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272 SURGICAL FOUNDATIONS: ESSENTIALS OF BREAST SURGERY
shows agonist activity in some tissues on binding to ERa, has no agonistic activity when it
interacts with ERb. In addition, the partial agonist activity of tamoxifen that is manifest
through ERa can be completely abolished on
coexpression of ERb. When coexpressed in
tumor cells, ERb functions as a transdominant
inhibitor of ERa transcriptional activity at subsaturating hormone levels and decreases overall cellular sensitivity to estradiol.
Tamoxifen
Tamoxifen is the most studied hormonal therapy
for breast cancer and the most widely prescribed
anticancer drug in the world (Box 17–4). Tamoxifen is given at a dose of 20 mg/day for 5 years.
Trials of higher doses (30 or 40 mg/day) have
not demonstrated any increased benefit. Several trials have looked at varying durations. At
least four trials have demonstrated a significant
improvement in outcome with 5 years as compared to 2 years of tamoxifen therapy. However,
taking tamoxifen for longer than 5 years is
controversial. Twoof three trials, a National Surgical and Adjuvant Breast Project (NSABP) trial and
a Scottish trial, suggest that taking tamoxifen for
longer than 5 years may be associated with a
worse outcome. The incidence of endometrial
cancer appeared to double in women who took
tamoxifen for longer than 5 years (2.1% versus
1.1%). One of the three trials, an Eastern Cooperative Oncology Group (ECOG) trial, suggests that
prolonged treatment with tamoxifen may
improve relapse-free survival and possibly overall
survival (OS). Longer-term follow-up is pending;
however, recent studies have suggested that the
sequential administration of aromatase inhibitors
after 5 years of tamoxifen may be optimal
therapy.
Benefits of Tamoxifen in the Adjuvant Setting
Relapse and Mortality
As with chemotherapy, it is worth bypassing a
lengthy discussion of the individual trials and
moving straight to the data from the EBCTCG.
The 1998 overview demonstrated a 47% proportional reduction in recurrence and a 27%
improvement in mortality rates over a 10-year
period (Table 17–1). The 2000 update of the
BOX 17–4 ANTIHORMONAL THERAPIES IN BREAST CANCER
Drug Mechanism Setting Side Effects Risks
Tamoxifen
(Nolvadex)
Toremifene
(Fareston)
Fulvestrant
(Faslodex)
Letrozole
(Femara)
Anastrozole
Exemestane
(Aromasin)
Goserelin
(Zoladex)
Leuprolide
(Lupron)
Megestrol
acetate
(Megace)
Selective estrogen
receptor modulator
Selective estrogen
receptor modulator
Eliminates estrogen
receptor
Inhibit aromatase
and block
nonovarian
production of
estrogen
(Arimidex)
Aromatase
inactivator
Blocks ovarian
production of
estrogen.
Progesterone
analog
Adjuvant or
metastatic
Metastatic
Metastatic Hot flashes, nausea, or
Adjuvant or
metastatic
Adjuvant or
metastatic
Metastatic Headache, nausea,
Fatigue, hot flashes,
vaginal discharge, mood
swings, headache, skin
rash, nausea, and fluid
retention/weight gain
fatigue
Joint stiffness, bone, and
joint pain, nausea,
headache, and fluid
retention/weight gain
Hot flashes and
menopause symptoms.
dizziness, SOB, hot
flashes, insomnia, and
weight gain
Thromboembolic
Osteoporosis
Osteoporosis
Thromboembolic
events, uterine
cancer, and
cataracts
events and allergic
reactions
27317—PRINCIPLES OF ADJUVANT HORMONAL THERAPY
TABLE 17–1Annual Percentage Risk
Reduction with 5 Years of Tamoxifen
from the Early Breast Cancer Trialists
Collaborative Group Overview
Relapse Death
Overall 42 322 4
Hormonal
status
Lymph nodes Positive
Chemotherapy 52 847 9
Age <50
ER positive
ER unknown
ER negative
Negative
50 to 59
60 to 69
>70
50 4
37 8
6 11
43 4
49 4
45 8
37 6
54 5
54 13
28 5
21 9
3 11
28 6
25 5
32 10
11 8
33 6
34 13
EBCTCG database now shows that these benefits extend to 15 years.
The studies included trials of 1, 2, and 5 years
of tamoxifen and showed a highly significant
trend toward greater effect with longer duration
of therapy. The EBCTCG was not able to examine duration longer than 5 years, but the data
from the aforementioned studies address this
issue.The data also includedabout 8000patients
who were included in these studies but were ER
negativeor low risk.These patients clearly derive
no benefit from adjuvant tamoxifen.
Is there one group that benefits from tamoxifen more than others? No. The relative benefit
of tamoxifen was similar for patients who were
both node positive and node negative (although
the absolute benefit is obviously greater for
patients who are node positive) and is irrespective of age, menopausal status, and whether or
not tamoxifen is used alone or in conjunction
with chemotherapy. The data is clear that hormonal therapy is not indicated in patients who
are ER and PR negative; however, one less clear
population are those patients who are ER negative but PR positive. The overview suggests a
benefit of tamoxifen in these patients, but the
numbers are too small to be conclusive.
Beyond the reduction in relapse and death,
there are other benefits to adjuvant tamoxifen.
Tamoxifen is ass ociated with a n incre ase in bone
mineral density in postmenopausal women and
may reduce fractures. It is also associated with a
reduction inlow-densitylipoproteincholesterol.
Although it was hypothesized that tamoxifen
may reduce the risk for coronary heart disease,
and this was suggested by some individual
studies, this has not been validated. However,
one of the strongest side benefits of tamoxifen
is the prevention of new breast cancers. In the
1995 EBCTCG review, tamoxifen reduced the
incidence of new contralateral breast cancer by
46%. This is similar to what was seen in the
NSABP P-01 prevention trial (see Chapter 8).
Risks of Tamoxifen
Although the risk-to-benefit ratio for tamoxifen
is greatly in its favor, the drug is notwithout risks
and side effects. Tamoxifen is associated with an
increased incidence of hot flashes, vaginal discharge, and night sweats. Sexual dysfunction is
not a common complaint, although it may correlate with vaginaldryness. In addition tomenopause symptoms, there is an increased risk of
tamoxifen inducing menopause in premenopausal women, although this is restricted to
women 45 years or older and is in part related
to the normal aging process. Several studieshave
shown that despite these symptoms, quality of
life in women undergoing therapy with tamoxifen is not significantly worse than women
receiving placebo. Tamoxifen has also been
associated with ocular toxicities, specifically corneal changes and retinopathy. For this reason,
it has been recommended that women consider a baseline ophthalmic evaluation during
the first year of initiating tamoxifen and have
appropriate follow-up.
Thromboembolic disease is a worrisome risk
of tamoxifen because these can lead to fatal
consequences. This appears to affect less than
1% of patients and is more common in women
over the age of 50.
The most significant risk of tamoxifen appears
to be that of uterine cancer. Most of these cases
consist of adenocarcinoma of the endometrium,
although a small percentage of reported cases of
uterine cancers consist of uterine sarcoma, a rare
and aggressive form of uterine cancer. Half of
these cases are mixed mullerian tumors, which
have been linked to estrogen use and carry
a worse prognosis. In the prevention trial of
tamoxifen, the incidence of endometrial adenocarcinoma was 2.2 per 1000 woman-years for
women on tamoxifen (and with an intact uterus)
compared with 0.71 per 100 woman-years for
placebo. For sarcomas, the incidence was 0.17
compared with 0. Routine screening with transvaginal ultrasound or endometrial biopsy is not
useful and thus not recommended. Instead,
women should be counseled about the need to
alert their physician for abnormal vaginal bleeding and undergo regulargynecologic evaluations.
274 SURGICAL FOUNDATIONS: ESSENTIALS OF BREAST SURGERY
Raloxifene
Raloxifene (Evista) resulted from efforts to
design SERMs that have estrogen activity in
bone and cardiovascular tissue but not in the
reproductive tissues, for the purpose of lowering the risk of osteoporotic fractures. They
have been found to have similar effect to
tamoxifen on the chemoprevention of breast
cancer. This was incidentally discovered in a
trial of raloxifene or placebo in over 7700 postmenopausal women with osteoporosis. With
4 years of follow-up, there was an 84% relative
reduction in the incidence of ER-positive
breast cancer. This data prompted the Study
of Tamoxifen and Raloxifene (STAR) trial,
which randomized postmenopausal women
who are high risk for the development of
breast cancer to receive either tamoxifen or raloxifene. The initial results of STAR show that
the drug raloxifene is as effective as tamoxifen
in reducing the breast cancer risk of the
women on the trial. In STAR, both drugs
reduced the risk of developing invasive breast
cancer by about 50% (see Chapter 8). However, raloxifene has never been studied in the
adjuvant setting, and its effect on known
breast cancer remains unknown. Thus it is
not recommended for the adjuvant therapy
of breast cancer in postmenopausal women.
Aromatase Inhibitors
Although tamoxifenhas had tremendoussuccess
in the treatment of hormone-receptor-positive
breast cancer, it is not without problems. As a
partial estrogen agonist it has several potentially
serious side effects and tamoxifen resistance
poses a significant problem for clinicians. The
introduction of aromatase inhibitors (AIs) has
changed the scope of adjuvant hormonal therapy for postmenopausal women.
AIs act by inhibiting the cytochrome P450
enzyme aromatase, which is responsible for
the peripheral aromatization of androgens,
converting them to estrogens. In postmenopausal women, aromatase is primarily located
in the skeletal muscle and fat and represents
the predominant source of estrogen in the
body. AIs can either be steroidal inhibitors,
(formestane or exemestane) which are irreversible, or nonsteroidal inhibitors (anastrazole,
letrozole), which bind to a site distant to the
hormone-binding site and are reversible. AIs
do not impact the ovaries, and thus they are
only effective in postmenopausal women.
Several trials have examined AIs in the adjuvant setting (Table 17–2). Most of these trials
compared an AI to tamoxifen or placebo. Little
data has emerged comparing one AI to
another. One has to be careful in interpreting
data interchangeably for anastrozole, letrozole,
and exemestane. Likewise, findings from AI
trials in early breast cancer can only be applied
to the select group of patients in which the
trial was conducted. Further trials meant to
better define the use of AIs in the adjuvant
setting are ongoing, and the recommendations
for AI use in the adjuvant setting are likely
to continue to change over the next several
years.
Anastrozole
The Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial randomized 9366 postmenopausal women to either tamoxifen or
anastrozole or the combination of the two.
The goal of this study was not only to see
TABLE 17–2Aromatase Inhibitors in the Adjuvant Setting
Trial Groups N Median
Arimidex, Tamoxifen,
Alone or in
Combination
Italian T versus A after 2–3
MA-17 L versus placebo after
Intergroup Exemestane
Study
A, Arimidex; DFS, disease-free survial; E, exemestane; L, Letrozole; T, tamoxifen.
T versus A versus
combination
years of tamoxifen
5 years of tamoxifen
T versus E after 2–3
years of tamoxifen
9366 68 DFS: A > T 42% reduction
5187 29 DFS: L >
4742 31 DFS: E > T 56% reduction
FollowUp
426 30 DFS: A > T Study too small
DiseaseFree
Survival
placebo
Contralateral
Tumors
with A
46% reduction
with L
with E
27517—PRINCIPLES OF ADJUVANT HORMONAL THERAPY
whether Arimidex was superior to tamoxifen,
but also if the combination might be synergistic. In the most recently published results,
after a median follow-up of 68 months, anastrazole significantly prolonged disease-free
survival (DFS; hazard ratio 0.87, p ¼ 0.01).
Time to recurrence and number of distant
metastases were also significantly improved.
It will take considerably more time before
any conclusions regarding OS can be made.
Anastrozole was also superior to the combination of anastrazole and tamoxifen, and this
approach has been abandoned.
Three trials have examined the benefits of
switching to Arimidex after 2 or 3 years of
tamoxifen, including the Austrian Breast and
Colorectal Cancer Study Group (ABCSG) 8 trial,
the Arimidex-Nolvadex (ARNO) 95 trial, and
the Italian Tamoxifen Anastrazole (ITA) trial.
All three showed a benefit to switching to
anastrazole.
Finally, the PreOperative Arimidex Compared
with Tamoxifen (PROACT) and Immediate Preoperative Arimidex, Tamoxifen or Combined
with Tamoxifen (IMP ACT)trials compared preoperative treatment with anastrazole with the
preoperative treatment of tamoxifen in postmenopausal women with large hormone-receptorpositive breast cancer. In both studies, 3 months
of anastrazole appears to increase the likelihood
of breast-conserving surgery compared with
tamoxifen (43% versus 31%, combined data,
p ¼ 0.019).
Exemestane
The Intergroup Exemestane Study (IES) randomized 4742 postmenopausal women who had
completed 2 or 3 years of tamoxifen to either
continue with tamoxifen to a total of 5 years
or to switch to exemestane. At 3 years followup, switching to exemestane was associated
with a significantly improved DFS but no difference in OS. Fewer toxic effects were seen
with exemestane.
Letrozole
The MA.17 study performed by the National
Cancer Institute of Canada looked at the role
of letrozole in women who have completed 5
years of tamoxifen.Over 5000 women were randomized to placebo or letrozole after 5 years of
tamoxifen. The 4-year DFS was 93% for patients
receiving letrozole and 87% for patients receiving placebo (p < 0.001). Unfortunately, without
longer follow-up, it is unclear whether OS or
distant DFS is improved or if long-term adverse
effects may preclude the benefit.
The BIG 1-98 trial is a four-arm trial comparing 5 years of letrozole, 5 years of tamoxifen,
2 years of letrozole followed by 3 years of
tamoxifen, and 2 years of tamoxifen followed
by 3 years of letrozole. Mature data are not yet
available, although preliminary data suggest
that 5 years of letrozole may be better than 5
years of tamoxifen, with an improvement in
DFS (0.81, p < 0.001). As with the ATAC trial,
an improvement in OS has not yet been seen
and will require much longer follow-up.
Toxicity of Aromatase Inhibitors
The AIs have a considerably different side
effect profile than SERMs. Because anastrazole,
letrozole, and exemestane have different structures and pharmacokinetic profiles, it cannot
be assumed they will all have the same safety
profiles. However, long-term data (beyond 5
years) is available only for anastrazole and
head-to-head comparisons have not been
performed.
Gynecological events, a problem for tamoxifen, do not appear to be as much of a problem
for AIs. In the ATAC trial, anastrazole was associated with significantly fewer effects on the
endometrium, less endometrial cancer, and
reductions in hot flashes, vaginal bleeding,
and discharge compared with tamoxifen. Similar findings were reported with exemestane
and letrozole from those studies, although
not all were significant.
Another major concern of tamoxifen is the
risk of thromboembolic disease. Again, AIs
seem to have a lower risk compared to tamoxifen, as evidenced from both the ATAC trial and
BIG 1-98 trial. In the ATAC trial, there was a significant reduction of ischemic cerebrovascular
and thromboembolic events with anastrazole.
In contrast, patients on AIs will not receive
the estrogen agonist benefits of tamoxifen. This
is particularly true for the tamoxifen-induced
promotion of bone mass and protective effects
on bone. Thus AIs have a higher rate of fracture
and joint disorders. These may be minimized
by monitoring bone densities and the use of
bisphosphonates, where appropriate. Another
presumed advantage to tamoxifen is the protection against heart disease by estrogen-induced
changes in plasma lipids. However, the data is
mixed, and in some cases contradictory, as to
whether AIs confer a higher cardiac risk than
tamoxifen.
276 SURGICAL FOUNDATIONS: ESSENTIALS OF BREAST SURGERY
Adjuvant Therapy with Aromatase Inhibitors
With all this recent data about the potential of
AIs, how does one incorporate this into clinical practice when treating postmenopausal
women? Should postmenopausal women go
directly to an AI or should they start with
tamoxifen and then switch after 2 or 3 years?
Should women already on tamoxifen switch
now or finish 5 years and then continue therapy
with an AI? Should AIs even be considered in the
absence of OS data and long-term safety studies?
Several groups, including ASCO, the National
Comprehensive Cancer Network (NCCN), and
the St. Gallen Expert Consensus Group have
concluded that an AI should be included in the
adjuvant treatment of postmenopausal women
with hormone-receptor-positive breast cancer.
The decision should obviously be based partly
on the patient’s history, including thromboembolic risk, priorhysterectomy, cardiovascularrisk
factors, osteopenia, and osteoporosis. In the
absence of these factors leading one way or the
other, only the NCCN has made specific recommendations. They have recommended that anastrazole should be used as initial therapy for
women newly diagnosed with breast cancer
and beginning adjuvant hormonal therapy;
switching treatment from tamoxifen to either
anastrazole or exemestane in postmenopausal
women 2 to 3 years into tamoxifen therapy,
and extending hormonal therapy for an additional 5 years with letrozole in women who have
completed 5 years of tamoxifen.
Ovarian Suppression/Ablation
The original hormonal therapy consisted of
ovarian ablation, either by surgery, irradiation, or pharmacologic methods. This still
remains an option for premenopausal women
with hormone-receptor-positive breast cancer
(Table 17–3). Ovarian ablation can be achieved
through several mechanisms. The first is surgical oophorectomy. The safety of this approach
has increased with the introduction of laparoscopic surgery, and there may be additional
benefits in regard to prophylaxis against ovarian cancer in high-risk patients, such as those
with breast cancer gene 1 and 2 (BRCA 1 and
2) mutations or those with a family history of
ovarian cancer. Ovarian irradiation can also be
effective at ablating ovarian function. However,
there are morbidities associated with both of
these approaches, and they are irreversible,
which may be a problem for young patients
with breast cancer. An alternative approach is
the use of LHRH agonists, a medical form of
ovarian ablation. Goserelin acetate is an analogue of LHRH, which suppresses ovarian function, allowing patients to maintain their
function after completion of therapy.
The benefits of ovarian ablation/suppression
are seen in the meta-analysis conducted by the
EBCTCG. A 2000 EBCTCG overview analyzed
4900 women who underwent ovarian suppression with or without chemotherapy. Ovarian
suppression was associated with an improvement in OS in women who did not receive chemotherapy, but there was no impact on
survival in patients who did receive chemotherapy. The survival benefit of ovarian ablation
alone was similar to the survival benefit of
chemotherapy alone.
Several individual trials highlight the potential of goserelin as an alternative to chemotherapy in premenopausal women with ER-positive
tumors. The Zoladex Early Breast Cancer
Research Association (ZEBRA) trial randomized
women to either 2 years of goserelin or cyclophosphamide, methotrexate, and fluorouracil
(CMF) chemotherapy. Among patients who
were ER positive, survival was equal, whereas
CMF was significantly better among patients
who were ER negative. Importantly, menses
returned in the majority of women randomized
to goserelin, whereas 77% of women on CMF
had ovarian ablation with permanent amenorrhea. Another trial, the ABCSG 05 trial, compared CMF to goserelin plus tamoxifen. Again,
no difference in survival was seen, and the
authors concluded that goserelin plus tamoxifen is more effective and better tolerated.
The EBCTCG overview found no benefit to
ovarian suppression in women receiving adjuvant chemotherapy; however, many women
receiving adjuvant chemotherapy will have
chemotherapy-induced ovarian ablation. So is
there a benefit to ovarian ablation/suppression
among women receiving chemotherapy who
maintain ovarian function? This has been
addressed in several trials without definitive
results. The Zoladex in Premenopausal Patients
(ZIPP) analysis combined data from four randomized trials initiated by international collaborative groups. Initial results (median follow-up of
4.3 years) suggest that the addition of goserelin
to standard chemotherapy will decrease the risk
of recurrence, although OS was not improved.
Intergroup trial INT-0101 randomized patients
TABLE 17–3Adjuvant Therapy with Ovarian Ablation/Suppression
Trial N Patients Arms Results
ZEBRA 1640 Node positive G 2 years
IBCSG 1063 Node negative Chemo
Scottish Trial 332 Node positive CMF
Scandinavian Trial 732 Node positive
ER positive
TABLE 600 Node positive
ER positive
ABCSG 1034 ER positive CMF
GROCTA 244 ER positive OA þ T
France 162 Node positive
ER positive
FACS 06 333 Node positive
ER positive
ZIPP 2631 G
INT-0101 1504 Node positive
ER positive
Vietnam 709 OA þ T
France 926 Chemo
Mam-1 GOSCI 466 Node positive Chemo
IBCSG 174 Node positive
ER positive
CMF
G 2 years
Chemo þ G
OA
CMF
OA
CMF
Leuprorelin 2 years
G þ T
CMF
FAC
OA þ T
Triptorelin þ T
FEC
T
G þ T
No further treatment
CAF
CAF þ G
CAF þ G þ T
No further treatment
Chemo þ OA
Chemo þ G þ T
Chemo þ OA þ T
OA þ T
No difference in DFS
No difference in DFS
OS better for OA for ER
20 but worse for ER < 20
No difference in DFS or OS
No difference in DFS or OS
G þ T improved DFS
No difference in DFS or OS
No difference in DFS or OS
No difference in DFS or OS
G improved DFS
T improved DFS
" DFS and OS with OA þ T
No difference in DFS or OS
DFS " with G þ T
No difference in DFS or OS
27717—PRINCIPLES OF ADJUVANT HORMONAL THERAPY
CAF, cyclophosphamide, doxorubicin, fluorouracil; CMF, cyclophosphamide, methotrexate, and fluorouracil; DFS,
disease-free survival; ER, estrogen receptor; FAC, fluorouracil, doxorubicin, cyclophosphamide; FEC, fluorouracil,
epirubicin, cyclophosphamide; G, Goserelin; Mam-1 OA, ovarian ablation; OS, overall survival; T, tamoxifen;
ZEBRA, Zoladex Early Breast Cancer Research Association; ZIPP, Zoladex in Premenopausal Patients.
to chemotherapy, chemotherapy plus goserelin,
or chemotherapy plus goserelin plus tamoxifen.
The triple therapy arm had an improvement
in 5-year DFS, with no improvement in OS.
The effect was greatest in women less than 40,
which may be as a result of the higher fraction
of women who maintained ovarian function.
However, there was no chemotherapy plus
tamoxifen arm, which is the standard of care,
so it is difficult to know how to use this data
clinically. Finally, the International Breast Cancer Study Group (IBCSG) trial randomized
women to chemotherapy, goserelin, or both
(a no adjuvant treatment group was dropped
during the course of the trial). No difference in
DFS or OS was seen between the three groups.
Further data is necessary to answer whether
ovarian suppression added to chemotherapy
and tamoxifen is beneficial in patients who are
premenopausal and ER positive, particularly if
ovarian function is maintained after chemotherapy . An ongoing study of ovarian ablation/suppression will hopefully answer this question. For
now , the only conclusion one can make is that
ovarian ablation/suppression is a potential alternative to chemotherapy in this subset of patients.
278 SURGICAL FOUNDATIONS: ESSENTIALS OF BREAST SURGERY
Suggested Readings
1. Arimidex, Tamoxifen, Alone or in Combination
(ATAC) Trialists’Group, Forbes JF, Cuzick J, et al. Effect
of anastrozole and tamoxifen as adjuvant treatment
for early-stage breast cancer: 100-month analysis of
the ATAC trial. Lancet Oncology 2008;9(1):45–53.
2. Baum M, Budzar AU, Cuzik J, et al. Anastrozole
alone or in combination with tamoxifen versus
tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first
results of the ATAC randomized trial. Lancet
2002;359(9324):2131–2139.
3. Buzdar AU. Aromatase inhibitors: Changing the
face of endocrine therapy for breast cancer. Breast
Disease 2006;24:107–117.
4. Coombes RC, Hall E, Gibson LJ, et al. A randomized
trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary
breast cancer. N Engl J Med 2004;350(11):1081–1092.
5. Fisher B, Costantino J, Redmond C, et al. A randomized clinical trial evaluating tamoxifen in the
treatment of patients with node-negative breast
cancer who have estrogen-receptor positive tumors.
N Engl J Med 1989;320(8):479–484.
6. Fisher B, Dignam J, Bryant J, , et al. Five versus more
than five years of tamoxifen therapy for breast
cancer patients with negative lymph nodes and
estrogen receptor positive tumors. J Natl Cancer
Inst 1996;88(21):1529–1542.
7. Goss PE, Ingle JN, Martino S, et al. A randomized trial
of letrozole in postmenopausalwomen after five years
of tamoxifen therapy for early stage breast cancer.
N Engl J Med 2003;349(19):1793–1802.
8. Ovarian ablation for early breast cancer. Cochrane
Database Syst Rev 2000;3:CD000485.
9. Ovarian ablation for early breast cancer: overview
of the randomized trials. Early Breast Cancer Trialists’ Collaborative Group. Lancet 1996;348(9036):
1189–1196.
10. Tamoxifen for early breast cancer. Cochrane Database Syst Rev 2001;(1):CD000486.
11. Tamoxifen for early breast cancer: an overview of
the randomised trials. Early Breast Cancer Trialists’
Collaborative Group. Lancet 1998;351:1451.
12. Winer EP, Hudis C, Burstein HJ, et al. American
Society of Clinical Oncology technology assessment working group update: use of aromatase inhibitors in the adjuvant setting. J Clin Oncol 2003;
21(13):2597–2599.
13. Yager JD, Davidson NE. Estrogen carcinogenesis in
breast cancer. N Engl J Med 2006;354:270–282.
18
Neoadjuvant Therapy
NEOADJUVANT THERAPY
REGIMENS
PATIENT SELECTION FOR
NEOADJUVANT THERAPY
NEOADJUVANT
CHEMOTHERAPY AND SURGERY
Breast Conservation Rates
Local Recurrence Rates after
Neoadjuvant Chemotherapy
Primary Surgery after Neoadju-
vant Chemotherapy
Neoadjuvant Therapy: Key Points
Describe the potential benefits of delivering chemotherapy
before surgery.
Know the indications and contraindications to neoadjuvant chemotherapy.
Be familiar with the implications of neoadjuvant chemotherapy on breast
surgery.
Develop an algorithm for interrogating the sentinel lymph node in patients
undergoing neoadjuvant chemotherapy.
Understand the potential of neoadjuvant hormonal therapy.
Sentinel Lymph Node Biopsy
after Neoadjuvant
Chemotherapy
NEOADJUVANT
CHEMOTHERAPY AND
OUTCOME
Does Earlier Delivery of Che-
motherapy Improve Survival?
Can Neoadjuvant Chemother-
apy Be Used as a Chemosensitivity Test?
Neoadjuvant therapy refers to the delivery of
systemic therapy before surgical intervention
in an attempt to not only control distant disease, but also to decrease the size of the primary
tumor. This allows for the potential resection
of an inoperable cancer or the use of breastconservation therapy (BCT) in a case in which
a mastectomy would have been indicated. Neoadjuvant therapy can include preoperative chemotherapy or preoperative hormonal therapy.
Using systemic therapy upfront is considered the standard treatment for patients who
present with inoperable breast cancer. This
includes patients with locally advanced tumors
279
280 SURGICAL FOUNDATIONS: ESSENTIALS OF BREAST SURGERY
(T4 tumors), inflammatory breast cancer, and
patients with involvement of the supra or infraclavicular lymph nodes (N3). This was not
always the case because there was concern that
the effect of chemotherapy would increase the
surgical complication rate or negatively affect
overall survival (OS) by delaying the surgery.
However, surgery first was associated with dismal results in treating locally advanced breast
cancer (LABC), and trials of primary chemotherapy quickly demonstrated the benefits of
preoperative downstaging of disease to improve
respectability. This will be discussed in more
detail in Chapter 19.
The success of primary systemic therapy in
inoperable breast cancer led to the suspicion that
it may be preferable in operable breast cancer.
Today, the phrase neoadjuvant therapy typically
refers to the use of preoperative chemotherapy
as an alternative to postoperative chemotherapy.
Based on the experience with LABC, it was
thought that giving the chemotherapy before
surgery to treat the occult micrometastases at an
earlier time may increase survival. However, all
the large randomized trials of preoperative chemotherapy demonstrated equivalentdisease-free
survival (DFS) and OS. What did become apparent was that the rate of breast conservation was
significantly increasedafter neoadjuvant therapy
(T able 18–1). The primary indication today for
neoadjuvant chemotherapy is the patient with
operable breast cancer (good candidates for mastectomy) who desires breast conservation. It may
TABLE 18–1Breast Conservation
Rates After Neoadjuvant
Chemotherapy
Breast-Conservation
Therapy Rate
Study Patients Preopera-
Institut
Bergonie
Institut Curie 414 82 77
Royal
Mardson
NSAPB B18 1523 68 60
EORTC 698 37 21
ECTO 892 71 35
ABCSG 423 67 60
ABCSG, Austrian Breast and Colorectal Cancer Study
Group; ECTO, European Cooperative Trial; EORTC,
European Organization for Research and Treatment
of Cancer; NSAPB, National Surgical and Adjuvant
Breast Project.
tively (%)
272 63.1 0
309 89 78
Postoperatively (%)
BOX 18–1 POTENTIAL
ADVANTAGES TO NEOADJUVANT
CHEMOTHERAPY
May allow for breast-conservation
therapy in a woman who would
otherwise require a mastectomy.
May improve the aesthetic outcome of a
lumpectomy by decreasing the volume of
tissue needing to be resected.
Allows for an assessment of the response
of the tumor to chemotherapy. This may
allow for modifications of therapy based
on response. In addition, a demonstrable
response may also have a positive effect
on the patient’s compliance with further
treatment and on the patient’s willingness
to accept some adverse events.
Allows patients to delay surgery so they
have more time to accept the need for
mastectomy, consider reconstructive
options, or undergo genetic counseling
and testing if prophylactic mastectomies
are considered.
Allows women in their second or third
trimester of pregnancy to delay the
surgery and radiotherapy until after
delivery.
May reduce distant metastases compared
with classic adjuvant systemic therapy.
also be considered for patients who could technically undergo a lumpectomy but will receive a
better cosmetic outcome if the tumor decreases
in size (Box 18–1).
It must be remembered that delivering the
chemotherapy preoperatively is an alternative
to adjuvant chemotherapy. The determinant
for the use of chemotherapy is the risk of distant recurrence. Therefore, neoadjuvant chemotherapy should only be offered to patients
who, based on clinical staging (tumor size,
grade, estrogen receptor/progesterone receptor [ER/PR] status, clinically involved lymph
nodes, and possibly genetic profiling), would
be candidates for chemotherapy. It should
not be used to shrink a primary tumor in a
patient who would not otherwise require systemic therapy. For example, a small-breasted
woman with a 1.5-cm, intermediate-grade,
ER/PR-positive primary tumor, clinically node
negative, may benefit from shrinking the
tumor, but she might not require adjuvant
chemotherapy based on her low risk of distant
recurrence. This would be particularly true if
her genomic profiling suggested a low risk of
recurrence (see Chapter 16). An improved
28118—NEOADJUVANT THERAPY
BOX 18–2 SITUATIONS IN WHICH
NEOADJUVANT CHEMOTHERAPY
IS NOT NECESSARILY APPROPRIATE
Women for whom the use of
chemotherapy is not indicated based on
clinical staging or not clear
Women with diffuse microcalcifications
throughout the breast
Women with multicentric breast cancer
Women who can not undergo
radiotherapy and so are not candidates
for breast conservation
cosmetic result does not justify the toxicity
and sequelae of chemotherapy. In addition,
as the primary goal of neoadjuvant chemotherapy is to allow BCT, patients who will still
require mastectomy after chemotherapy (Box
18–2), are not ideal candidates, although there
are other reasons why neoadjuvant chemotherapy might be considered.
There are other potential and real advantages
to neoadjuvant therapy. In addition to allowing
more women to proceed with breast conservation, it also allows women who will require mastectomy to come to terms with their diagnosis,
think about whether to have reconstruction
and what type of reconstruction to have, and
possibly undergo genetic counseling and testing
and decide whether to undergo bilateral mastectomies. In addition, the patient’s response to the
chemotherapy provides prognostic information.
Patients who have a complete pathological
response (pCR) have a better long-term outcome
than those who do not. Whether this information can be used to adjust pre- or postsurgical
chemotherapy is still an area of investigation.
However, clinical trials using neoadjuvant chemotherapy do allow for a more rapid and less
expensive means for evaluating the efficacy of
new agents and regimens. Adjuvant therapy
trials require many patients over many years,
whereas neoadjuvant therapy trials can be completed over the course of just a few years. This
chapter will address several of these issues.
Neoadjuvant Therapy Regimens
Most of the attention in neoadjuvant therapy
has been focused on chemotherapy. However,
hormonal therapy plays a crucial role in the
management of breast cancer, particularly
among women who are post-menopausal and
TABLE 18–2Hormonal Therapy
in the Neoadjuvant Setting
Study Therapy Breast-
IMPACT anastrazole 46
tamoxifen 22
anastrazole þ
tamoxifen
Letrozole
024 Trial
St. Petersburg anastrazole 21
IMPACT, Immediate Preoperative Arimidex, Tamoxifen
or Combined with Tamoxifen.
letrozole 45
tamoxifen 35
doxorubicin
and
paclitaxel X4
Conservation
Therapy Rate (%)
26
37
hormone-receptor positive. This patient population often does not require systemic chemotherapy. It should then seem reasonable to believe
that these patients could receive the benefits of
preoperative therapy without the need for chemotherapy. Neoadjuvant hormonal therapy
has been less extensively studied than chemotherapy protocols, but it is a viable option for
postmenopausal women who have hormonereceptor-positive disease. Several trials examined
the effect of preoperative hormonal therapy.
In a direct comparison of hormonal therapy to
chemotherapy, the St. Petersburg trial showed
that comparable, though not equivalent, rates
of both response (75.8% versus 89.8%) and
breast conservation (21% versus 37.2%). Other
studies demonstrated that neoadjuvant aromatase inhibitors were superior to tamoxifen in the
neoadjuvant setting (Table 18–2). The data sug-
gest that primary endocrine therapy is a valid
option for postmenopausal patients with hormone-receptor-positive breast cancer who desire
breast conservation but for whom cytotoxic
chemotherapy is not indicated.
At least 3 to 4 months of neoadjuvant endocrine therapy is generally needed to achieve a
significant clinical response, and this may need
to be continued for 6 months to see a benefit.
As opposed to chemotherapy, the response takes
a longer time to become clinically apparent.
Often a response is not visible until 2 months
into therapy, a point important for surgeons
and patients alike, so they do not discontinue
therapy and proceed with surgery too quickly.
Current data suggests that aromatase inhibitors
may offer better clinical responses than tamoxifen and increased rates of breast-conserving