Key words
pre-menopause - breast cancer - compliance - ovarian function suppression - tamoxifen
- aromatase inhibitors
Schlüsselwörter
Prämenopause - Mammakarzinom - Compliance - Ovarialsuppression - Tamoxifen - Aromatasehemmer
“Treatment can only be successful if it is actually carried out.”
Introduction
Endocrine therapy for breast cancer treatment is the oldest targeted therapy. Around
70 to 80 % of breast cancer tumours express oestrogen receptors (ORs) and/or progesterone
receptors (PRs). These hormone receptor-sensitive tumours can be treated by modifying
the endocrine milieu. Generally, this can be achieved through ablative therapy, in
which the bodyʼs own oestrogen production is suppressed. In pre-menopausal women,
this is achieved with ovarian function suppression (OFS) by means of bilateral oophorectomy,
radiation-induced ablation or chemical suppression with GnRH analogues. For ablation
in post-menopausal women without functioning ovaries, aromatase inhibitors (AIs) are
used to suppress the enzyme aromatase, which reduces the formation of oestrogen in
peripheral tissue. A second option for endocrine therapy involves selective blockade
of the hormone receptors with selective oestrogen receptor modulators (SERMs), among
which tamoxifen (TAM) is most commonly used. For pre-menopausal women, tamoxifen is
the gold standard for adjuvant endocrine therapy. Depending on the tumour biology
and risk level, chemotherapy (± anti-HER2 therapy) is sometimes administered prior
to tamoxifen treatment [1].
Historically, oophorectomy was the first somewhat regularly used endocrine adjuvant
therapy for pre-menopausal breast cancer patients. Love and Philips [2] compared oophorectomy to taking aspirin for health: “it keeps reappearing as an
effective therapy with new twists”. In fact, the significance of OFS as an adjuvant
to tamoxifen has been debated for decades. Opinions about the use of OFS have fluctuated
regularly depending on the different interpretations of the same, relatively old database.
The AGO Breast Committee Guidelines issued over the past 15 years are a good reflection
of this. Furthermore, in the past decade it was shown that for post-menopausal breast
cancer patients, AIs have some advantages over TAM. It would therefore appear to be
worthwhile to use OFS to render pre-menopausal patients post-menopausal in order for
them to benefit from the advantages of AI therapy.
The first published results of new trials (ABCSG-12, TEXT, SOFT) have fuelled this
debate and have led to considerable uncertainty about the “right” therapy [3], [4], [5], [6].
This article therefore aims to describe the clinical role of OFS today.
Oophorectomy for Breast Cancer Treatment
Oophorectomy for Breast Cancer Treatment
In 1882, long before German Nobel laureate Adolf Butenandt discovered and isolated
the female sex hormones in 1929, English physician Thomas William Nunn proposed an
association between the ovaries and breast cancer. Nunn had observed a regression
of breast cancer in a patient 6 months after she entered menopause. German surgeon
Albert Schinzinger also observed that the prognosis of breast cancer in older women
appeared to be better than for younger women and speculated that performing oophorectomy
would cause the women to age prematurely, causing the mammary gland to atrophy, along
with any breast tumour. At the 18th congress of the German Society for Surgery in
1889, Schinzinger therefore proposed surgical oophorectomy as a treatment for advanced
breast cancer and to prevent recurrence. Schinzinger, however, never performed the
surgery himself and apparently was unable to convince his fellow surgeons to use the
procedure [2].
Scottish surgeon George Thomas Beatson also considered oophorectomy as a treatment
for breast cancer, since castration was used to prevent lactation in cattle. In 1895,
Beatson performed the first bilateral oophorectomy in a breast cancer patient with
extensive recurrence and subsequently reported the patientʼs complete remission. This
constituted the first application of ablative endocrine therapy for breast cancer.
English surgeon Stanley Boyd then performed the first bilateral oophorectomy as adjuvant
breast cancer treatment in 1897. He also developed a hypothesis about the mechanisms
that appeared to be at work, which foreshadowed our current knowledge: “My working
hypothesis is that internal secretion of the ovaries in some cases favours the growth
of the cancer”. In 1900, Boyd published a summary of his cases in which he reported
that one third of the patients had clearly benefited from the procedure [2].
However, due to the very high rate of morbidity and mortality associated with the
procedure at the time, bilateral oophorectomy therapy did not become established.
It was not until the 1950s that the U. S. Nobel laureate Charles Huggins and his research
assistant Thomas Dao again brought oophorectomy, now combined with adrenalectomy,
to the focus of cancer treatment [2].
At the time, however, it was not yet possible to predict which patients would benefit
from ablative hormone therapy. Elwood Jensenʼs ground-breaking studies finally made
this possible. Jensen synthesized tritium-labelled oestradiol and in 1962, demonstrated
that in rats, the steroid was bound only to target organs for oestrogen (e.g. the
uterus) and not to tissue not sensitive to oestrogen (e.g. lung, skeletal muscle).
Based on these findings, Jensen developed the concept of an oestrogen receptor that
would mediate the effect of oestrogen in the target tissue. In 1971, he described
a predictive test that he used to determine the presence of this receptor protein
in breast cancer cytosols and reliably predict the effect of the ablative therapy
[7]. In the 1990s, the test from the cytosol was replaced by immunohistological determination
of the receptor protein and this test is still performed today [8].
In the 1960s and 1970s, several small-scale randomized trials on adjuvant OFS in pre-menopausal
breast cancer patients were conducted. The general consensus was that these trials
did not demonstrate any benefit of the therapy [2]. This opinion was not shifted until 1992, when the Early Breast Cancer Trialistsʼ
Collaborative Group (EBCTCG)’s meta-analysis of updated data from these trials was
performed, which clearly demonstrated the direct long-term benefits of adjuvant OFS.
This report and the updated analysis performed in 2005 proved that disease-free survival
(DFS) and overall survival (OS) in receptor-positive tumours were clearly improved.
However, even after Jensenʼs development of receptor determination, it still took
several decades for testing the receptor status to become established as the clinical
standard. This means that many studies on endocrine therapy for breast cancer treatment,
especially the EBCTCG meta-analyses, also include data from patients in whom the receptor
status was not determined and thus also include receptor-negative tumours [9], [10].
In the 1990s and early 2000s, several randomized trials were published that showed
that chemical OFS (with GnRH agonists) or surgical OFS in women with receptor-positive,
node-positive or node-negative tumours were at least as effective as chemotherapy
with cyclophosphamide, methotrexate and fluorouracil (CMF) or even with anthracyclines
[11], [12], [13], [14], [15]. However, no comparison has been undertaken with the third-generation chemotherapy
containing taxanes commonly administered today, which is why OFS does not constitute
an alternative to chemotherapy.
Moreover, in the meantime TAM has become established as an effective adjuvant endocrine
therapy, with or without chemotherapy.
Ovarian Failure Due to Chemotherapy
Ovarian Failure Due to Chemotherapy
In addition to its direct cytotoxic effect, adjuvant chemotherapy has an indirect
endocrine effect in pre-menopausal women with receptor-positive tumours because it
induces ovarian failure. Chemotherapy-induced amenorrhoea (CIA) favourably impacts
survival, even if it is only temporary. The incidence of CIA is dependent on the patientʼs
age and on the chemotherapy regimen. Incidence is highest among women older than 40
using alkylating agents (e.g. cyclophosphamide) [16], [17], [18].
Tamoxifen
In the 1950s and 1960s, English endocrinologist Arthur L. Walphole and his team at
ICI Pharmaceuticals worked on the development of anti-oestrogens with the aim of developing
a morning-after contraceptive pill. In 1967, they synthesized the substance ICI-46,474
(later named tamoxifen). Up to the early 1970s, the working groupʼs focus was only
on reproductive endocrinology. While TAM was unsuitable as a contraceptive, however,
it was approved for fertility treatment [7]
There were also indications of its efficacy for breast cancer treatment. However,
for various reasons, including the prevailing opinion of the time that adjuvant endocrine
therapy would not provide additional benefits for the existing range of breast cancer
treatments, in 1972 ICI decided not to further pursue the oncological potential of
ICI-46,474 [7].
Thanks to a number of coincidences, however, this potential was re-explored. A small-scale
trial with ICI-46,474 for breast cancer treatment in post-menopausal women demonstrated
efficacy and a favourable side-effect profile. Furthermore, the oncological effect
was confirmed in many animal experiments. This served as the basis for further development,
primarily advanced by the British-American physician V. Craig Jordan. As a result,
TAM developed from a failed contraceptive to a pioneer substance for targeted cancer
therapy and chemoprevention of breast cancer and was added to the World Health Organization
(WHO)’s List of Essential Medicines [7].
Numerous studies tested the effect of TAM in metastatic and early breast cancer and
demonstrated its efficacy with a good toxicity profile. The pharmacology of the SERMs
was decoded in the 1980s. In the 1990s, five-year treatment with TAM became the therapy
of choice for post-menopausal breast cancer patients [7].
However, it wasnʼt until 1998 that EBCTCGʼs meta-analysis definitely proved that several
years of adjuvant TAM therapy of patients with receptor-positive breast cancer reduced
mortality, regardless of age or menopausal status, while only 1 year of therapy is
not effective, just as treatment of receptor-negative cancer [7].
A new EBCTCG meta-analysis of randomized trials performed in 2011 showed that 5 years
of treatment with TAM reduced the recurrence rate over 10 years (by 47 % in years
1 to 4 and by 32 % in years 5 to 9). No further benefits were observed after 10 years
of treatment. The use of TAM reduced breast cancer mortality over the entire 15-year
observation period by around one third (around 29 % in years 1 to 4, around 34 % in
years 5 to 9 and around 32 % in years 10 to 14). The benefits were independent of
age, node status, tumour size or additional chemotherapy and were the same for both
post-menopausal and pre-menopausal patients. However, the therapeutic effect can only
be proven for receptor-positive tumours ([Table 1]). Major side effects were endometrial cancer and thromboembolic disease in women
older than 55. The contralateral breast cancer incidence was reduced by 50 % [19]. The effects of the adjuvant therapy with tamoxifen and chemotherapy are complementary.
According to an EBCTCG meta-analysis treatment of women younger than 50 with tamoxifen
after anthracycline-based chemotherapy reduces the 15-year mortality rate by 57 %
[10].
Table 1 Effect of 5 years of tamoxifen (TAM) therapy in patients with hormone-sensitive breast
cancer. Breast cancer mortality and overall mortality in 2 614 pre-menopausal women
(younger than 45) and in 4 373 post-menopausal women (between 55 and 69). Absolute
mortality in per cent after 5, 10 and 15 years of observation; absolute benefit and
relative risk (RR) with 95 % confidence intervals (CIs) after 15 years of observation.
In the overall group, the effect of TAM therapy was independent of the application
of chemotherapy (N+: percentage of women with node-positive tumours; chemotherapy:
percentage of women who had undergone chemotherapy) (results of the EBCTCG meta-analysis
of the randomized trials, modified after [19]).
|
Age at diagnosis
|
N+
|
Chemotherapy
|
Observation period
|
Breast cancer mortality
|
Overall mortality
|
|
Mortality in %
|
Benefits after 15 years
|
Mortality in %
|
Benefits after 15 years
|
|
Control group
|
5 years TAM
|
Absolute
|
RR (CI)
|
Control group
|
5 years TAM
|
Absolute
|
RR (CI)
|
|
< 45 years
|
44 %
|
79 %
|
5 years
|
13.4
|
10.3
|
10.6
|
0.71 (0.62–0.83)
|
13.9
|
11.0
|
11.2
|
0.71 (0.62–0.83)
|
|
10 years
|
28.0
|
21.0
|
29.0
|
22.0
|
|
15 years
|
35.9
|
25.3
|
38.1
|
26.8
|
|
55–69 years
|
27 %
|
24 %
|
5 years
|
12.6
|
8.1
|
11.7
|
0.63 (0.56–0.71)
|
15.4
|
11.1
|
9.5
|
0.78 (0.71–0.85)
|
|
10 years
|
26.4
|
16.4
|
33.0
|
23.7
|
|
15 years
|
34.9
|
23.2
|
46.4
|
36.9
|
The findings of the ATLAS trial demonstrate that no benefits are derived from TAM
therapy extended to 10 years (compared to 5 years of TAM) in the first 10 years post-diagnosis.
However, in the period after the first 10 years post-diagnosis, the recurrence rate
is 25 % lower and mortality is 29 % lower. The 10-year therapy reduces mortality in
the first 10 years by a third and in the second ten years by 50 % ([Table 2]). The effects are independent of age and menopausal status. For 10 years of therapy,
the incidence of endometrial cancer and pulmonary embolism is significantly increased,
while contralateral breast cancer and ischemic heart disease are significantly reduced.
With 10 years of TAM therapy compared to 5 years TAM therapy, absolute breast cancer
mortality drops by 3 %, while non-breast cancer mortality increases by 0.2 % [20]. In this trial, however, only 9 % of the patients were pre-menopausal. The low number
of cases most likely accounts for the fact that no statistical relevance was reached
for pre-menopausal women.
Table 2 Results of the ATLAS trial. The results are presented for 6 846 women with receptor-positive
tumours who either discontinued TAM therapy after 5 years (n = 3 418) or continued
TAM therapy for a total of 10 years (n = 3 428). The age distribution and distribution
of menopausal status are presented. The recurrence rates and breast cancer mortality
for different time periods after initiation of treatment are presented as relative
risks (95 % confidence interval). In so doing, the results of the EBCTCG meta-analysis
(5 years of TAM vs. control group) (presented after [19]), the results of the ATLAS trial (5 vs. 10 years of TAM) and the hypothetical situation
of 10 years of TAM vs. control group as an extrapolation from these two analyses are
compared.
|
Age (percentage in the groups with 10/5 years of TAM)
|
Menopausal status (percentage in the groups with 10/5 years of TAM)
|
|
< 45 years
|
45–54 years
|
55–69 years
|
≥ 70 years
|
Pre-menopausal
|
Peri-menopausal or not known
|
Post-menopausal
|
|
19/18
|
32/32
|
40/40
|
9/10
|
10/9
|
2/2
|
89/89
|
|
Risk of recurrence
|
|
Years after treatment initiation
|
5 years TAM vs. control group
|
5 vs. 10 years TAM
|
10 years TAM vs. control group
|
|
0–4 years
|
0.53 (0.48–0.57)
|
1
|
0.53 (0.48–0.57)
|
|
5–9 years
|
0.68 (0.60–0.78)
|
0.90 (0.79–1.02)
|
0.61 (0.51–0.73)
|
|
≥ 10 years
|
0.94 (0.79–1.12)
|
0.75 (0.62–0.90)
|
0.70 (0.54–0.91)
|
|
Breast cancer mortality
|
|
Years after treatment initiation
|
5 years TAM vs. control group
|
5 vs. 10 years TAM
|
10 years TAM vs. control group
|
|
0–4 years
|
0.71 (0.62–0.80)
|
1
|
0.71 (0.62–0.80)
|
|
5–9 years
|
0.66 (0.58–0.75)
|
0.97 (0.79–1.18)
|
0.64 (0.50–0.82)
|
|
≥ 10 years
|
0.73 (0.62–0.86)
|
0.71 (0.58–0.88)
|
0.52 (0.40–0.68)
|
The aTTom trial also compared 5 years of TAM therapy with 10 years of TAM therapy
and presented similar results [21]. To date, this trial has been published only in abstract form. Combining the results
of the aTTom and the ATLAS trials increases the statistical significance of the benefits
of extended treatment with TAM with respect to the rate of recurrence, breast cancer
mortality and overall mortality.
Study results also demonstrate that it is worthwhile to resume interrupted tamoxifen
therapy and to initiate tamoxifen therapy even several years after breast cancer diagnosis.
Even if tamoxifen therapy is initiated up to 5 years after diagnosis, DFS and OS benefits
are derived after 10 years. In tamoxifen therapy initiated in patients more than 5
years after diagnosis, DFS is still significantly better than in patients who have
not undergone TAM therapy [22].
OFS versus Tamoxifen
There are not enough data to make a reliable statement about the efficacy of TAM compared
to OFS in pre-menopausal women. The only trial addressing this issue included only
320 patients in whom the receptor status was not always known. This trial did not
observe any differences [23].
Aromatase Inhibitors
While in pre-menopausal women oestrogens are primarily produced in the ovaries, in
post-menopausal women, oestrogens are produced in peripheral tissue through the conversion
of other steroids by means of the enzyme aromatase. Aromatase inhibitors (AIs) suppress
this enzyme conversion. For this reason, AIs are not effective in pre-menopausal women.
In fact, the converse is true: the reduction in the peripheral oestrogen levels activates
the hypothalamic-pituitary axis. This increases gonadotropin secretion, which stimulates
the ovaries, resulting in increased oestrogen levels. This effect is helpful in reproductive
medicine [24]. For this reason, AIs are not suitable for endocrine therapy for breast cancer treatment
in pre-menopausal women.
Clinical trials on the application of AIs in adjuvant breast cancer therapy were analysed
in a current EBCTCG meta-analysis of individual patient data. These trials included
31 920 post-menopausal women with receptor-positive breast cancer. The randomized
trials compared 5 years of AIs vs. 5 years of TAM, 5 years of AIs vs. 2 to 3 years
of TAM, followed by AIs up to year 5, and compared 2 to 3 years of TAM followed by
AIs up to year 5, all compared to 5 years of TAM. The analysis showed that compared
to TAM, AIs reduced the recurrence rate by around 30 % as long as the different therapy
continued, but not thereafter. Five years of AIs reduce 10-year breast cancer mortality
by around 15 % compared with 5 years of TAM and reduce 10-year breast cancer mortality
by around 40 % compared to no endocrine therapy [25].
No differences in the efficacy of the available AIs in adjuvant therapy were observed,
although there were slight differences in the side effect profile [26], [27].
However, these data apply only to post-menopausal patients. AIs are contraindicated
in pre-menopausal women; for these patients, AI therapy may be considered only when
combined with OFS.
OFS Combined with Tamoxifen and/or Chemotherapy
OFS Combined with Tamoxifen and/or Chemotherapy
An EBCTCG meta-analysis of the randomised trials published in 2005 failed to find
evidence that ovarian function suppression or oophorectomy combined with chemotherapy
offer any benefits, apart from in women younger than 40, for whom it may possibly
be beneficial [10].
A study of over 1500 pre-menopausal high-risk patients compared the efficacy of CAF
chemotherapy alone with that of CAF + OFS (CAF-Z) and of CAF + OFS + TAM (CAF-ZT).
With a median follow-up of 9.6 years, compared to CAF-Z, CAF-ZT demonstrated improved
DFS but not OS. Adding OFS to CAF did not demonstrate any overall benefits. In an
unplanned retrospective analysis, however, women younger than 40 undergoing OFS showed
improved DFS [28].
Cuzick et al. [29] also performed a meta-analysis of individual patient data from 16 published trials
in which 11 906 pre-menopausal women (including 2884 with receptor-negative tumours;
at study begin, receptor analysis was not a standard technique, see above) had undergone
OFS. In a sub-group of 1013 women in whom TAM was compared with TAM plus OFS, no significant
differences in survival rates were observed. If this sub-group is sub-divided into
women younger than 40 and women older than 40, however, a measurable, but not statistically
significant benefit of the combination of OFS and TAM can be observed for the younger
women. In the group of patients who had undergone chemotherapy, OFS demonstrated significant
benefits for women younger than 40 regardless of adjuvant TAM therapy ([Table 3]).
Table 3 Luteinizing hormone-releasing hormone agonists in adjuvant therapy of pre-menopausal
patients with hormone receptor-positive breast cancer. Meta-analysis of individual
patient data from randomized trials (modified after [29]) (RRR: relative risk reduction, CI: 95 % confidence interval, n: number of patients,
Chemo: Chemotherapy, LHRH: ovarian function suppression with LHRH, TAM: tamoxifen).
|
Age
|
n
|
RRR
|
CI
|
p
|
|
Chemo ± LHRH
|
|
< 40 years
|
714
|
− 24.7
|
− 39.5 to 6.2
|
0.01
|
|
> 40 years
|
1 662
|
− 5.1
|
− 20.1 to 12.7
|
0.55
|
|
Chemo + TAM ± LHRH
|
|
≤ 40 years
|
81
|
− 31.2
|
− 67.5 to 46.0
|
0.33
|
|
> 40 years
|
284
|
5.3
|
− 33.3 to 66.3
|
0.82
|
|
(Chemo ± TAM) ± LHRH (combination of previous comparisons: Chemo ± LHRH and Chemo
+ TAM ± LHRH)
|
|
≤ 40 years
|
795
|
− 25.2
|
− 39.4 to − 7.7
|
0.01
|
|
> 40 years
|
284
|
− 3.9
|
− 18.1 to 12.9
|
0.63
|
These analyses coincide with the results of the EBCTCG meta-analysis and with a Cochrane
analysis [11] that show that women younger than 40 benefit from OFS combined with chemotherapy
without TAM and may benefit from OFS combined with TAM without chemotherapy.
Younger women have a lower risk of permanent CIA than older women [16], [17], [18]. This may explain why women younger than 40 are observed to benefit from OFS.
Since today the standard therapy for women with receptor-positive tumours comprises
TAM alone or following chemotherapy, the option of combining chemotherapy with OFS
is generally not considered for pre-menopausal women. However, the question as to
whether OFS in addition to TAM or in addition to TAM + chemotherapy offers significant
benefits is relevant. The meta-analyses do not answer this question.
OFS Combined with Tamoxifen or AIs
OFS Combined with Tamoxifen or AIs
CIA appears to be a good prognostic factor [16], [17]. However, to date no data have been available that demonstrate the benefits of administering
OFS after resumption of menstruation [11], [29].
The randomized SOFT and TEXT trials studied the effect of 5-year endocrine therapy
with a combination of TAM or the AI exemestane with OFS in pre-menopausal patients
with receptor-positive breast cancer [4], [5]. OFS was achieved with the GnRH agonist triptorelin or with oophorectomy or radiation
therapy to the ovaries. For the TEXT trial, 2672 patients underwent OFS combined with
either TAM or exemestane no later than 12 weeks post-surgery. The SOFT trial treated
3066 women. Stratification was undertaken according to whether adjuvant chemotherapy
was performed. Patients were included who did not undergo chemotherapy (46.7 % of
the patients) or who had remained pre-menopausal within 8 months after completion
of the chemotherapy (53.3 %). The patients were randomly allocated to 3 groups: TAM
alone, OFS + TAM, or OFS + exemestane. The combined results of the 2 trials showed
benefits for OFS only in patients whose risk was so high that chemotherapy was indicated.
The efficacy of the AI exemestane combined with OFS was superior to that of TAM combined
with OFS. The 5-year overall survival rate in the 2 trials was over 95 % in all groups.
The observation period is still too short to make a statistically valid statement
about potential differences in OS.
In a joint analysis of the TEXT and SOFT trials with 4690 patients [4] who underwent OFS, after a median observation period of 68 months, the 5-year disease-free
survival rate (DFS: no recurrence and no invasive secondary cancer of the breast or
other organs) and the breast cancer-free survival rate (BFS: no incidents of breast
cancer) in the group treated with exemestane were significantly better than in the
group treated with tamoxifen (DFS 91.1 vs. 87.3 %; hazard ratio (HR) 0.72; 95 % confidence
interval (CI) 0.60–0.85; p < 0.001; BFS 92.8 vs. 88.8 %; HR 0.66; CI 0.55–0.80; p < 0.001)
([Tables 4] and [5]).
Table 4 Ovarian function suppression plus aromatase inhibitors compared to tamoxifen with
ovarian function suppression in adjuvant therapy of pre-menopausal patients with hormone
receptor-positive breast cancer. Results of the ABCSG-12 trial (GnRH + anastrozole/tamoxifen
for 3 years) and the combined analysis of the TEXT and SOFT trials (OFS + exemestane/tamoxifen
for 5 years). In the ABCSG-12 trial, 1 803 patients were analysed and in the SOFT/TEXT
trials, 4 690 (of a total of 4 717) patients were analysed. Half the patients in the
ABCSG-12 trial also received zoledronic acid for 3 years. This group showed significantly
better DFS and non-significantly better OS than the group not receiving zoledronic
acid. For the TEXT and SOFT trials, the DFS was also reported dependent on the administration
of chemotherapy. 42.6 % of the patients did not undergo chemotherapy, while 57.4 %
underwent chemotherapy either after (TEXT) or before (SOFT) randomization (modified
after [3], [4], [5]).
|
TEXT/SOFT
|
ABCSG-12
|
|
Median follow-up
|
5.7 years
|
7.9 years
|
|
Median age
|
43 years
|
45 years
|
|
n
|
OFS + AI (%)
|
OFS + TAM (%)
|
RR (CI)
|
p
|
n
|
OFS + AI (%)
|
OFS + TAM (%)
|
RR (CI)
|
p
|
|
RR: relative risk, CI: 95 % confidence interval, DFS: disease-free survival, OS: overall
survival, OFS: ovarian function suppression, AI: aromatase inhibitor, TAM: tamoxifen,
with chemo: with chemotherapy, n: number of patients, without chemo: patients without
chemotherapy, with chemo: patients with chemotherapy
|
|
DFS
|
|
4 690
|
91.1
|
87.3
|
0.72 (0.60–0.85)
|
< 0.001
|
1 803
|
85.2
|
87.0
|
1.13 (0.88–1.45)
|
0.33
|
|
DFS without chemo
|
TEXT
|
1 053
|
96.1
|
93.0
|
0.54 (0.32–0.92)
|
|
|
|
|
|
|
|
SOFT
|
943
|
95.8
|
93.1
|
0.68 (0.38–1.19)
|
|
|
|
|
|
|
|
DFS with chemo
|
TEXT
|
1 607
|
89.8
|
84.6
|
0.69 (0.53–0.90)
|
|
|
|
|
|
|
|
SOFT
|
1 087
|
84.3
|
80.6
|
0.84 (0.62–1.13)
|
|
|
|
|
|
|
|
OS
|
|
4 690
|
95.9
|
96.9
|
1.15 (0.86–1.51)
|
0.37
|
1 803
|
94.1
|
96.3
|
1.63 (1.05–2.52)
|
0.03
|
Table 5 Survival rates after tamoxifen monotherapy compared to tamoxifen or exemestane combined
with ovarian function suppression and dependent on administration of chemotherapy.
Results of the SOFT trial. 3 066 patients were randomly allocated to 3 groups that
received either tamoxifen monotherapy, tamoxifen plus ovarian function suppression,
or exemestane plus ovarian function suppression for 5 years. 46.7 % of the patients
did not undergo chemotherapy and 53.3 % underwent chemotherapy and remained pre-menopausal
(modified after [5]).
|
SOFT
|
|
Median follow-up
|
5.7 years
|
|
Median age
|
Total: 43 years; without chemo: 46 years; with chemo: 40 years
|
|
n
|
5-year %
|
HR
|
CI
|
Significance
|
|
HR: hazard ratio, CI: 95 % confidence interval, DFS: disease-free survival, OS: overall
survival, OFS: ovarian function suppression, AI: aromatase inhibitor, TAM: tamoxifen,
with chemo: with chemotherapy, n: number of patients, ns: not significant, s: significant,
without chemo: patients without chemotherapy, with chemo: patients with chemotherapy
|
|
DFS
|
TAM
|
1 018
|
84.7
|
1
|
|
|
|
TAM + OFS
|
1 015
|
86.6
|
0.83
|
0.66–1.04
|
ns
|
|
AI + OFS
|
1 014
|
89.0
|
0.68
|
0.53–0.86
|
s
|
|
DFS without chemo
|
TAM
|
476
|
93.3
|
|
|
|
|
TAM + OFS
|
473
|
93.4
|
0.83
|
0.52–1.34
|
ns
|
|
AI + OFS
|
470
|
95.2
|
0.61
|
0.36–1.03
|
ns
|
|
DFS with chemo
|
TAM
|
542
|
77.1
|
|
|
|
|
TAM + OFS
|
542
|
80.7
|
0.82
|
0.64–1.07
|
ns
|
|
AI + OFS
|
544
|
83.8
|
0.70
|
0.53–0.92
|
s
|
|
OS
|
TAM
|
1 018
|
95.1
|
|
|
|
|
TAM + OFS
|
1 015
|
96.7
|
0.74
|
0.51–1.09
|
ns
|
|
AI + OFS
|
1 014
|
95.3
|
0.97
|
0.68–1.40
|
ns
|
|
OS without chemo
|
TAM
|
476
|
99.8
|
|
|
|
|
TAM + OFS
|
473
|
99.2
|
3.84
|
0.81–18.08
|
ns
|
|
AI + OFS
|
470
|
98.8
|
4.03
|
0.86–18.99
|
ns
|
|
OS with chemo
|
TAM
|
542
|
90.9
|
|
|
|
|
TAM + OFS
|
542
|
94.5
|
0.64
|
0.4–0.96
|
s
|
|
AI + OFS
|
544
|
92.3
|
0.87
|
0.59–1.27
|
ns
|
In the SOFT trial [5] no significant benefit of OFS in addition to TAM for 5-year DFS was observed after
67 months median observation in patients both with and without chemotherapy. (overall
group: TAM monotherapy 84.7 %; TAM plus OFS 86.6 %; HR 0.83, CI 0.66–1.04; p = 0.10;
patients with chemotherapy: TAM monotherapy 78.0 %, TAM + OFS 82.5 %; HR 0.78; CI
0.60–1.02). A significant difference was observed between TAM monotherapy and exemestane
plus OFS in the group of patients who had undergone chemotherapy due to increased
risk. The 5-year breast cancer survival rate was 85.7 % for OFS plus exemestane and
78.0 % for TAM monotherapy (HR 0.65; CI 0.49–0.87). The most obvious benefit obtained
from OFS was observed in the group of women younger than 35, 94 % of whom had undergone
chemotherapy. BFS after 5 years was 67.7 % for TAM monotherapy, 78.9 % for TAM plus
OFS, and 83.4 % for exemestane plus OFS. However, the number of cases included in
the analysis, at 233, was too low for a valid statistical statement to be made ([Tables 4] and [5]).
The ABCSG-12 trial treated 1803 pre-menopausal patients with hormone receptor-positive
breast cancer and fewer than 10 affected lymph nodes for 3 years with a combination
of GnRH analogues and the AI anastrozole or TAM. Most of the patients did not undergo
chemotherapy. After a median 94.4-month observation period, no benefits of anastrozole
for DFS were observed compared to TAM. In fact, the mortality rate for the group treated
with anastrozole was significantly higher (HR = 1.63; CI 1.05–1.45; p = 0.030) [3] ([Tables 4] and [5]).
The reason for the discrepancy between the results of ABCSG-12 and TEXT/SOFT is unclear.
In the ABCSG-12 trial, the endocrine therapy was carried out for 3 years as compared
to 5 years for the SOFT and TEXT trials. However, despite the shorter treatment period
and the relatively high risk – around one third of the patients were node-positive
with up to 9 lymph nodes affected and only 5.8 % had undergone chemotherapy – DFS
after 5 years in this trial, at 94 %, was also very high [3]. The different results cannot be explained by differences in the efficacy of the
AIs used [26], [27].
Absolute and Relative Benefits of Adjuvant Therapies
Absolute and Relative Benefits of Adjuvant Therapies
The therapeutic effects mentioned so far entail relative improvements valid for a
group of patients. For individual patients, only the absolute benefit is relevant.
The absolute benefit is derived from the mortality risk and the relative benefit.
The lower a tumourʼs risk of recurrence and mortality, the lower the individual benefit
of a therapy [6].
Side Effects and Compliance
Side Effects and Compliance
Side effects, most often in the form of menopausal symptoms are common during endocrine
therapy. The severity of the side effects varies widely from patient to patient, independent
of the oncological treatment benefit.
The oncological benefits of endocrine therapy are achieved only if compliance is high,
meaning that the patient must take the recommended dose regularly over the planned
period. The more the therapy period or the dose density deviate from the recommendations,
the lower the therapeutic effect will be. In patients whose compliance was less than
60 %, mortality increases by a factor of up to 3.6 compared to patients with full
compliance [30].
The long duration of endocrine therapy, comprising 5 to 10 years, requires a high
level of motivation on the part of the patient and makes it particularly susceptible
to early discontinuation. For this reason, the compliance reported in trials cannot
be transferred to routine treatment. In endocrine therapy trials, a relatively high
compliance level is achieved. In year 5, over two-thirds of the participants are usually
still compliant. This was shown by the IBIS-II prevention trial, for example, which
recruited healthy subjects in order to test whether an AI can prevent breast cancer
[31]. During routine treatment, this compliance level is not reached, as numerous studies
have shown. These studies report that in year 5, only around half the patients are
still undergoing the endocrine therapy [30], [32]. In addition to inadequate awareness about the value of the therapy and waning motivation,
side effects are often responsible for the patient discontinuing the therapy. While
muscle and joint pain, as well as menopausal symptoms, are typical side effects of
endocrine therapy, they are also typical symptoms of ageing. The need to explain the
reason for the symptoms makes patients attribute new symptoms to the therapy, even
if there is no causal relation. This is especially true if the package insert describes
these symptoms as possible side effects of the therapy. A current study shows that
the odds of treatment discontinuation were higher in patients who reported a greater
number of symptoms (poor sleep quality, fatigue, mood swings, anxiety, difficulty
concentrating) prior to treatment initiation. If 3 to 5 of these symptoms were already
in place prior to treatment initiation, the likelihood of the patient discontinuing
AI therapy was twice as high as for women with no more than 2 such symptoms [33].
Unfortunately, physicians apparently do not address adequately the symptoms occurring
during hormonal therapy when they counsel their patients. Comparative studies show
that patients experience side effects much more frequently and intensively than physicians
realize [34]. If they are not addressed, they cannot be treated.
For this reason, when selecting the optimal treatment, compliance during the entire
planned therapy period must be taken into consideration. No matter how effective treatment
may be, if it is discontinued early by the patient due to lack of acceptance or side
effects that cannot be treated properly, it will be less beneficial than a therapy
that is considered to be second-best in terms of study results but is in fact accepted
and carried out. It may be more worthwhile to implement a limited range of therapy
modalities with optimal patient compliance than to carry out a number of interventions
with only half-hearted compliance.
This aspect must be taken into account when translating the data from the TEXT and
SOFT trials into clinical routine.
These trials reported significant differences in the side effect rate [4], [5]. The side effects included typical menopausal symptoms such as hot flushes, sweating,
loss of libido, vaginal dryness, poor sleep quality, depression, musculoskeletal pain,
hypertension, impaired glucose tolerance and osteoporosis. Level 3 and 4 toxicity
was reported by 23.7 % of participants using tamoxifen monotherapy (SOFT trial), while
in the groups with OFS (SOFT and TEXT trials) and exemestane, it was reported by 30.5 %
of the participants and for the groups with OFS and TAM, by 29.4 % of participants.
Osteoporosis (T-score < −2.5) was diagnosed in 3.5 % of patients undergoing tamoxifen
monotherapy, in 6.4 % of patients undergoing OFS plus TAM, and in 13.2 % using OFS
plus exemestane, respectively.
The higher side effect rate associated with OFS may be accompanied by the risk of
reduced compliance. While with the combination of OFS and TAM, treatment is still
effective if one of the treatment components is discontinued, in the combination of
OFS and exemestane, discontinuing OFS stops the oncological efficacy of exemestane.
The activation of ovarian function stimulated by the AI could even be damaging. For
this reason, the benefits of OFS, which based on current analysis are limited to DFS
in women who have undergone chemotherapy, must be weighed against the higher rate
of side effects and the risk of compromised compliance.
Combined therapy with OFS and TAM and especially with OFS and exemestane should therefore
be initiated only if long-term high-quality care for the patient and a high level
of reliability on the part of the patient are absolutely guaranteed. Otherwise, the
therapy may lead to a worse prognosis rather than a better one.
AGO Breast Committee Guidelines
AGO Breast Committee Guidelines
For these reasons, the AGO Breast Committee currently recommends prudence when prescribing
OFS combined with TAM or exemestane for pre-menopausal women. It does not recommend
this therapy as the standard treatment but instead mentions it as a treatment option
on a case-by-case basis, for example, for women younger than 35 with reliable long-term
gynaecological care in whom high compliance can be anticipated and who are undergoing
chemotherapy due to a high risk of recurrence and have resumed an ovarian cycle within
6 months. For pre-menopausal women, 5-year treatment with TAM is still the gold standard.
Depending on the risk situation and the tumour biology, this treatment is carried
out after the patient has undergone chemotherapy and/or it is extended to 10 years.
If the patient becomes post-menopausal during endocrine therapy, the sequence with
an AI also makes sense ([Figs. 1] and [2]) [35].
Fig. 1 Guidelines of the AGO Breast Committee on tamoxifen and ovarian function suppression
in adjuvant therapy of pre-menopausal women with hormone-sensitive breast cancer (OFS:
ovarian function suppression, LoE: level of evidence, GR: grade of recommendation
according to Oxford guidelines, AGO: recommendation of the AGO Breast Committee) [35].
Fig. 2 Guidelines of the AGO Breast Committee on adjuvant endocrine therapy and chemotherapy
of pre-menopausal women with hormone-sensitive breast cancer (LoE: level of evidence,
GR: grade of recommendation according to Oxford guidelines, AGO: recommendation of
the AGO Breast Committee) [35].
