Download Neoadjuvant therapy for breast cancer

Journal of Surgical Oncology 2010;101:283–291
REVIEW
Neoadjuvant Therapy for Breast Cancer
STEPHEN V. LIU, MD,1 LALEH MELSTROM, MD,2 KATHY YAO, MD,3 CHRISTY A. RUSSELL,
STEPHEN F. SENER, MD4
MD,
1
*
AND
1
Division of Medical Oncology, Department of Medicine, Norris Comprehensive Cancer Center,
University of Southern California Keck School of Medicine, Los Angeles, California
2
Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois
3
Northshore University HealthSystem, Department of Surgery, University of Chicago Pritzker School of Medicine, Chicago, Illinois
4
Division of Surgical Oncology, Department of Surgery, Norris Comprehensive Cancer Center,
University of Southern California Keck School of Medicine, Los Angeles, California
The past few decades have seen an increase in both the role and the complexity of neoadjuvant therapy for breast cancer. Neoadjuvant therapy was
initially described as systemic chemotherapy for inflammatory or locally advanced breast cancer but now entails a combination of chemotherapy,
endocrine therapy, and targeted therapy. Neoadjuvant systemic therapy is employed for inoperable inflammatory and locally advanced breast
cancer, and also for patients with operable breast cancers who desire breast-conserving therapy (BCT) but are not candidates based on the initial
size of the tumor in relation to the size of the breast. Neoadjuvant therapy in this subset of patients may impact the surgical options. This review
will summarize the benefits of neoadjuvant systemic therapy and implications for BCT, the timing of sentinel node biopsy, and the utility of
magnetic resonance imaging (MRI) to predict response to therapy.
J. Surg. Oncol. 2010;101:283–291. ß 2010 Wiley-Liss, Inc.
KEY WORDS: breast cancer; neoadjuvant therapy; sentinel node; MRI
INTRODUCTION
Nearly all patients with advanced breast cancer will derive some
benefit from systemic therapy, which in the non-metastatic setting is
typically offered following surgical removal of the tumor (i.e., adjuvant
therapy). However, preoperative (neoadjuvant) systemic therapy is
currently preferable for patients with inoperable inflammatory or
locally advanced breast cancer. A favorable clinical response to
neoadjuvant therapy can convert many patients with inoperable
cancers into candidates for surgical resection. For patients with
operable tumors, which are large in relation to the size of the breast,
breast-conserving surgical therapy (BCT) may not be feasible. In this
clinical setting, neoadjuvant therapy may lead to a reduction in tumor
size, which if significant, may allow consideration of BCT.
Neoadjuvant therapy initially referred to systemic chemotherapy,
but in recent years endocrine therapy for tumors expressing estrogen
and/or progesterone receptors has been established as a well-tolerated
and effective alternative neoadjuvant strategy. Also, for patients whose
tumors overexpress human epidermal growth factor receptor 2
(HER2), the targeted agent, trastuzumab, has been incorporated into
neoadjuvant strategies.
In addition to the impact on the surgical options, either by
facilitating BCT or by rendering a tumor operable at all, neoadjuvant
therapy may provide other benefits. Although preclinical models
suggested that neoadjuvant therapy might impact the biology of the
tumor and improve survival outcomes compared to adjuvant therapy,
this has not been demonstrated in the clinical trials. However,
neoadjuvant therapy does provide an in vivo model to assess the
efficacy of a specific regimen, in contrast to adjuvant therapy, for which
there are no clinical markers to follow.
This article will provide a review of neoadjuvant therapy for breast
cancer, including preclinical data, results of clinical trials, implications
ß 2010 Wiley-Liss, Inc.
for BCT, timing of sentinel node biopsy in relation to neoadjuvant
therapy, and the utility of magnetic resonance imaging (MRI) to aid in
decision-making regarding BCT after neoadjuvant therapy.
PRECLINICAL CONSIDERATIONS AND DATA
Six hypotheses have been described that offer theoretical advantages to neoadjuvant over adjuvant chemotherapy:
(1) Earlier initiation of systemic therapy. Neoadjuvant systemic
therapy can target clinically occult micrometastases when the
tumor burden of metastatic disease is potentially lower [1]. The
preoperative delivery of non-cross resistant agents may minimize
the development of a resistant cell population that can form from
spontaneous mutations [2].
(2) Reduction of microscopic tumor dissemination caused during
surgical removal of tumor.
(3) Prevention of tumor growth spurt after surgical resection. Studies
with animal models have shown that removal of a primary tumor
accelerated the growth of metastatic tumors [3,4]. This appears to
be mediated by an increase in the rapidity of tumor growth in any
residual tumor following removal of a tumor of the same type [5].
*Correspondence to: Christy A. Russell, MD, Norris Comprehensive
Cancer Center, University of Southern California, 1441 Eastlake Avenue,
Suite 3448, Los Angeles, CA 90033. Fax: þ323-865-0061.
E-mail: [email protected]
Received 28 September 2009; Accepted 30 September 2009
DOI 10.1002/jso.21446
Published online in Wiley InterScience
(www.interscience.wiley.com).
284
Liu et al.
Fisher et al. [6] administered cyclophosphamide to mice with two
separate mammary adenocarcinoma tumor implants, prior to
resection of one of these tumors. Preoperative cyclophosphamide
resulted in a lower labeling index of the residual tumor when
compared to postoperative cyclophosphamide. In a separate
experiment, preoperative administration of the endocrine agents
tamoxifen or goserelin, a luteinizing hormone-releasing hormone
(LH-RH) analog, also prevented the increase in tumor growth
kinetics of the distant tumor [7].
(4) Opportunity to deliver cytotoxic agents to the tumor with intact
native vasculature. As blood flow is much higher in tumor tissue
than in normal breast tissue, the tumor’s intact vasculature can
theoretically be exploited to more effectively deliver cytotoxic
agents to the tumor and any micrometastases prior to surgical
resection [8].
(5) Neoadjuvant therapy provides an in vivo model to assess the
response of tumor to specific cytotoxic agents. In the adjuvant
setting, regimens are empirically used, but there is no way to assess
response since all visible tumors have been removed. With the
tumor in place, ineffective chemotherapy can be more easily
detected and changed. The clinical and pathologic response to
neoadjuvant therapy provides valuable prognostic information.
(6) Once BCT was established as a viable surgical option, neoadjuvant
therapy became a possible means to allow patients to undergo a
less extensive surgical procedure with potentially improved
cosmesis.
Theoretical disadvantages to neoadjuvant treatment include:
(1) Delay in curative local therapy, which may allow the primary
tumor to metastasize or progress to an inoperable state during the
course of neoadjuvant therapy.
(2) Concern for loss of accurate staging information, as many early
trials noted a lack of invasive cancer in the surgical specimens of
women after neoadjuvant therapy.
(3) While treatment of micrometastases is generally felt to be
beneficial, Skipper [9] had proposed that the primary tumor
and micrometastases need not necessarily respond to the same
therapy.
(4) While the tumor vasculature may be intact prior to surgical
resection, neoadjuvant therapy will have to treat a much greater
burden of disease than if used after tumor removal.
(5) Exposure to neoadjuvant therapy could promote drug resistance.
(6) Increased risk of surgical or radiation complications after
neoadjuvant therapy.
NEOADJUVANT CHEMOTHERAPY FOR
INFLAMMATORY AND LOCALLY ADVANCED
(INOPERABLE) BREAST CANCER
The term ‘‘inflammatory breast cancer’’ was coined by Lee and
Tannenbaum [10] in 1924. They described 28 patients with breast
cancer that had a unique skin involvement, in which the ‘‘skin becomes
deep red or reddish purple, and to the touch is brawny and infiltrated.’’
This condition was further characterized in 1956 by Haagensen [11],
who established the clinical criteria for the diagnosis, including rapidly
enlarging breast, generalized breast induration, and erythema involving
at least a third of the breast. Using current National Cancer Center
Network (NCCN) criteria, inflammatory breast cancer is a clinical
syndrome in women with ‘‘invasive breast cancer that is characterized
by erythema and edema (peau d’orange) of a third or more of the skin
of the breast and with a palpable border to the erythema [12].’’ Physical
examination reveals an erythematous and warm breast, often in the
absence of a dominant breast mass. The clinical course is more rapid
Journal of Surgical Oncology
than non-inflammatory breast cancer and diagnosis is often delayed,
with many patients diagnosed as having breast infections prior to
biopsy. The underlying biology of inflammatory breast cancer
includes dermal lymphatic invasion, which accounts for its clinical
presentation as well as its explosive clinical course. Most patients
with inflammatory breast cancer have involvement of regional lymph
nodes, and 17–36% have distant metastases at the time of diagnosis
[13].
Inflammatory breast cancer is classically considered inoperable,
as surgery alone has been described as ineffective, with a 5-year
survival rate of less than 5% [14]. Radiation has been studied, either
alone or in conjunction with surgery, but in prior clinical trials, there
was no impact on the survival rates [15]. Even in the absence of
locoregional failure, most patients died with distant metastases.
These circumstances led to the study of systemic chemotherapy prior
to surgery, which yielded dramatically better outcomes. A retrospective analysis of 50 patients with inflammatory breast cancer
found that patients treated with chemotherapy, radiotherapy, and
surgery had a better 5-year survival rate than patients who did not
receive all three modalities (50% vs. 7%) [16]. Inflammatory breast
cancer is relatively uncommon, which explains the relative paucity of
large trials. With few exceptions, patients with inflammatory breast
cancer are treated in trials for patients with locally advanced breast
cancer, as both of these groups fare poorly with locally directed
therapies.
Locally advanced breast cancer is loosely defined but typically
includes patients with clinical stage IIIb and IIIc breast cancer, though
some clinicians would also include clinical stage IIb and IIIa. Some of
the characteristics of locally advanced breast cancer include a tumor
size greater than 5 cm (T3), skin or chest wall involvement (T4),
matted axillary lymph nodes (N2), or involvement of the internal
mammary, infraclavicular or supraclavicular lymph nodes. For these
patients, treatment with surgery and radiation can offer local control,
but survival is still poor because the most common type of treatment
failure is distant metastatic disease. This led to the study of
neoadjuvant chemotherapy for patients with both inflammatory and
locally advanced breast cancer. No randomized trials have compared
neoadjuvant and adjuvant chemotherapy for these patients, in part
because many surgeons consider these tumors inoperable prior to
chemotherapy. In general, these studies have shown that neoadjuvant
chemotherapy is tolerable and significantly improves outcomes
compared to surgery alone. As a result of these studies (Table I),
patients with inflammatory and locally advanced breast cancer receive
neoadjuvant chemotherapy as part of standard treatment, though no
standard regimen has been established.
NEOADJUVANT CHEMOTHERAPY FOR
OPERABLE BREAST CANCER
As neoadjuvant therapy became more accepted, its efficacy in
locally advanced inoperable tumors was extrapolated to patients who
presented with operable tumors, particularly for patients who desired
breast-conserving therapy (BCT). BCT with lumpectomy, axillary
dissection, and whole breast radiation became accepted as equivalent
to a modified radical mastectomy based largely on the B-06 trial of the
National Surgical Adjuvant Breast and Bowel Project (NSABP) [17].
For patients who desired BCT but whose tumor to breast size ratio
precluded satisfactory cosmesis, neoadjuvant therapy was a logical
option. If neoadjuvant therapy garnered a clinical response, it could
potentially facilitate BCT for a patient who was not initially a
candidate. Bonadonna et al. [18] described five different neoadjuvant
regimens given to 165 patients with breast cancer. All patients were
initially candidates only for mastectomy, but following therapy 81%
became eligible for BCT.
Journal of Surgical Oncology
174
113
107
31
172
34
372
42
64
50, 47
54
166
448
51
126
138
30
30
33
193
74
45
15
51
102
265
41
1,390
60
1996
1997
1998
1999
2001
2001
2002
2003
2003
2003
2004
2004
2004
2004
2004
2004
2004
2005
2005
2005
2005
2006
2006
2007
2008
2009
Patients
1988
1988
1992, 2004
Year
IBC
LABC
LABC
LABC and IBC
LABC
LABC
LABC
LABC þ IBC
LABC þ IBC
LABC
LABC
LABC
LABC and IBC
LABC
IBC
LABC and IBC
LABC and IBC
LABC and IBC
LABC and IBC
LABC and IBC
IBC
LABC
LABC
IBC
LABC
LABC
LABC
LABC and IBC
LABC and IBC
Population
CMF or FAC
CVAP
CEF, EC þ filgrastim
ET
PC
CMF or CAF
Docetaxel þ capecitabine
ET
NR
VACP
CMF
Docetaxel
T þ vinorelbine þ XRT
Docetaxel
FEC-HD
AC þ T, metronomic AC þ T
ECX
TAC
ATX
CAP
FAC, FACVP, FACVP MV
A
FAC
FAC T
FAC
CVAP, CVAP þ docetaxel
FAC
CAFVP
CAFM
Chemotherapy regimen
30%
15%
14%, 20%
18%
16%
13%
10%
13.3%
12%
12.2%
18.9%
10%
46.7%
20%
14.7%
17%, 26%
19%
22.2%
8.3%
8%
NR, NR, NR
21%
12%
14%
NR
16%, 34%
16.7%
NR
29%
pCR rate
52%
75%
79.9%, 85.7%
78%
91%
53%
90%
76.7%
85%
83.4%
88%
49%
93%
75%
91.1%
NR, NR
74%
100%
77%
76.7%
74%
65%
NR
81%
92%
66%, 94%
NR
72%
57%
Overall RR
49%
NR
NR, NR
NR
63%
46%
NR
NR
70%
51%
52%
NR
33% (4 years)
NR
35.7% (10 years)
NR, NR
NR
NR
76% (3 years)
29% (6 years)
32%
77% (3 years)
NR
NR
58%
77% (3 years), 90% (3 years)
84% (for IIIa), 33% (for IIIb)
NR
NR
5-year DFS
56%
NR
53%, 51%
NR
85%
55%
NR
NR
78%
60%
79.9%
80%
56% (4 years)
78% (2 years)
41.2% (10 years)
NR, NR
NR
NR
90% (3 years)
84% (for IIIa), 44% (for IIIb)
NR
61% (for IIIa), 36% (for IBC),
31% (for non-IBC IIIb)
28% (6 years)
40%
88% (3 years)
NR
NR
75%
84% (3 years), 97% (3 years)
5-year OS
RR, response rate; DFS, disease-free survival; OS, overall survival; IBC, inflammatory breast cancer; LABC, locally advanced breast cancer; NR, not reported; XRT, radiation therapy; CAFVP,
cyclophosphamide þ doxorubicin þ fluorouracil þ vincristine þ prednisone; FAC, fluorouracil þ doxorubicin þ cyclophosphamide; VP, vincristine þ prednisone; CMF, cyclophosphamide þ methotrexate þ 5-fluorouracil;
CAF, cyclophosphamide þ doxorubicin þ 5-fluorouracil; MV, methotrexate þ vinblastine; FEC, 5-fluorouracil þ epirubicin þ cyclophosphamide; A, doxorubicin; AC, doxorubicin þ cyclophosphamide; T, paclitaxel; CAP,
cyclophosphamide þ doxorubicin þ cisplatin; CAFM, cyclophosphamide þ doxorubicin þ 5-fluorouracil þ methotrexate; CVAP, cyclophosphamide þ vincristine þ doxorubicin þ prednisolone; ET, epirubicin þ docetaxel;
PC, paclitaxel þ cisplatin; VACP, vincristine þ doxorubicin þ cyclophosphamide þ prednisone; AT, doxorubicin þ docetaxel; EC, epirubicin þ cyclophosphamide; CEF, cyclophosphamide, þ epirubicin þ fluorouracil; TAC,
docetaxel þ doxorubicin þ cyclophosphamide.
Hortobagyi et al. [66]
Perloff et al. [67]
Pierce et al. [68]
and Low et al. [69]
Colozza et al. [70]
Ueno et al. [71]
Clark et al. [72]
Kuerer et al. [26]
Cristofanilli et al. [73]
Favret et al. [74]
Smith et al. [28] and
Hutcheon et al. [75]
Harris et al. [76]
McIntosh et al. [77]
Therasse et al. [78]
Espinosa et al. [79]
Ezzat et al. [80]
Gajdos et al. [81]
Lebowitz et al. [82]
de Matteis et al. [83]
Shen et al. [84]
Thomas et al. [30]
Erol et al. [85]
Gradishar et al. [86]
Kao et al. [87]
Tham et al. [88]
Veyret et al. [89]
Ellis et al. [27]
Villman et al. [90]
von Minckwitz et al. [91]
Manga et al. [92]
Study
TABLE I. Neoadjuvant Chemotherapy for Inflammatory and Locally Advanced Breast Cancer (Non-Trastuzumab Based)
Journal of Surgical Oncology
NR, NR, NR
67.7%, 71.1%,
70.0%
RR, response rate; DFS, disease-free survival; OS, overall survival; NR, not reported; N/A, not applicable; FEC, fluorouracil þ epirubicin þ cyclophosphamide; AC, doxorubicin þ cyclophosphamide; CMF,
cyclophosphamide þ methotrexate þ fluorouracil; FAC, fluorouracil þ doxorubicin þ cyclophosphamide; 3M, mitomycin þ mitoxantrone þ methotrexate with tamoxifen; 2M, mitoxantrone þ methotrexate with
tamoxifen; AT, doxorubicin þ paclitaxel; EVM/MTV, epirubicin þ vincristine þ methotrexate followed by mitomycin C þ thiotepa þ vindesine.
NR
84.4%, 77.1%
69%, 70%
53%, 52%
NR, NR
82%, 84%
NR
74%, 80%
55%, 53%
50%, 48%
NR, NR
65%, 70%
81%
63%, 62%
67.8%, 59.8%
89%, 78%
63.1%, 100%
NR, NR
65%, 34%
NR, NR, NR
77%
65%, N/A
77%, N/A
83%, N/A
NR, NR
NR, N/A
78%, N/A
NR, NR, NR
Neoadjuvant CMF, neoadjuvant FAC, neoadjuvant FEC
4.2%
Neoadjuvant FAC, adjuvant FAC
NR, N/A
Neoadjuvant AC, adjuvant AC
13%, N/A
Neoadjuvant þ adjuvant 3M or 2M, adjuvant 3M or 2M
18%, N/A
Neoadjuvant EVM/MTV, adjuvant EVM/MTV
NR, N/A
Neoadjuvant FEC, adjuvant FEC
2%, N/A
Neoadjuvant AT þ CMF, adjuvant CMF AT
20%, N/A
Neoadjuvant AC, neoadjuvant AC þ docetaxel,
12.9%, 26.1%,
neoadjuvant AC þ adjuvant docetaxel
14.4%
165
200, 190
760, 763
157, 152
134, 138
698
451, 904
768, 767, 776
1990
1995, 1999
1998
1998
1999
2001
2005
2006
Bonadonna et al. [18]
Scholl et al. [93,94] and Broet et al. [95]
Fisher and co-workers (B-18) [96,97]
Makris et al. [19]
Mauriac et al. [98]
Van der Hage et al. [99]
Gianni et al. [100]
Bear et al. (B-27) [23]
DFS
BCT rate
Overall RR
pCR rate
Chemotherapy regimen
Patients
Year
Study
A high clinical response rate but lack of survival benefit was
demonstrated in a randomized trial by Makris et al. [19]. In this study,
initially reported by Powles et al. [20], patients with operable breast
cancer were randomized to receive preoperative (neoadjuvant) or
postoperative (adjuvant) chemotherapy. Patients received either
mitomycin þ mitoxantrone þ methotrexate (3M) or mitoxantrone þ
methotrexate (2M). Patients in the adjuvant arm received eight cycles,
and those in the neoadjuvant arm received four cycles prior to surgery
and four cycles following surgery. Neoadjuvant therapy was associated
with a pathologic complete response rate of 18%, and 89% of patients
were eligible for BCT (77% were eligible prior to treatment). There
was no significant difference in disease-free or overall survival rates
between the neoadjuvant and adjuvant arms. However, if neoadjuvant
therapy were relatively much less efficacious than adjuvant therapy, it
would be difficult to discern differences in survival rates between the
two regimens [21].
In the subsequent NSABP B-18 trial, patients received either
neoadjuvant or adjuvant chemotherapy after being stratified by age,
tumor size, and clinical node status [22]. Patients in the neoadjuvant
arm did not receive any chemotherapy after surgery, regardless of
response of the tumor to primary chemotherapy. This study
randomized 1,523 patients with operable invasive breast cancer to
four cycles of preoperative versus postoperative doxorubicin and
cyclophosphamide (AC) chemotherapy plus tamoxifen (if >50 years of
age). Of the 683 patients who received preoperative chemotherapy,
36% had a clinical complete response and 9% achieved a pathological
complete response. The breast conservation rate in the group receiving
preoperative chemotherapy (67%) was significantly higher than in the
group receiving postoperative chemotherapy (60%; P ¼ 0.002). There
was no difference in the overall or disease-free survival rates between
the two groups. But a subset analysis demonstrated that those with
pathologic complete responses after preoperative chemotherapy had
significantly improved overall and disease-free survival rates than
those with pathologic incomplete responses to preoperative treatment.
In addition, the rate of BCT was related to initial tumor size. So, only
20% of those presenting with an initial tumor >5 cm and having
preoperative chemotherapy were able to have breast conservation.
The benefit of incorporating a taxane into therapy was demonstrated
in the NSABP B-27 trial, which examined the role of docetaxel (T)
following neoadjuvant AC [23]. In this study, 2,411 patients with
operable invasive breast cancer were randomized to one of the three
treatment arms: (1) neoadjuvant AC followed by surgery; (2)
neoadjuvant AC followed by T and then surgery; or (3) neoadjuvant
AC followed by surgery and then T. The addition of T did not
significantly improve disease-free or overall survival rates, despite the
fact that the pathologic complete response rate (25.6%) was twice that
in NSABP B-18 (13.7%). In addition, the lumpectomy rate did not
significantly differ between the treatment arms of AC alone (61%)
versus AC followed by T (63%; P ¼ 0.70). Based primarily on these
data, neoadjuvant therapy became widely accepted not only for
patients with inflammatory and locally advanced breast cancer but also
for those who desired BCT but were not eligible based on initial tumor
size.
A meta-analysis by Mauri et al. [24] included nine randomized
studies that compared neoadjuvant therapy with adjuvant therapy,
regardless of regimen and local therapy. The analysis did not detect
significant differences between the two treatment regimens in
mortality, disease progression, or distant recurrence rates. Neoadjuvant
therapy was associated with an increased risk of loco-regional
recurrence compared to adjuvant therapy. It is noted that a portion of
patients receiving neoadjuvant therapy had only primary radiation for
local control, whereas those receiving adjuvant therapy all had surgical
resection. The conclusion from the meta-analysis was that neoadjuvant
and adjuvant chemotherapy had equivalent rates of survival and disease
progression (Table II).
5-year OS
Liu et al.
TABLE II. Trials Comparing Neoadjuvant and Adjuvant Chemotherapy for Operable Breast Cancer
286
Neoadjuvant Therapy for Breast Cancer
PREDICTORS OF RESPONSE AND
MANAGEMENT OF NON-RESPONDERS TO
NEOADJUVANT CHEMOTHERAPY
Despite the compelling preclinical data and theoretical advantages,
survival benefit to neoadjuvant chemotherapy has not been convincingly demonstrated in clinical trials. Neoadjuvant therapy does permit
assessment of response to therapy, which does lend prognostic
information. Many patients who have a complete clinical response
will have pathologic evidence of residual tumor, and occasionally
patients with a clinical partial response will have no viable tumor in the
surgical specimen. In most cases, lack of a clinical response to
chemotherapy is a negative predictive factor for achieving pathologic
complete response (pCR) [25].
The tumor profile has been identified as a predictor of clinical and
pathologic response to neoadjuvant therapy. Bonadonna et al. [18]
observed a higher overall response rate in patients with ER-negative
versus ER-positive tumors and with PR-negative versus PR-positive
tumors. A large study by Kuerer et al. [26] demonstrated that ERnegative status and higher nuclear grade were independently associated
with pCR. The Southwest Oncology Group (SWOG)-0012 trial
comparing classical neoadjuvant chemotherapy with metronomic
chemotherapy demonstrated lower pCR rates in patients with either
ERþ or PRþ tumors than those with ER or PR tumors [27].
Patients who do not achieve a clinical response from neoadjuvant
therapy have a poor outcome. One of the proposed advantages of
neoadjuvant chemotherapy was to identify non-responders to systemic
chemotherapy. This in vivo model of chemosensitivity would
theoretically allow a different, non-cross resistant chemotherapy
regimen to replace the ineffective regimen. Unfortunately, attempts
to exploit this in vivo model have met with disappointing results. In
a study by the Aberdeen group, patients with large or locally
advanced breast cancer received neoadjuvant cyclophosphamide,
vincristine, doxorubicin, and prednisone (CVAP) [28]. Of the 159
patients, 104 demonstrated a clinical response. These patients were
then randomly assigned to continue CVAP or to receive docetaxel
(T), a non-cross resistant agent. The non-responders all received
T. Switching to T resulted in a pCR rate of 34% in responders and 2%
in non-responders.
The second part of the GeparTrio trial randomized patients who
were non-responsive to neoadjuvant TAC to continue with TAC or to
switch to vinorelbine and capecitabine [29]. Over 300 patients were
included in each study arm, and the pCR rate was about 5% in both
groups. These disappointing results suggested that non-responders
have chemoresistant disease, and changing to a different regimen
appears to not be of much utility.
For patients who do not achieve a pCR after neoadjuvant therapy,
further chemotherapy after surgical resection does not appear to be of
much benefit. In a study by Thomas et al. [30], 193 patients with
locally advanced breast cancer received neoadjuvant CAVP and had a
clinical response rate of 83.4% and a pCR rate of 12.2%. Of the 106
patients who did not achieve pCR, 51 were randomized to receive
additional CAVP and 55 received vinblastine, methotrexate, leucovorin, and fluorouracil (VbMF). Disease-free and overall survival rates
were not statistically different between the two groups, suggesting little
benefit to postoperative (adjuvant) chemotherapy when neoadjuvant
therapy does not induce a pCR. Outside of a clinical trial, patients who
complete standard neoadjuvant therapy should not be given additional
chemotherapy after surgery, even if pCR is not achieved.
NEOADJUVANT TARGETED THERAPY
Amplification of the HER2/neu gene in breast cancer is a poor
prognostic feature, associated with advanced stage and higher grade.
Journal of Surgical Oncology
287
The HER2/neu protein, an epidermal growth factor (EGF) receptor,
has been successfully targeted by the development of monoclonal
antibodies, such as trastuzumab. Use of these antibodies has
impressively affected the natural history of HER2þ tumors, and
their incorporation into adjuvant and metastatic treatment programs
has become standard practice. Their use has now been studied in
patients who are candidates for neoadjuvant therapy, with equal
success.
In a study by Buzdar et al. [31], 64 patients with HER2þ inoperable
breast cancer were randomized to receive neoadjuvant paclitaxel
followed by fluorouracil þ epirubicin þ cyclophosphamide (FEC). Of
these, 19 were randomized to FEC alone while 23 were randomized to
FEC with 24 weeks of trastuzumab (22 were later added and assigned
to receive trastuzumab). The pCR rate was 60% in those receiving
trastuzumab and was 26% for patients who did not receive
trastuzumab. Neoadjuvant docetaxel and carboplatin (TC) was
compared to the same combination with trastuzumab (TCH) in a
phase II study published in abstract form by Chang et al. [32]. The pCR
rate was 36% for the 11 patients receiving trastuzumab and was 9% for
the 11 patients not receiving trastuzumab, with comparable cardiotoxicity rates.
Lapatinib is a tyrosine kinase inhibitor, which targets both the
HER2 receptor and the EGF receptor. This agent is the focus of several
planned trials including Neo-ALTTO, a phase III randomized trial
administering neoadjuvant paclitaxel with lapatinib, trastuzumab, or
both agents together [33]. The NSABP B-41 trial will also examine
lapatinib in a phase III study in which patients receive neoadjuvant AC
and are then randomized to receive either lapatinib, trastuzumab, or
both agents [34].
NEOADJUVANT ENDOCRINE THERAPY
Though there is a large body of evidence for neoadjuvant
chemotherapy, preoperative endocrine therapy has been shown to be
safe and effective for patients with ERþ tumors. Responses have been
moderate, with pCRs relatively uncommon. Neoadjuvant endocrine
therapy was initially limited to elderly patients who were not felt to be
good candidates for systemic chemotherapy, due to either comorbidities or to limited lifespan. The somewhat lower response rates
were often an acceptable exchange for decreased morbidity associated
with treatment. Several early trials comparing neoadjuvant tamoxifen
followed by surgical resection to resection followed by adjuvant
tamoxifen demonstrated no significant differences in overall survival
rates [35–37]. In a study of patients >70 years of age with locally
advanced breast cancer, Horobin et al. [38] identified clinical responses
rates to neoadjuvant tamoxifen which were complete in 33%, partial in
15%, and unchanged in 30%. These data established neoadjuvant
tamoxifen as a reasonable option for older patients.
As the efficacy of aromatase inhibitors (AI) in the adjuvant setting
was established, several studies compared AI to tamoxifen in the
neoadjuvant setting. After early favorable trials comparing neoadjuvant tamoxifen with anastrozole, tamoxifen and an AI were studied in
the IMPACT trial, in which postmenopausal patients with ERþ tumors
were randomized to receive 3 months of neoadjuvant anastrazole,
tamoxifen, or the two together [39]. Results from this double-blinded,
randomized trial demonstrated no differences in clinical response rates
between groups (about 37%), with BCT rates of 44%, 31%, and 24%,
respectively.
In a phase II study comparing neoadjuvant endocrine therapy to
neoadjuvant chemotherapy, 239 postmenopausal patients with ERþ
tumors were randomized to endocrine therapy (second randomization
to either exemestane or anastrazole for 3 months) or chemotherapy
(doxorubicin and paclitaxel every 3 weeks for four cycles) prior to
surgical resection [40]. There were no differences between the two
groups in rates of clinical response, pCR, or BCT.
288
Liu et al.
NEOADJUVANT CHEMOTHERAPY:
IMPLICATIONS FOR BCT
Factors that have been shown to affect local recurrence rates after
neoadjuvant therapy and subsequent BCT are initial tumor size,
presence of lymphatic invasion, nodal status, or presence of diffuse
microcalcifications on mammogram [41,42]. The typical conundrum
presented to the surgeon after neoadjuvant chemotherapy is that tumors
do not shrink in a concentric fashion, rather they often shrink to ‘‘Swiss
cheese’’ or multicentric smaller deposits of tumor. How to best assess
clinical response to neoadjuvant therapy is controversial, and physical
exam is often unreliable. Many clinicians use mammography and/or
ultrasound to determine tumor shrinkage, but breast MRI is an
emerging yet controversial technique.
UTILITY OF MRI TO ASSESS RESPONSE TO
NEOADJUVANT TREATMENT
MRI may be superior to physical examination, sonography, and
mammography in assessing tumor response following neoadjuvant
chemotherapy [43,44]. Therefore, MRI may become the ideal imaging
modality in determining appropriate candidates for breast conservation
after neoadjuvant chemotherapy. Several studies have demonstrated
that MRI findings accurately predicted residual tumor size and
correlated with pathological findings after resection [45–47]. However, the MRI findings may be influenced by the chemotherapy agents
employed and the tumor phenotype. In a study of 55 patients who had
neoadjuvant chemotherapy and MRI evaluation at various times
through the course of neoadjuvant therapy, Chen et al. [45] found that a
prediction of pCR by MRI criteria was accurate in 74% of patients and
was influenced by the HER2 status of the tumor. The accuracy to
predict a pCR by MRI was 50% for HER2-negative tumors versus 95%
for HER2-positive tumors. In one of the largest studies of breast MRI
and neoadjuvant chemotherapy, Chen et al. [48] showed that the
presence of pCR or minimal residual disease prompted surgeons to
recommend breast conservation surgery. The authors hypothesized that
if MRI can accurately predict disease response, it could be a valuable
tool for surgeons to aid them in recommending the appropriate surgical
procedure. In an ancillary study, the same investigators demonstrated
that the diagnostic performance of MRI was comparable between those
patients receiving bevacizumab and those not receiving bevacizumab,
with a significant limitation of MRI in cases in which tumor was
‘‘broken down’’ to scattered islands of tumor instead of shrinking in
concentric fashion. MRI accurately predicted a pCR in 57% of the
patients, with an overall diagnostic accuracy of 70% [49].
More studies are needed to evaluate the accuracy of breast MRI in
patients undergoing neoadjuvant therapy, but it appears likely that MRI
will have a role in the future management of these patients.
TIMING OF SENTINEL LYMPH NODE BIOPSY
The timing of sentinel lymph node biopsy in relation to neoadjuvant
chemotherapy remains controversial. The status of the axillary lymph
nodes is one of the most critical prognostic indicators for patients with
invasive breast cancer, and yet axillary lymph node dissection remains
one of the most morbid aspects of breast surgery [50]. Two of the initial
goals of neoadjuvant therapy were to prevent excessive axillary surgery
and to allow for BCT. Proponents in favor of sentinel node biopsy prior
to neoadjuvant chemotherapy have argued that knowledge of the nodal
status prior to treatment can influence choice of chemotherapy agents
or radiation fields, while providing clinicians with an accurately
staged patient. They also have argued that sentinel node biopsy after
chemotherapy may not be accurate and may be associated with a
high false-negative rate. There has been concern voiced by some
Journal of Surgical Oncology
investigators that neoadjuvant chemotherapy may alter the anatomy
of the lymphatics, rendering the sentinel lymph node biopsy an
inadequate representation of disease in the axilla after neoadjuvant
treatment [51]. This concern was initially amplified by studies
demonstrating low sentinel node identification rates and high falsenegative rates [52–55]. These findings may have been attributed to the
inclusion of patients in these studies with inflammatory tumors and
clinically positive axillary lymph node metastases. Subsequently,
studies of patients with clinically negative axillary lymph node status
have demonstrated more favorable results with sentinel lymph node
biopsy after neoadjuvant chemotherapy [56–59]. Multiple studies have
now demonstrated that sentinel lymph node biopsy is feasible after
neoadjuvant therapy, with acceptable sentinel lymph node identification rates and false-negative rates [60,61]. Without neoadjuvant
chemotherapy, sentinel lymph node identification rates for patients
with operable breast cancer have ranged from 84% to 100% with falsenegative rates of 0–13% [62,63]. A recent meta-analysis was
performed of literature between 1996 and 2007, including sentinel
node mapping in patients with early-stage breast cancer after
neoadjuvant chemotherapy [64]. The proportion of patients who had
successful lymph node mapping ranged from 63% to 100%, with 79%
of studies reporting a rate less than 95%. The summary rate of
successful sentinel node identification was 89.6% (95% confidence
interval [CI]: 0.860–0.923). The summary false-negative rate was
8.4% (95% CI: 0.064–0.109).
Proponents in favor of sentinel node biopsy after neoadjuvant
chemotherapy have argued that this approach may spare approximately
20–30% of patients an axillary node dissection and its associated
morbidity. In NSABP B-18, there was a significantly lower percentage
of involved lymph nodes in the neoadjuvant chemotherapy arm versus
the adjuvant chemotherapy arm (41% vs. 57%, P < 0.001) [22]. In
NSABP B-27, where patients underwent sentinel node biopsy after
neoadjuvant chemotherapy, 36% had a positive sentinel lymph node
[23]. Sabel et al. [65] demonstrated that 50% of patients were sentinel
node positive prior to neoadjuvant treatment. Thus, it appears that there
will likely be more axillary dissections performed in patients having
sentinel node biopsy prior to than subsequent to neoadjuvant
chemotherapy.
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