Vol.

4, 2089-2093, September 1998 Clinical Cancer Research 2089

In Vivo Inhibition of Aromatization by Exemestane, a Novel

Irreversible Aromatase Inhibitor, in Postmenopausal
Breast Cancer Patients1

Jfirgen Geisler, Nick King, Gun Anker, ation aromatase inhibitor AG3 has been used for breast cancer
Giorgio Ornati, Enrico Di Salle, treatment for more than two decades (1). Because of substantial
side effects associated with AG treatment, several new aro-
Per Eystein L#{248}nning,2 and Mitch Dowsett
matase inhibitors have been introduced in clinical trials.
Department of Oncology, Haukeland University Hospital, N-502l
Aromatase inhibitors can be divided into two major classes
Bergen, Norway [J. G., G. A., P. E. L.]; Academic Department of
Biochemistry, Royal Marsden Hospital, London, SW3 6JJ, United of compounds, steroidal and nonsteroidal drugs. Nonsteroidal
Kingdom [N. K., M. D.]; and Department of Experimental aromatase inhibitors include AG and the imidazole/triazole
Endocrinology, Pharmacia and Upjohn, 20014 Nerviano, Italy [G. 0., compounds. With the exception of testololactone, a testosterone
E. D. S.]
derivative (2), steroidal aromatase inhibitors are all derivatives
of A, the natural substrate for the aromatase enzyme (3).
The second generation steroidal aromatase inhibitor, 4-
ABSTRACT
hydroxyandrostenedione (4-OHA, formestane), was found to
The effect ofexemestane (6-methylenandrosta-1,4-
inhibit peripheral aromatization by -85% when administered
diene-3,17-dione) 25 mg p.o. once daily on in vivo aromati-
by the i.m. route at a dosage of 250 mg every 2 weeks as
zation was studied in 10 postmenopausal women with ad-
recommended (4) but only by 50-70% (5) when administered
vanced breast cancer. Aromatization was determined before
p.o. Thus, a major disadvantage with this drug is that it has to be
treatment and after 6-8 weeks on therapy by administering
administered by the i.m. route to maximize its pharmacological
a bolus injection of [3lllandrostenedione (500 aCl) and
effect (6).
[‘4C]estrone (5 pCi) followed by measurement of the isotope
Exemestane (6-methylenandrosta-l,4-diene-3,17-dione) is
ratio of urinary estrogens after high-performance liquid
a third generation steroidal aromatase inhibitor developed for
chromatography purification. In addition, plasma endoge-
oral administration. Treatment with exemestane given p.o. has
nous estrogens were measured with highly sensitive radio-
been shown to be well tolerated, and chronic treatment was
immunoassays after separation with high-performance liq-
found to suppress plasma estrogen levels by about 85-95%
wd chromatography. Treatment with exemestane
when the drug was administered at a dose of 10 mg o.d. (7).
suppressed whole body aromatization from a mean pretreat-
Although this suggests exemestane to be a potent aromatase
ment value of 2.059% to 0.042% (mean suppression of
inhibitor, direct measurement of in vivo aromatase inhibition
97.9%). Plasma levels of estrone, estradiol, and estrone sal-
during treatment with exemestane has not been conducted thus
fate were found to be suppressed by 94.5%, 92.2%, and
far.
93.2%, respectively. This is the first study revealing near
In the present study, we measured in vivo aromatization
total aromatase inhibition in vivo with the use of a steroidal
before and during treatment with exemestane (25 mg o.d. by the
aromatase inhibitor. The observation that exemestane is a
oral route) by administering radiolabeled bolus injections of
highly potent aromatase inhibitor, together with the fact
[3H]androstenedione and [‘4C]estrone followed by determina-
that the drug is administered p.o. and causes limited side
tion of the isotope ratio in urinary estrogens. In addition, plasma
effects, suggests that exemestane is a promising new drug for
levels of E1, B2, and E1S were determined before and during
the treatment of hormone sensitive breast cancer.
treatment with exemestane.

INTRODUCTION PATIENTS AND METHODS

Aromatase inhibition is a well-established therapeutic op- Patients. Postmenopausal women suffering from locally
tion in postmenopausal breast cancer patients. The first gener- advanced or metastatic breast cancer failing on tamoxifen were
eligible and were treated as part of a larger multicenter, Phase II
study evaluating the clinical effects of exemestane 25 mg o.d.
The associated biochemical study presented here was approved
by the regional ethical committee, and the patients gave their
Received 12/30/97; revised 6/9/98; accepted 6/10/98.
written informed consent in addition to their consent for enroll-
The costs of publication of this article were defrayed in part by the
payment of page charges. This article must therefore be hereby marked
advertisement in accordance with 18 U.S.C. Section 1734 solely to
indicate this fact.
I Supported by the Norwegian Cancer Society. J. G. is a research fellow
of the Norwegian Cancer Society. 3 The abbreviations used are: AG, aminoglutethimide; o.d., once daily;
2 To whom requests for reprints should be addressed, at Department of E1, estrone; B2, estradiol; E3, estriol; E1S, estrone sulfate; A, andro-
Oncology, Haukeland University Hospital, N-5021 Bergen, Norway. stenedione; HPLC, high-performance liquid chromatography; CI, con-
Phone: 47-55-97-20-10; Fax: 47-55-97-20-46. fidence interval; RIA, radioimmunoassay; SBS, substrate binding site.

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Research.
2090 Aromatase Inhibition with Exemestane

ment in the clinical study. Previous treatment was terminated at Table 1 Influence of treatment with exemestane on percentage of
least 4 weeks before commencing treatment with exemestane, peripheral aromatization
and no other anticancer treatment was allowed during the study Patient Pretreatment” Exemestane” % suppression
period. A total number of 11 patients was enrolled in the I 2.095 0.174 91.7
biochemical study. 2 2.596 0.063 97.6
Study Protocol. Whole body aromatization was meas- 3 1.399 0.028 98.0
4 1.174 0.042 96.4
ured before treatment with exemestane and after 6 to 8 weeks on
5 1.531 0.051 96.7
treatment (8, 9). Exemestane was administered by the oral route 6 4.462 0.032 >99.1
at a dose of 25 mg o.d. The patients received their first dose of 7 1.445 0.015 99.0
exemestane after the completion of the first urine collection 8 3.989 0.028 >99.1
period. 9 1.893 0.091 95.2
10 2.052 0.020 99.0
Measurement of Whole Body Aromatization. Aroma-
tization of A to E1 can be measured in vivo by either adminis- Ge o. mean” 2.059 0.042 97.9
CI (1.498-2.829) (0.025-0.071) (96.3-98.8)
tration of a steady-state infusion or a bolus injection of A and E1
a Percentage of aromatization.
labeled with different isotopes followed by determination of the
b ceo. mean, geometric mean value.
isotope ratio in plasma estrogens or urinary estrogens, respec-
tively. In this study, we used a HPLC technique to measure the
isotope ratio in urinary estrogens after a bolus injection of
[3H]androstenedione (500 pCi) and [‘4C]estrone (5 p.Ci) dis-
solved in 50 ml of saline containing 8% ethanol (w/w; Ref. 8). graphic system used for the purification of the steroids. The

Aliquots of the isotopes in the injection mixture were taken to intra-assay coefficient of variation was < 10% for each estrogen.
calculate the 3H: “C ratio. Urine was collected for a period of Statistical Methods. Previous studies by our group have
96 h, pooled, and kept frozen (-20#{176}C) until processing. A shown plasma estrogen levels in postmenopausal women to be
recent assessment of the sensitivity of this method revealed that log-normal distributed (13). Thus, plasma estrogen levels as

inhibition of whole body aromatization up to 99.1% is detects- well as aromatization levels obtained before and during treat-

ble (10). ment with exemestane are given as their geometric mean value
with 95% CI of the mean. For estrogen levels below the sensi-
Hormone Measurements. Blood samples for hormone
measurements were obtained immediately before the radiotracer tivity limit of the assays, the sensitivity limit was used for
injections administered on day -4 and after 6-8 weeks on statistical analysis.
treatment with exemestane. After an overnight fast, the blood
samples were collected between 8 and 10 a.m. before intake of RESULTS
the drug. Plasma was separated by centrifugation and stored at The percentage of aromatase inhibition could not be eval-
-20#{176}Cuntil processing. Each plasma estrogen (E1, E2, and E1S) uated in one patient (patient 1 1). This patient received her
was measured by RIAs after HPLC purification according to proper tracer dose, but although radioactivity was recovered
methods currently developed in the laboratory of Di Salle et al. from the crude urine samples in both test situations, little radio-
(7) to avoid possible nonspecific interactions that have been activity (‘4C and 3H) was recovered from the purified estrogen
suspected in earlier reports of estrogen suppression with cx- fractions in the second test situation. Repeated measurements
emestane therapy (7, 1 1, 12). The detection limits for E1, E2, and suggested that the reason for the low amount of radioactivity in
E3S were 6.7, 2.6, and 22.2 pmol/liter, respectively. The results the urinary E1 and E3 fractions in this particular patient could
obtained were corrected for mean recovery, which was deter- not be due to technical flaws. A major estrogen metabolite in the
mined by passing 3H-labeled steroids through the chromato- urine is 2-hydroxyestrone (14). Enhanced 2-hydroxylation,

Table 2 Influen cc of treatmen t with exeme stane on plasma estrogen leve ls (pmol/liter)

E1 B2 E1S

Patient Pretreat.” Exemestane % supp. Pretreat. Exemestane % supp. Pretreat. Exemestane % supp.
1 272.0 12.2 95.5 50.7 <2.6 >94.9 1824 178 90.3
2 125.8 7.0 94.4 26.1 <2.6 >90.1 1380 115 91.7
3 152.8 7.4 95.2 43.3 4.4 89.8 1554 130 91.7
4 94.0 <6.7 >92.9 24.2 <2.6 >89.4 662 63 90.5
6 142.5 1 1.5 91.9 26.1 <2.6 >90.1 781 63 91.9
7 174.3 8.9 94.9 27.5 <2.6 >90.7 1410 70 95.0
8 112.1 10.7 90.4 68.6 <2.6 >96.3 1166 48 95.9
9 407.4 11.8 97.1 76.7 2.9 96.2 5501 233 95.8
10 141.0 <6.7 >95.3 17.6 <2.6 >85.4 662 44 93.3
Geo. mean 162.4 8.9 94.5 35.6 2.8 92.2 1320 89 93.2
CI 114.5-230.5 7.3-10.9 92.8-95.8 24.1-52.7 2.4-3.2 88.7-94.7 798-2181 57-141 91.2-94.8
a itret., pretreatment value; % supp., percentage of suppression from baseline; Geo. mean, geometric mean value.

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Research.
 Clinical Cancer Research 2091

second test situation, which left 10 patients evaluable for the

A
NADPH, 2 NADP determination of in vivo aromatase inhibition (Table 1). One of
these patients (patient 5) had plasma E2 levels below the detec-
tion limit and an E1 level close to the detection limit in the
pretreatment situation, which left nine patients for the assess-
ment of plasma E1, E2, and E1S suppression (Table 2).
The percentage of total body aromatization was 2.059%
A.ROMATASE before the initiation of treatment (geometric mean value; 95%
COMPLEX CI, 1.498-2.829) and fell to a mean value of 0.042% (95% CI.
0.025-0.071) during treatment with exemestane. This corre-
sponds to an aromatase inhibition of 97.9% (geometric mean
value; 95% CI, 96.3-98.8). Thus, all but 1 of the patients
experienced a suppression of total body aromatization by
>95%, and 5 of 10 patients experienced suppression by at least

B 98%.
NADPH, 02 NADP The influence of exemestane therapy on plasma estrogen
levels is shown in Table 2. Plasma E2 was suppressed from a
mean level of 35.6 pmollliter (95% CI, 24. 1-52.7 pmollliter)
before treatment to a mean of 2.8 pmollliter (95% CI, 2.4-3.2
EXEMESTANE pmol/liter) during exemestane therapy, whereas plasma levels of
E1 fell from a mean pretreatment value of 162.4 pmollliter (95%
CI, 1 14.5-230.5 pmollliter) to 8.9 pmol/liter (95% CI, 7.3-10.9
pmol/liter) during treatment with exemestane. In addition,
plasma levels of E1S fell from a mean level of 1320 pmol/liter
(95% CI, 798-2181 pmollliter) before treatment to 89 pmol/liter
(95% CI, 57-141 pmol/liter). Accordingly, treatment with ex-
emestane decreased plasma levels of E1, E,, and E1S by mean
values of 94.5% (95% CI, 92.8-95.8%), 92.2% (95% CI, 88.7-
C 94.7%), and 93.2% (95% CI, 91.2-94.8%), respectively. Corn-
NADPH, 02
paring the percentage of plasma estrogen suppression with the
percentage of aromatase inhibition in individual patients re-

I EM
vealed 0.403 :S R 0.477 for all of the three plasma estrogens.

LETROZOLE
DISCUSSION
The present trial reveals for the first time near total in vito
aromatase inhibition by an aromatase inhibitor belonging to the
NCCCNCN
steroidal class. Administered at a dose of 25 mg o.d. by the oral
route (the dose currently recommended for clinical use), we
found exemestane to inhibit aromatization by a mean of 97.9%
in breast cancer patients. This aromatase inhibition is signifi-
cantly better than that reported for the second generation steroi-
Fig. 1 Mechanisms of action of steroidal (Type-I) and nonsteroidal
(Type-Il)aromatase inhibitors at the aromatase complex. A, A occupies
dal aromatase inhibitor, formestane (4), and testololactone (2),
the SBS. B, the steroidal aromatase inhibitor exemestane occupies the the only other steroidal aromatase inhibitors for which in vito
SBS and excludes A. Heme activity is required for the suicide inhibition aromatase inhibition has been determined. The findings also
(inactivation) of the enzyme. The 6-methylene group of exemestane reveal exemestane to be pharmacologically more effective than
probably sticks into one ofthe hydrophobic pockets (HP). C, the triazole
first and second generation nonsteroidal inhibitors like AG (1),
group of the nonsteroidal aromatase inhibitor letrozole coordinates the iron
atom of the heme, occupies part of the SBS, and reversibly excludes A. rogletimide (17), and fadrozole (18) at their clinically used
doses. The extent of whole body aromatase inhibition found
during treatment with exemestane is comparable to what has
recently been found for anastrozole and close to that found for
which may be caused by, among other factors, dietary corn- letrozole, two highly potent arornatase inhibitors belonging to
pounds (15), will increase the synthesis of this metabolite (and the triazole class (10, 19). Although the degree of aromatase
other catechol estrogens also) with a similar drop in the excre- inhibition achieved with these drugs has not been compared in
don of other estrogen metabolites. Because no antioxidant was randomized trials, all of these results were obtained in the same
added to our solvent systems, all catechol estrogens would be laboratory within a limited time frame, which suggests that these
destroyed during the purification procedures (16). Thus, one results may be reliably compared.
possible explanation for the finding of little E1 and E3 could be Plasma estrogen measurements in patients on exemestane
enhanced production of catechol estrogens in this patient in her treatment require HPLC purification before RIA analysis (7).

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2092 Aromatase Inhibition with Exemestane

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 Clinical Cancer Research 2093

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In vivo inhibition of aromatization by exemestane, a novel
irreversible aromatase inhibitor, in postmenopausal breast
cancer patients.
J Geisler, N King, G Anker, et al.

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