North Wales Cancer Network
THE USE OF HORMONE THERAPY
FOR BREAST CANCER
Revised 03/07/06
1
CONTENTS:
ADJUVANT HORMONE THERAPY................................................................ 3
THE USE OF TAMOXIFEN ............................................................................. 3
THE USE OF AROMATASE INHIBITORS ...................................................... 3
AROMATASE INHIBITORS IN NEWLY DIAGNOSED PATIENTS WHO ARE
POST-MENOPAUSAL .................................................................................... 4
THE USE OF AROMATASE INHIBITORS FOLLOWING 2-3 YEARS OF
TAMOXIFEN .................................................................................................... 5
THE USE OF AROMATASE INHIBITORS FOLLOWING 5 YEARS OF
TAMOXIFEN9. ................................................................................................. 6
PRIMARY HORMONE THERAPY................................................................... 7
DELAY OF SURGERY FOR PERSONAL REASONS .................................... 7
FIRST LINE RELAPSE THERAPY ................................................................. 8
TAMOXIFEN FAILURE/INTOLERANCE IN PREMENOPAUSAL WOMEN ... 9
HORMONE REPLACEMENT THERAPY (HRT) AND AROMATASE
INHIBITORS .................................................................................................... 9
MALE BREAST CANCER AND HORMONE THERAPY ................................ 9
FOLLOW-UP AND HORMONE THERAPY ..................................................... 9
SUMMARY OF GUIDANCE ON THE USE OF HORMONE THERAPY ........ 11
HORMONE THERAPY TREATMENT MATRIX FOR .................................... 12
OESTROGEN RECEPTOR POSITIVE BREAST CANCER .......................... 12
APPLICATION FOR FUNDING FOR A NON-FORMULARY ONCOLOGY
DRUG/REGIMEN........................................................................................... 13
Revised 03/07/06
2
ADJUVANT HORMONE THERAPY
Women with oestrogen-receptor-positive tumours should be
offered hormone treatment. The exception is for small grade
one, node negative tumours (T1 NO MO) where the absolute
survival benefit of hormone therapy is 1% or less.
Adjuvant hormonal therapy produces significantly better outcomes
in women with oestrogen-receptor-positive tumours. There is no
evidence of benefit to patients who are ER/PR negative.
Oestrogen receptor (ER) status should be measured for all women
prior to discussion of adjuvant therapy.
THE USE OF TAMOXIFEN
Tamoxifen is a well established effective drug which reduces the risk
of relapse from breast cancer by 47% and the risk of death by 26%
in ER positive patients.¹
The last Oxford overview reviewed data on 35,874 ER positive
patients; these data continue to mature and show benefit at 15
years follow up. New data on the benefit of other therapies needs
to be reviewed with this in mind, as the true benefit of a therapy
may take many years to emerge.
Pre-menopausal women should have tamoxifen at a dose of
20 mg a day for at least 5 years. This remains the gold
standard for pre-menopausal women.
Tamoxifen improves recurrence-free and overall survival in all age
groups.
1
No benefit has been shown with tamoxifen in women with
oestrogen-receptor-negative tumours.
There is no evidence to support the continued use of tamoxifen
after five years. Prolonged use of tamoxifen does increase the risk
of endometrial cancer²
THE USE OF AROMATASE INHIBITORS
There has been considerable interest on data from the recent large
randomised looking at the use of aromatase inhibitors as adjuvant
therapy in ER positive post-menopausal women.
Early Breast Cancer Trialists’ Collaborative Group. Tamoxifen for early breast cancer: an
overview of the randomised trials. Lancet 351; 1451-1467, 1998
1
Revised 03/07/06
3
Aromatase inhibitors are not appropriate for pre-menopausal
women.
Aromatase inhibitors can be considered as adjuvant therapy for
post-menopausal women.
It may be appropriate to use these as the only adjuvant therapy;
following 2-3 years of tamoxifen; or as prolonged sequential
therapy following 5 years of tamoxifen.
The trials considered included the MA-17 study³, the ATAC4 study,
the Intergroup Exemestane study, ABCSCG 8 study and the ARNO
955 study. Factors considered in determining guidance included
overall survival, disease free survival, the incidence of distant and
local recurrence and contralateral primary tumours.
When considering aromatase inhibitors a discussion with the patient
regarding absolute benefit, balanced with potential side effects
should take place.
Side effects reported with Al include increase in the number of
fractures due to osteoporosis, arthralgia and myalgia and potential
cardiac problems. There are however fewer incidences of
gynaecological side effects and thromboembolic events than with
tamoxifen.
All clinicians prescribing adjuvant therapy should have
access to Adjuvant! Online in the multidisciplinary meeting
and in the clinic to give a prediction of absolute benefit.
2
AROMATASE INHIBITORS IN NEWLY DIAGNOSED
PATIENTS WHO ARE POST-MENOPAUSAL
The ATAC study (6186 patients) and the BIG1-98 study (8010
patients) were reviewed to form guidance on the use of anastrozole
or letrozole in place of tamoxifen.
Letrozole is not yet licensed in this setting; anastrozole is currently
licensed in this setting where there is tamoxifen intolerance or
tamoxifen is contraindicated.6
2
Royal College of Radiologists Clinical Oncology Information Network (COIN Breast Cancer
Working Group). Guidelines on the Non-surgical Management of Breast Cancer. Royal College of
Radiologists, 1999
3 Goss PE, Ingle JN, Martino S et al. A randomized trial of letrozole in postmenopausal women after
five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med 349: 1793-1802
4 Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of
postmenopausal women with early stage breast cancer. Cancer Nov, 2003, 98(9): 1802-1810
5 Jakesz R, Kaufmann M, Gnant M et al. Benefits of switching postmenopausal women with hormone
sensitive early breast cancer to anastrozole after 2 years adjuvant tamoxifen: combined results from
3,123 women enrolled in the ABCSG 8 and the ARN095 trial. Br Ca Res and Treatment 2004:88
(suppl 1):S7 Abs 2
Revised 03/07/06
4
The ATAC study to date has not shown an overall survival benefit7.
It has shown a benefit in disease free survival, the absolute benefit
being 3.7%, with reduced distant and local recurrence and reduced
numbers of contralateral primary tumours.
The BIG 1-98 has not shown a survival benefit but the data is not
yet mature. Improved disease free surgical is shown with a current
absolute benefit of 2.6%, again with reduced distant and local
recurrence and decreased incidence of contralateral primaries. This
study does however show potential cardiac problems with a higher
incidence of MI and CVA in the letrozole group.
Aromatase inhibitors are not recommended for routine use in this
situation. Anastrozole may be considered where an additional
disease free survival benefit of 5% or above over tamoxifen therapy
is identified by Adjuvant! Online and/or per the indications of the
pharmaceutical licence. The use of letrozole is not yet supported by
mature data and is not yet licencesed for this situation.
THE USE OF AROMATASE INHIBITORS FOLLOWING
2-3 YEARS OF TAMOXIFEN
The Intergroup Exemestane study (IES)8 and ABCSG 5&* were
reviewed to identify if sequential use of exemestane or anastrozole
following 2-3 years of tamoxifen could be recommended.
The IES (4742 patients) switched patients to exemestane following
2-3 years of tamoxifen and has to date not shown a survival
benefit. It has shown significant disease free survival, with a
reduction in distant and local recurrence and contralateral
primaries. To date there is an encouraging absolute benefit of
4.7%.
3
6 Scottish Medicines Consortium, NHS Scotland, Medicines advice no 90/04 Anastrozole 8 th February
2004
7 ATAC trialists’ Group. Results of the ATAC trial after completion of 5 years’ adjuvant therapy for
breast cancer. Lancet 2005: 465:60-62
8 R C Commbes et al. A randomised trial of Exemestane after two to three years of Tamoxifen therapy
in post menopausal women with a primary breast cancer. New Eng J Med 2004, 350(11): 1081-1092
9 Scottish Medicines Consortium, NHS Scotland, Medicines advice no 152/05 Letrozole 2.5mg Tablets
4th February 2005.
Revised 03/07/06
5
The side effects of this therapy included an increased incidence of
osteoporosis, arthralgia and increased cardiac events. The cardiac
complications are as yet undefined, but patients with a history of
cardiac disease may need to be assessed prior to using this regime.
The ABCSG 5 & 8 (3123 patients when combined) switched patients
to anastrozole following 2 years of tamoxifen and has not shown a
survival benefit to date. This has also shown a disease free benefit
with reduced distant and local recurrence and contralateral
primaries. To date there is an absolute benefit of 3%.
Currently there is either not enough evidence or appropriate
licences to recommend a routine switch to aromatase
inhibitor from tamoxifen at 2-3 years.
It would be reasonable to switch where there is tamoxifen
intolerance or at patients request, following a discussion of the
potential side effects.
This guidance will be reviewed in …………………………………….
THE USE OF AROMATASE INHIBITORS FOLLOWING
5 YEARS OF TAMOXIFEN9.
The MA17 study (5178 patients) was reviewed to determine if
extended adjuvant therapy with letrozole could be recommended.
This study has not to date shown an overall survival benefit in all
subgroups. However in an unplanned sub-group analysis a survival
benefit was seen in node positive patients. There is a reduction in
distant and local recurrence and contralateral primaries.
The side effects recorded included osteoporosis, arthralgia, muscle
aches and hot flushes, but were small numbers.
Letrozole is currently licensed in this setting for all sub-groups.
It is recommended the letrozole is used following 4.5-6 years
of previous tamoxifen therapy where Adjuvant! Online has
shown an absolute survival benefit to the patient of above or
equal to 5%. Letrozole should then be prescribed for 5
years.
It tamoxifen therapy has been ceased Letrozole can be commenced
within 3 months of ceasing tamoxifen therapy.
Revised 03/07/06
6
PRIMARY HORMONE THERAPY
Primary hormone therapy is not a substitute for the established
methods of surgery and radiotherapy, and should only be used firstline if the patient is very infirm or refuses surgery. Surgery with or
without radiotherapy remains the treatment of choice for the
majority of elderly patients.
The indications for primary hormone therapy are:

Selected postmenopausal ER positive patients with operable
breast cancer >4 cm size who express a strong desire to
avoid masectomy, and in whom primary chemotherapy is
considered unsuitable.

Patients with any tumour who are truly unfit for surgery or
primary chemotherapy.

Patients who refuse surgery and in whom primary
chemotherapy is considered unsuitable.

Patients with T4 breast cancer and in whom primary
chemotherapy is considered unsuitable.
Tamoxifen therapy produces a partial response in 75% of elderly
patients with oestrogen-receptor-positive breast cancer. Complete
pathological responses are rare, and tamoxifen alone controls
disease in less than 30% of elderly patients at five years15.
It is recommended that aromatase inhibitors are used in the
first instance as these have proven to be more effective than
tamoxifen16 17
Letrozole is the only licensed aromatase inhibitor in this setting.
The IMPACT trial is as yet unpublished and is attempting to show
that anastrozole may also be effective for this group of patients.
Letrozole 2.5 mg/day should be used as first line therapy for
these groups of patients.
DELAY OF SURGERY FOR PERSONAL REASONS
Primary hormone therapy should not be given routinely prior to
surgical treatment. Tamoxifen increases thrombo–embolytic risk,
and interferes with the mechanism of action of chemotherapy.
Revised 03/07/06
7
However there are occasions when surgical treatment is delayed
due to patients’ circumstances. If this is to be beyond 2 months,
primary hormone therapy is appropriate if the patient if ER positive.
FIRST LINE RELAPSE THERAPY
Hormone therapy is appropriate to use when disease progression is
relatively slow and a rapid clinical response is not required. Patients
with oestrogen4
receptor-positive tumours and those with a long disease-free
interval between initial surgery and relapse are most likely to
respond to this therapy.
Patients with extensive visceral disease or rapidly progressive
disease usually require chemotherapy.
The choice of therapy needs to take into account previous hormones
prescribed as adjuvant therapy.
Patients currently on tamoxifen or who have previously completed a
course of tamoxifen should be prescribed an aromatase inhibitor,
either letrozole or anastrozole.
15 Robertson J F R, Todd J H, Ellis I O, Elston C W, Blamey R W. Comparison of mastectomy with
tamoxifen for treating elderly patients with operable breast cancer. BMJ 297: 511-514, 198
16 Phase 111 study of Letrozole versus tamoxifen as first line therapy of advanced breast cancer in
postmenopausal women: analysis of survival and update of efficacy from the International Letrozole
breast Cancer group. J Clin Onc; 21(11), 2003, 2101-2109
17 Bonneterre J, Budzar A, Nabholtz JM et al. Anastrozole is superior to tamoxifen as first line
therapy in hormone receptor advanced breast carcinoma.\Cancer 92:2247-2258, 2001
Revised 03/07/06
8
Patients who have not previously been prescribed tamoxifen
therapy should be given a licensed aromatase inhibitor; letrozole.
Relapse following the use of either letrozole or anastrozole in either
the adjuvant setting or as first line therapy, exemestane (or
tamoxifen if not previously used) should be prescribed.
TAMOXIFEN FAILURE/INTOLERANCE IN
PREMENOPAUSAL WOMEN
Relapse in premenopausal women following tamoxifen therapy can
be managed with an aromatase inhibitor such as exemestane,
anastrozole or letrozole, plus ovarian suppression by radiotherapy,
surgery or an LHRH analogue18.
Patients who have severe intolerance or tamoxifen often request an
alternative treatment. There is no data to provide a disease free
benefit in using ovarian suppression with aromatase inhibitors in the
adjuvant setting for pre menopausal women and this is not a
satisfactory alternative.
HORMONE REPLACEMENT THERAPY (HRT) AND
AROMATASE INHIBITORS
HRT, including vaginal administration, is contraindicated for patients
on aromatase inhibitors.
HRT may be appropriate for patients on tamoxifen who have low
risk of recurrence. This should be only prescribed for relief
vasomotor symptoms at the lowest possible dose for the shortest
period to relief symptoms. Topical administration is appropriate.
Decisions should be made on an individual basis, weighing the
possible increased risk of recurrence of breast cancer against the
beneficial effects on menopausal symptoms.
5
MALE BREAST CANCER AND HORMONE THERAPY
The principles of treatment should be followed in line with the
guidance for post menopausal women.
FOLLOW-UP AND HORMONE THERAPY
18 NICE Guidance. Improving Outcomes in Breast Cancer, 2002, p66
Revised 03/07/06
9
NICE guidance has suggested that patients should be discharged
from hospital based follow up after 2-3 years once active treatment
has ceased with a clear route back to the multidisciplinary team if
new problems occur19.
However patients on continuing hormone therapy are having active
treatment and should remain under specialist follow-up\is
recommended as research into hormone therapy is highly active
and guidance is subject to change.
Management of side effects such as osteoporosis also requires
monitoring.
Patients who are not attending outpatients’ clinic need to be flagged
up at 5 years to discuss hormone therapy.
6
19 NICE Guidance. Improving Outcomes in Breast Cancer, 2002, p 58-59
Revised 03/07/06
10
SUMMARY OF GUIDANCE ON THE USE
OF HORMONE THERAPY
Women with oestrogen-receptor-positive tumours should be
offered hormone treatment.
Pre-menopausal women should have tamoxifen at a dose of
20 mg a day for at least 5 years. This remains the gold
standard for pre-menopausal women.
All clinicians prescribing adjuvant therapy should have
access to Adjuvant! Online in the multidisciplinary meeting
and in the clinic to give a prediction of absolute benefit.
Aromatase inhibitors are not recommended for routine use in
newly diagnosed post menopausal patients but anastrozole
may be considered where there is an additional disease free
benefit of 5% or more over tamoxifen. (Review date October
2005).
Currently there is either not enough evidence or appropriate
licences to recommend a switch to aromatase inhibitor from
tamoxifen at 2-3 years. (Review date October 2005).
It is recommended the letrozole is used following 4.5-6 years
of previous tamoxifen therapy where Adjuvant! Online has
shown an absolute survival benefit to the patient of above or
equal to 5%. Letrozole should then be prescribed for 5
years.
Letrozole 2.5mg/day should be used as first line therapy for
patients who require primary hormone therapy.
Patients who have not previously been prescribed tamoxifen
therapy should be given a licensed aromatase inhibitor,
letrozole for first time relapse.
Relapse following the use of either letrozole or anastrozole
in either the adjuvant setting or as first line therapy,
exemestane (or tamoxifen if not previously used) should be
prescribed.
An urgent working party is needed to produce guidance on
baseline measurement, monitoring of bone density and
prophylactic therapy for patients on aromatase inhibitors.
Revised 03/07/06
11
HORMONE THERAPY TREATMENT MATRIX FOR
OESTROGEN RECEPTOR POSITIVE BREAST CANCER
This table represents a summary of guidance for the use of
hormone therapy and should be read in conjunction with the
guidelines document.
TAMOXIFEN
LETROZOLE
ANASTROZOLE
*
*
PREMENOPAUSAL WOMEN
POSTMENOPAUSAL
WOMEN FOLLOWING
DIAGNOSIS
POSTMENOPAUSAL
WOMEN AFTER 2-3 YEARS
OF TAMOXIFEN
POSTMENOPAUSAL
WOMEN AFTER 5 YEARS OF
TAMOXIFEN
PRIMARY HORMONE
THERAPY
POSTMENOPAUSAL
WOMEN
1ST LINE RELAPSE
THERAPY (PREVIOUS
TAMOXIFEN GIVEN)
1ST LINE RELAPSE
POSTMENOPAUSAL (NO
PREVIOUS TAMOXIFEN)
1ST LINE RELAPSE
PREMENOPAUSAL (NO
PREVIOUS TAMOXIFEN)
KEY: RED = RECOMMENDED, PINK = RECOMMENDED IF AN ABSOLUTE
SURVIVAL BENEFIT OF 5% OR ABOVE, GREEN = AWAITING FURTHER
DATA/LICENCE, BLUE = 5% BENEFIT ABOVE TAMOXIFEN
 In premenopausal women this may be considered alongside ovarian
ablation.
Revised 03/07/06
12
EXEMESTAN
APPLICATION FOR FUNDING FOR A
NON-FORMULARY ONCOLOGY
DRUG/REGIMEN
Complete all details
Attach protocol
Submit to Network Oncology Group
Name of drug/regimen
Patients name:
DoB
Address
LHB
Treatment site
Diagnosis
License status of drug
NICE status
Approved
not approved
this year
next year
not on programme
Approval status
elsewhere in UK
Drug cost
Additional cost
Application by
date
Approved/not approved
Revised 03/07/06
date
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