Lani
05-05-2006, 03:55 AM
Comment
Chemoprevention of breast cancer
Although the outcome from breast cancer has improved
over the past several decades, because of earlier diagnosis
and improved treatments, the best approach remains
prevention, by targeting the disease at the earliest stages
of development. Tamoxifen, a selective oestrogen-
receptor modulator (SERM), was chosen as a possible
chemopreventive for breast cancer because of the strong
rationale from laboratory models,1 the ability to prevent
contralateral breast cancers,2 and its acceptable adverse
event profi le.2 In 1998, the National Surgical Adjuvant
Breast and Bowel Project (NSABP) P-1 trial3 showed a
substantial reduction in women at high-risk for breast
cancers, who received 5 years of tamoxifen compared with
placebo. This trial was recently updated at a follow-up of
7 years4 and continues to show a signifi cant reduction in
breast cancer incidence in those women who received
tamoxifen, regardless of age, at the expense of an increase
in endometrial cancer in women older than 50 years and
of thromboembolic events. The results from three other
prevention trials,5–7 in which women at high-risk received
tamoxifen, have not showed such impressive results
for several possible reasons, such as including diff erent
risk populations. Nonetheless, an analysis combining all
the chemoprevention trials,8 shows a 38% reduction in
the incidence of breast cancer in patients treated with
tamoxifen (95% CI 28–46%). None of these trials4–7 to
date has shown improved survival with tamoxifen as a
chemopreventive. Although tamoxifen is approved in
the USA for the prevention of breast cancer in high-risk
women, it remains unclear what degree of breast cancer
risk justifi es the possible adverse events that could occur
with the use of tamoxifen in these otherwise healthy
women.
An obvious solution to the issue of risk-benefi t with
tamoxifen is the development of new agents that are
equally eff ective but with a better side-eff ect profi le.
Raloxifene is also a SERM, and has been approved
for the prevention and treatment of osteoporosis
in postmenopausal women. The incidence of breast
cancer in osteoporosis trials was substantially less
in patients treated with raloxifene compared with
placebo.9 Raloxifene, unlike tamoxifen, does not have
any oestrogen-like eff ects on the uterus in rodents,10 and
did not result in endometrial thickening in osteoporosis
trials.11 These fi ndings led to the second NSABP
prevention trial, the Study of Tamoxifen And Raloxifene
(STAR), the results of which will be available in June,
2006 (table). Unfortunately, like tamoxifen, raloxifene is
associated with an increase in thromboembolic events.9
The aromatase inhibitors are better than tamoxifen
as adjuvant treatment for early-stage breast cancer.12
All of the adjuvant trials show that aromatase inhibitors
are more eff ective than tamoxifen in preventing
contralateral breast cancers.12 Additionally, there is
no increase in endometrial cancer with aromatase
inhibitors, and thromboembolic events are less than with
tamoxifen.12 These fi ndings have led to the initiation of
two international trials, IBIS-II and MAP3, comparing
aromatase inhibitors with placebo in high-risk women
(table). However, neither raloxifene nor aromatase
inhibitors can be used because they do not suppress
oestrogen levels adequately in premenopausal patients,
who represent a substantial proportion of women
entered in tamoxifen prevention trials. In this group of
women, tamoxifen remains the chemopreventive of
choice.
Because tamoxifen acts through the oestrogen receptor,
it is not surprising that only oestrogen-receptor-positive
cancers were reduced in the tamoxifen prevention
trials, and that there was no eff ect on the incidence of
oestrogen-receptor-negative breast cancers.8 All the
agents currently in development as chemopreventives
in breast cancer act through the oestrogen receptor,
and are therefore unlikely to aff ect the incidence of
oestrogen-receptor-negative cancers. This is of particular
importance in women with BRCA1 mutations, who
develop oestrogen-receptor-negative cancers and would
be unlikely to benefi t from chemoprevention with these
agents. New agents that target other pathways involved
in carcinogenesis, such as trastuzumab or oral tyrosine
Trial Intervention Status
STAR Raloxifene 60 mg daily ×5 years
Tamoxifen 20 mg daily ×5 years
Accrued 19 000 women
IBIS II Anastrozole 1 mg daily ×5 years
Placebo daily ×5 years
Open (planned 6000 women)
MAP3
(NCIC)
Exemestane 25 mg daily ×5 years
Placebo daily ×5 years
Open (planned 5000 women)
STAR=Study of Tamoxifen and Raloxifene, IBIS=International Breast Cancer Intervention
Study, NCIC=National Cancer Institute, Canada.
Table: Ongoing breast cancer chemoprevention trials
Comment
kinase inhibitors, need to be examined in laboratory
chemopreventive models to address this issue.
The updated results of the NSABP P-1 trial confi rm
the role of tamoxifen as a chemopreventive for women
at high-risk of breast cancer. Although the benefi t of
tamoxifen exceeds possible risks in patients with breast
cancer, it remains unclear what degree of risk is appropriate
for use of tamoxifen as a chemopreventive. New agents,
with better side-eff ect profi les, are in development as
chemopreventives for oestrogen-receptor-positive breast
cancer, and it is imperative that we identify agents that
might decrease the incidence of oestrogen-receptor-
negative breast cancers. Despite the improved outcome
from breast cancer, it remains certain that an ounce of
prevention is better than a pound of cure.
Chemoprevention of breast cancer
Although the outcome from breast cancer has improved
over the past several decades, because of earlier diagnosis
and improved treatments, the best approach remains
prevention, by targeting the disease at the earliest stages
of development. Tamoxifen, a selective oestrogen-
receptor modulator (SERM), was chosen as a possible
chemopreventive for breast cancer because of the strong
rationale from laboratory models,1 the ability to prevent
contralateral breast cancers,2 and its acceptable adverse
event profi le.2 In 1998, the National Surgical Adjuvant
Breast and Bowel Project (NSABP) P-1 trial3 showed a
substantial reduction in women at high-risk for breast
cancers, who received 5 years of tamoxifen compared with
placebo. This trial was recently updated at a follow-up of
7 years4 and continues to show a signifi cant reduction in
breast cancer incidence in those women who received
tamoxifen, regardless of age, at the expense of an increase
in endometrial cancer in women older than 50 years and
of thromboembolic events. The results from three other
prevention trials,5–7 in which women at high-risk received
tamoxifen, have not showed such impressive results
for several possible reasons, such as including diff erent
risk populations. Nonetheless, an analysis combining all
the chemoprevention trials,8 shows a 38% reduction in
the incidence of breast cancer in patients treated with
tamoxifen (95% CI 28–46%). None of these trials4–7 to
date has shown improved survival with tamoxifen as a
chemopreventive. Although tamoxifen is approved in
the USA for the prevention of breast cancer in high-risk
women, it remains unclear what degree of breast cancer
risk justifi es the possible adverse events that could occur
with the use of tamoxifen in these otherwise healthy
women.
An obvious solution to the issue of risk-benefi t with
tamoxifen is the development of new agents that are
equally eff ective but with a better side-eff ect profi le.
Raloxifene is also a SERM, and has been approved
for the prevention and treatment of osteoporosis
in postmenopausal women. The incidence of breast
cancer in osteoporosis trials was substantially less
in patients treated with raloxifene compared with
placebo.9 Raloxifene, unlike tamoxifen, does not have
any oestrogen-like eff ects on the uterus in rodents,10 and
did not result in endometrial thickening in osteoporosis
trials.11 These fi ndings led to the second NSABP
prevention trial, the Study of Tamoxifen And Raloxifene
(STAR), the results of which will be available in June,
2006 (table). Unfortunately, like tamoxifen, raloxifene is
associated with an increase in thromboembolic events.9
The aromatase inhibitors are better than tamoxifen
as adjuvant treatment for early-stage breast cancer.12
All of the adjuvant trials show that aromatase inhibitors
are more eff ective than tamoxifen in preventing
contralateral breast cancers.12 Additionally, there is
no increase in endometrial cancer with aromatase
inhibitors, and thromboembolic events are less than with
tamoxifen.12 These fi ndings have led to the initiation of
two international trials, IBIS-II and MAP3, comparing
aromatase inhibitors with placebo in high-risk women
(table). However, neither raloxifene nor aromatase
inhibitors can be used because they do not suppress
oestrogen levels adequately in premenopausal patients,
who represent a substantial proportion of women
entered in tamoxifen prevention trials. In this group of
women, tamoxifen remains the chemopreventive of
choice.
Because tamoxifen acts through the oestrogen receptor,
it is not surprising that only oestrogen-receptor-positive
cancers were reduced in the tamoxifen prevention
trials, and that there was no eff ect on the incidence of
oestrogen-receptor-negative breast cancers.8 All the
agents currently in development as chemopreventives
in breast cancer act through the oestrogen receptor,
and are therefore unlikely to aff ect the incidence of
oestrogen-receptor-negative cancers. This is of particular
importance in women with BRCA1 mutations, who
develop oestrogen-receptor-negative cancers and would
be unlikely to benefi t from chemoprevention with these
agents. New agents that target other pathways involved
in carcinogenesis, such as trastuzumab or oral tyrosine
Trial Intervention Status
STAR Raloxifene 60 mg daily ×5 years
Tamoxifen 20 mg daily ×5 years
Accrued 19 000 women
IBIS II Anastrozole 1 mg daily ×5 years
Placebo daily ×5 years
Open (planned 6000 women)
MAP3
(NCIC)
Exemestane 25 mg daily ×5 years
Placebo daily ×5 years
Open (planned 5000 women)
STAR=Study of Tamoxifen and Raloxifene, IBIS=International Breast Cancer Intervention
Study, NCIC=National Cancer Institute, Canada.
Table: Ongoing breast cancer chemoprevention trials
Comment
kinase inhibitors, need to be examined in laboratory
chemopreventive models to address this issue.
The updated results of the NSABP P-1 trial confi rm
the role of tamoxifen as a chemopreventive for women
at high-risk of breast cancer. Although the benefi t of
tamoxifen exceeds possible risks in patients with breast
cancer, it remains unclear what degree of risk is appropriate
for use of tamoxifen as a chemopreventive. New agents,
with better side-eff ect profi les, are in development as
chemopreventives for oestrogen-receptor-positive breast
cancer, and it is imperative that we identify agents that
might decrease the incidence of oestrogen-receptor-
negative breast cancers. Despite the improved outcome
from breast cancer, it remains certain that an ounce of
prevention is better than a pound of cure.