.4-10.1) (2.4-6.2)
5.7 ± 1.7 2.8 ±0.9
(4.5-6.8) (2.2-3.4)
4.3 ±0.8 2.5 ±0.9
(3.5-5.1) (1 6-3 4)
5.6 ± 1.8 3.6 ± 1.3
(4.9-6.3) (3.2-4.1)
No.
Baseline
a
Twelve
weeks
8
7.2 ±3.6
13
(4.7-9.7)
6.1 ±2.4
(4.8-7.3)
3.3 ±0.9
(2.6-4.0)
3.5± 1.1
(2.9-4.1)
2.6
(-)
3
(-)
5.9 ±1.9
(5.0-6.7)
2.9 + 0.9
(2.5-3.2)
1
21
7
_J
6
1.
3
2
500 mg group
Table 3. Second study: E2 (pg/ml) suppression (mean values ± SD and
95% Cl) and clinical response, by formestane dose.
250 mg
No.
Baseline
500 mg
Ten
No.
Baseline
weeks
CR
8
PR
7
SD
23
PD
13
7.7 ±3.4
(5.3-10 0)
5.8 ± 1.6
(4.6-7-0)
6.2 ±3.1
(4.9-7.5)
6.4 ± 1 9
(5.3-7.4)
5.1 ±5.2
(1.5-8.7)
3.3 ± 1.8
(1.9-4.7)
3 6±2.8
(2.4-4.7)
2.8 ±0.8
(2.4-3 3)
Ten
weeks
11
15
23
13
6.3 ±2.5
(4.8-7.8)
9.4 ± 6.4
(6.1-12.6)
6.4 + 2.7
(5.3-7.5)
5.2 ± 2.4
(3.8-6.5)
2.6±1.2
(1 9-3.4)
3.713.0
(2.2-5 2)
2.2 ±0.8
(1.8-2.5)
2.1 ±0.7
(1.7-2.4)
Table 4 Second study: El (pg/ml) suppression (mean values ± SD and
95% CI) and clinical response, by formestane dose.
250 mg
500 mg
weeks
- Complete Response
- Progression
Figure 1. First study: E2 suppression in patients with CR and PD
(mean 1 SEM).
more effective than the 250 mg dose, but this difference
was not statistically significant.
No. Baseline
Ten weeks
No. Baseline
Ten weeks
Table 3 shows the mean E2 values after 10 weeks of
CR
8 41.4 ± 14.9 27.3 1 17.9 10 33.0 ±11.0 19.2 ±4.3
treatment with formestane 250 mg in patients achieving
(31.0-51.8) (14.9-39.8)
(22.0-44.0) (16.3-22.0) a complete response (CR), and deserves some comments.
PR
7 35.2 ± 11.4 20 6 ±4.9
15 42.4 ±23.9 25.71 13.6
The mean values at baseline and after 10 weeks were
(26.7-43.6) (16.9-24.3)
(30.2-54.4) (18.9-32.6)
respectively 7.7(± 3.4) and 5.1(±5.2) pg/ml: the high
SD
24 33.8 ± 13.9 22.218.7
20 36.9113.5 21.618.2
(30.9-42.8) (17.9-25.1) standard deviation is due to the fact that one patient
(28.3-39.4) (18.7-25.7)
PD
14 36.6 ±8.9 19.3 ±7.3
12 28.3 112.2 17.717.6
(aged 63 years) had 6.6 pg/ml at baseline and 17.5 pg/ml
(21.3-35.2) (13.4-22.1) after treatment. Similarly, a 53-year-old patient with
(31.9-41.3) (15.5-23.1)
stable disease experienced an increase from 8.3 pg/ml
to 13.8 pg/ml.
Table 4 shows the mean (± SD and 95% CI) El levels
ments. It is likely that between-patient variability accounts for this low correlation rate, which suggests that observed in the second study; there was a significant
baseline estrogen values are poor predictors of plasma suppression of plasma El levels in both treatment
groups, and the formestane doses seem to be equally
estrogen suppression.
effective.
Figures 1 and 2 show the direct comparison between
Clinical response according to plasma estrogen
suppression
the degree of plasma E2 suppression in the patients
achieving CR and in those experiencing progressive
Tables 2 and 3 show the clinical response according to disease (PD), which was chosen because CR and PD
the mean E2 levels (±SD and 95% CI) observed at should be the most reliable antitumor responses. The
baseline and after 12 (first study) and 10 weeks (second degree and trend of plasma estrogen suppression in these
study). Plasma estrogen suppression was significant in two groups of patients was similar regardless of the
all of the treatment groups; the 500 mg dose seems to be response.
1020
250 mg group
weeks
500 mg group
weeks
- Complete Response
- Progression
Figure 2 Second study: E2 suppression in patients with CR and PD
(mean ± SEM).
It is worth noting that (as shown in Table 2), the
baseline E2 levels are lower in the CR than in the PD
patients. However, the number of patients with CR is
smaller, and so no direct comparison can be made;
when the number of patients with CR and PD increases
(as shown in Table 3), the E2 levels become more similar.
Furthermore, given the range of SEM in Figures 1 and 2,
it is clear that baseline estrogen levels are not different
between the two patient groups.
Discussion
Our analysis shows that the suppression of plasma
estrogens is not the only mechanism responsible for the
antitumor response induced by formestane, a finding
that is in line with the clinical evidence that all aromatase inhibitors are equally useful in the treatment of
advanced breast cancer patients (Table 1), regardless of
their suppressive potency. A comparison of the endocrine effects of formestane (steroidal) and anastrozole
(non-steroidal) has recently been made in 60 postmenopausal advanced breast cancer patients [21]. Anastrozole
led to a significantly greater mean suppression of E2
levels (P - 0.0001) than formestane (79% vs. 58%), and
a similar result was observed in the case of El and E1S.
The curve of estrogen suppression induced by formestane was similar to that previously reported in the
literature [5,19, 22], and there are still some concerns as
to the optimal dose to be used in clinical practice. The
antitumor response rate was no different between the
two treatment groups (17% and 10%, P = 0.482 ns), and
clearly demonstrates that both agents are effective despite the difference in the degree of plasma estrogen
suppression, as the authors themselves pointed out:
"The clinical significance of these differences in total
oestrogen suppression remains to be established."
The baseline estrogen levels considered in our analysis
do not appear to predict clinical response, as is also
clearly demonstrated by the results of two clinical trials
designed to identify the optimal dose of exemestane
[23, 24].
The key problem is why some breast cancer patients
do not respond to treatment with aromatase inhibitors,
despite a significant reduction in estrogen levels, and
the presence of all of the standard requirements for
hormonal treatment. It is likely that this resistance is
due to some still unidentified specific characteristics of
the tumour, and biological reasons may account for the
absence of any relationship between clinical response
and estrogen suppression.
Experimental models have demonstrated [25] that
tumor cells can adapt themselves to very low estrogen
levels, and so even a high degree of estrogen suppression
may be inadequate because the stimulation induced by
the residual low levels could lead to resistance over time.
Furthermore, peripheral tissues are not the only source
of estrogens in postmenopausal women because breast
cancer tissue itself is an endocrine organ. The cell concentrations of El, E2 and estrone sulphate (E1S) may be
higher than those in the circulation as a result of local
production factors, including aromatisation [26, 27],
and the synthesis of El via the estrone sulphatase and
estradiol dehydrogenase pathways may be the major
supply route of estrogen to the tumor [28]. A number
of investigations concerning intratumoral aromatase
activity are currently ongoing [29], some of which have
found that formestane [30] and vorozole [31] are capable
of significantly suppressing intratumoral aromatase
activity in breast cancer patients (by an average of
80%); however, little information is available in the case
of anastrozole [32] and letrozole [33]. It is also worth
noting that a correlation between tumor aromatase
activity and the response to AG was observed in a study
of 29 advanced breast cancer patients [34]. The tumor
aromatase values in the responders were significantly
higher than in the non-responders, with 10 of 14 patients
(71%) having values of more than 0.5 pmol ER produced/mg protein/h responding to the therapy as against
0 of 15 patients with lower values. These results have
been confirmed by another trial in which none of the five
patients with aromatase-negative tumors responded, as
against 11 of 18 patients (61%) with aromatase-positive
cancers [35]. The real significance of intratumoral aro-
1021
matase activity in breast cancer patients is still unclear,
as is the role played by aromatase inhibitors in suppressing or modulating this activity. An assay evaluating
intratumoral aromatase activity in surgically excised
breast tissue could lead to the identification of a marker
for targetting patients suitable for treatment with aromatase inhibitors (as is routinely done in the case of
estrogen receptors) especially in an adjuvant setting, and
may also help to differentiate these drugs from each
other.
In conclusion, there is evidence indicating that plasma
estrogen suppression per se is not the only mechanism
accounting for the antitumor activity of aromatase
inhibitors, and that it is not associated with tumor
response. There is a need to be able to target responsive
breast cancer patients in order to ensure a higher rate
of disease control, and avoid the use of aromatase
inhibitors in unsuitable patients. The routine assessment
of intratumoral aromatase activity by means of a specific assay could be an interesting challenge for the future.
12.
13.
14.
15.
16.
17.
Acknowledgements
18.
The authors would like to thank the Scientific Service of
the Italian Trials in Medical Oncology (ITMO) Group
for its editorial assistance.
19.
20.
References
1. Brodie AMH, Njar VCO. Aromatase inhibitors and breast
cancer. Semin Oncol 1996; 23: 10-20.
2. Buzdar AU, Plourde PV. Hortobagyi GN. Aromatase inhibitors
in metastatic breast cancer. Semin Oncol 1996; 23: 28-32.
3. Lonning PE. Aromatase inhibition for breast cancer treatment.
Acta Oncol 1996; 35: 38-43.
4. Dowsett M. Biological background to aromatase inhibition.
Breast 1996; 5: 196-201.
5. Jones AL. Mac Neill F, Jacobs S et al. The influence of intramuscular 4-hydroxyandrostenedione on peripheral aromatisation
in breast cancer patients. Eur J Cancer 1992; 28A: 1712-6.
6. Geisler J, King N, Anker G et al. In vivo inhibition of aromatization by exemestane, a novel irreversible aromatase inhibitor, in
postmenopausal breast cancer patients. Clin Cancer Res 1998; 4:
2089-93.
7 Geisler J, King N. Dowsett M et al. Influence of anastrozole
(Arimidex), a selective, non-steroidal aromatase inhibitor, on in
vivo aromatisation and plasma oestrogen levels in post-menopausal women with breast cancer. Br J Cancer 1996; 74: 1286-91.
8. Dowsett M, Jones A, Johnston SRD et al. In vivo measurement of
aromatase inhibition by letrozole (CGS 20267) in postmenopausal patients with breast cancer. Clin Cancer Res 1995; 1:
1511-5.
9. Lonning PE. Pharmacology of new aromatase inhibitors. Breast
1996; 5: 202-8.
10. Buzdar A, Jonat W, Howell A et al. Anastrozole, a potent and
selective aromatase inhibitor, versus megestrol acetate in postmenopausal women with advanced breast cancer: Results of an
overview analysis of two phase III trials. J Clin Oncol 1996; 14:
2000-11.
11. Dombernowsky P, Smith I, Falkson G et al. Letrozole, a new oral
aromatase inhibitor for advanced breast cancer: Double-blind
randomized trial showing a dose effect and improved efficacy and
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
tolerability compared with megestrol acetate. J Clin Oncol 1998.
16: 453-61.
Thurlimann B, Castiglione M, Hsu-Schmitz SF et al. Formestane
versus megestrol acetate in postmenopausal breast cancer patients after failure of tamoxifen: A phase III prospective randomised cross over trial of second-line hormonal treatment (SAKK
20/90), Eur J Cancer 1997; 33: 1017-24.
Goss PE, Winer EP, Tannock IF. Schwartz LH. Randomized
phase III trial comparing the new potent and selective thirdgeneration aromatase inhibitor vorozole with megestrol acetate
in postmenopausal advanced breast cancer patients. North America Vorozole Study Group. J Clin Oncol 1999: 17: 52-63.
Kaufmann M, Bajetta E, Dirix LYet al. Exemestane is superior
to megestrol acetate after tamoxifen failure in postmenopausal
women with advanced breast cancer: Results of a phase III
randomized double blind trial. J Clin Oncol 2000; 18. 1399-411.
Castiglione-Gertsch M. New aromatase inhibitors: More selectivity, less toxicity, unfortunately, the same activity. Eur J Cancer
1996, 32A: 393-5.
Hamilton A, Piccart M. The third-generation non-steroidal aromatase inhibitors: A review of their clinical benefits in the secondline hormonal treatment of advanced breast cancer. Ann Oncol
1999; 10: 377-84.
Gershanovich M, Chaudri HA, Campos D et al. Letrozole, a new
oral aromatase inhibitor. Randomised trial comparing 2.5 mg
daily, 0.5 mg daily and aminoglutethimide in postmenopausal
women with advanced breast cancer. Ann Oncol 1998; 9: 639-45.
Bergh J, Bonneterre J, Illiger HJ et al. Vorozole (Rivizor®) versus
aminoglutethimide (AG) in the treatment of postmenopausal
breast cancer relapsing after tamoxifen. Proc ASCO 1997; 16:
155a (Abstr 543).
Bajetta E, Zilembo N, Buzzoni R et al. Endocrinological and
clinical evaluation of two doses of formestane in advanced breast
cancer. Br J Cancer 1994, 70: 145-50.
Bajetta E, Zilembo N, Barni S et al. A multicentre, randomized,
pharmacokinetic, endocrine and clinical study in breast cancer
patients at first relapse: Endocrine and clinical results. Ann Oncol
1997; 8- 649-54.
Vorobiof DA, Kleeberg UR, Perez-Carrion R et al. A randomized, open, parallel-group trial to compare the endocrine effects
of oral anastrozole (Arimidex®) with intramuscular formestane
in postmenopausal women with advanced breast cancer. Ann
Oncol 1999; 10: 1219-25.
Coombes RC, Huges SWM, Dowsett M. 4-hydroxyandrostenedione: A new treatment for postmenopausal patients with breast
cancer. Eur J Cancer 1992, 28A: 1941-5.
Zilembo N, Noberasco C, Bajetta E et al. Endocrinological and
clinical evaluation of exemestane, a new steroidal aromatase
inhibitor. Br J Cancer 1995; 72: 1007-12.
Bajetta E, Zilembo N, Noberasco C ct al. The minimal effective
exemestane dose for endocrine activity in advanced breast cancer.
Eur J Cancer 1997; 33: 587-91.
Masamura S, Santner SJ. Heitjan DF, Santen RJ. Estrogen deprivation causes estradiol hypersensitivity in human breast cancer
cell. J Clin Endocrinol Metab 1995; 80: 2918-25.
Pasqualini JR, Chetrite G, Blacker C. Feinstein MC et al.
Concentrations of estrone, estradiol and estrone sulphate, and
evaluation of sulphatase and aromatase activities in pre- and
postmenopausal breast cancer patients. J Clin Endocrinol Metab
1996; 81; 1460-4.
Blankenstein MA, van de Ven J, Maitimu-Smeele I, Donker GH
et al. Intratumoral levels of estrogens in breast cancer. J Steroid
Biochem Mol Biol 1999; 69: 293-7.
Purhoit A, Wang DY, Ghilchik MW, Reed MJ. Regulation of
aromatase sulphatase in breast tumor cells. J Endocrinol 1996;
150: S65-71.
Miller WR, Mullen P, Telford J, Dixon JM. Clinical importance
of intratumoral aromatase. Breast Cancer Res Treat 1998; 49:
S27-32.
Reed MJ, Aherne GW. Ghilchik MW et al. Concentrations of
1022
31.
32.
33.
34.
estrone and 4-hydroxyandrostenedione in malignant and normal
breast tissue. Int J Cancer 1991, 49: 562-5.
de Jong PC, van de Ven J, Nortier HW et al. Inhibition of breast
cancer tissue aromatase activity and estrogen concentrations by
1
b
'
the third-generation aromatase inhibitor vorozole. Cancer Res
1997; 57: 2109-11.
Geisler J, Bernsten H, Ottestad L et al. Neoadjuvant treatment
with anastrozole (Anmidex) causes profound suppression of
intra-tumor estrogen levels. ProcASCO 1999; 18: 82a (Abstr 311).
Brodie A, Lu Q, Yue Wet al. Intratumoral aromatase model: The
effects of letrozole (CGS 20 267). Breast Cancer Res Treat 1998;
49 (Suppl 1): S23-6.
Bezwoda WR, Mansoor N, Dansey R. Correlation of breast
tumor aromatase activity and response to aromatase inhibition
with aminoglutethimide. Oncology 1987; 44: 345-9.
35. Miller WR, O'Neill J. The importance of local synthesis of estrogen within the breast. Steroids 1987; 50: 537-48.
„
•.,-,.,
. -,r>™
, -.-• •
->n™
Received 17 March 2000: accepted 27 June 2000.
Correspondence to.
E. Bajetta, MD
Division of Medical Oncology Unit B
Istituto Nazionale per lo Studio e la Cura dei Tumori
via Venezian 1
20133 Milano
Italy
E-mail' [email protected]