Download Sentinel node: Next Level questions

The Sentinel Node:
1) Neoadjuvant Chemotherapy
2) Ipsilateral Breast Cancer Recurrence
EJW 2006
Basic Concepts
Sentinel node (SLN) “biopsy” has been demonstrated to be remarkably
accurate in evaluating the axilla for nodal metastases. It is at least as
good for axillary assessment as axillary lymph node dissection (ALND)
and probably superior.(White 2001) In the past, standard pathology
evaluation of ALND nodes resulted in a 7-20% false negative result
when re-evaluated by serial sectioning.(Dowlatshahi, Fan et al. 1999;
Karalak and Homcha-Em 1999) SLN evaluation yields a 5-6% false
negative rate. In “early” breast cancer, and even after neoadjuvant
chemotherapy, studies show that when the sentinel node is positive it is
the only positive lymph node about 50% of the time.(Breslin, Cohen et
al. 2000; Villa, Gipponi et al. 2000) That fact may explain why standard
evaluation tends to miss more positive axillary states than the more
intensive study of the SLN.
Additionally, long term follow-up of sentinel node negative patients
with no ALND has recurrence rates of 1.5% or less.(Langer, Marti et al.
2005) From an axillary risk standpoint, even with a positive sentinel node
and standard BCT Rx, axillary recurrence is rare.(Fant, Grant et al. 2003;
Jeruss, Winchester et al. 2005)
Survival after negative SLN treated with adjuvant Rx is superior to
historical NSABP series with node negative standard ALND with
adjuvant Rx, suggesting that missed positive nodes in old studies lead to
errors in stage and prognosis. Improved data on modern SLN studies
leads to more accurate classification.(Fuhrman, Gambino et al. 2005)
Moreover, there is abundant data from randomized studies suggesting
that axillary node dissection, per se, provides no benefit to overall
survival.(Johansen, Kaae et al. 1990; Greco, Agresti et al. 2000; Fisher,
Jeong et al. 2002; Zurrida, Orecchia et al. 2002; Louis-Sylvestre, Clough
et al. 2004; Martelli, Boracchi et al. 2005) This may be especially true in
the setting of BCT where chemotherapy and radiation therapy
functionally target any “missed” axillary disease.(Wong, Recht et al.
1997; Gervasoni, Taneja et al. 2000; Chung, DiPetrillo et al. 2002; Lee,
Doliny et al. 2004; Low, Berman et al. 2004; Hennessy, Hortobagyi et al.
2005; Cox, Cox et al. 2006) The recent development of multigene assays
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capable of predicting pCR may further limit the need for axillary
dissection to those proven to be at high risk of incomplete
response.(Lymberis, Parhar et al. 2004; Hess, Anderson et al. 2006)
These studies were performed on RNA obtained by FNA of the tumor.
Therefore SLN (selective sentinel-lymphadenectomy) is
extraordinarily useful in obtaining needed information for treatment
planning while minimizing risk and morbidity.
Sentinel node: Next Level questions
There are new settings (previously thought to be contraindications) in which
sentinel node evaluation may be useful.
• Peri- neoadjuvant chemotherapy, (i.e. post or pre neoadjuvant.)
• Ipsilateral breast tumor recurrence (IBTR) with prior axillary
interventions.
Post Neo-adjuvant Chemotherapy Axillary Node Issues
Neoadjuvant chemotherapy has become increasingly used in the setting of
more advanced local disease. Originally used in inflammatory breast cancer,
it has been recently extended to locally advanced non-inflammatory cases in
the hope of reducing subsequent mortality as yet with no proof in that
application. Trends suggesting benefit in overall survival were noted in nine
year follow-up in the B-18 trials for pre-menopausal patients, but worsened
survival was noted in post-menopausal patients, and the net effect was no
overall change in survival.(Wolmark, Wang et al. 2001) (These issues may
prove to be very different with her-2-neu positive patients treated with
herceptin.)(Arnould, Gelly et al. 2006) Many studies show an approximate
25% complete pathologic response (cPR) to neo adjuvant chemotherapy.
That response predicts for a better long-term outcome. However, recent
evidence suggests that gene expression profiles of the tumor will allow
accurate prediction of cPR, possibly eliminating the need for the clinical
“test”.(Hess, Anderson et al. 2006) Certainly a significant number of
patients can be converted to BCT rather than mastectomy by neoadjuvant
chemotherapy, though there can be substantial theoretical questions about
this approach, (e.g., does the known increase risk for local recurrence after
conversion to BCT contribute to decreased overall survival and cancel the
benefit of neoadjuvant treatment?)(Rouzier, Mathieu et al. 2004; Schwartz
2005; Viswambharan, Kadambari et al. 2005; Huang, Strom et al. 2006;
Kaufmann, Dauphine et al. 2006; Loibl, von Minckwitz et al. 2006)
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With the increased frequency of neoadjuvant therapy there has not been a
standard approach to the axillary nodes. It would be appropriate to consider
some standards.
The fundamental question underlying this analysis will be:
“What do we want to know and why do we think we want to know it”
• Is sentinel node ID possible in this setting?
• Is the sentinel node concept meaningful in this setting? I.e. => (Will it
change therapy/ Surgery, Chemo or Rad Rx?)
• Does a positive sentinel node imply additional positive nodes?
• Can ALND be avoided if SLN Negative?
• Should the approach for clinical N0 be different from N1/N2 patients?
• Should SLN BX be done pre Neoadj Rx (instead of or in addition to)
• Should a positive sentinel node in the Axillary Node Dissection Group
lead to more detailed study of additional nodes? If a sentinel node is
positive, added levels used to evaluate non-sentinel nodes may result in ~
20% positive non-sentinel node? (Will evidence of additional positive
nodes change Rx.)
• In ALND patients, it is the sentinel node “positive” by SLN protocol,
remainder “negative” by standard protocol that may be significant. If the
sentinel node is not identified the positive status may be missed, since it
may be the only positive node 50% of the time. If ALND “only”, without
SLN ID, then may miss metastases (at only two levels per node). SLN
the Only + node ~30-50%(Reitsamer, Peintinger et al. 2003; Mamounas,
Brown et al. 2005)
Other Issues
• Sentinel node count may be lower post neoadjuvant Rx(Neuman, Carey et
al. 2006)
• What is the correlation between in breast CPR and nodal CPR. Can true
CPR in the axilla be based on “standard pathology” of a standard ALND?
Axillary Nodes After Neoadjuvant ChemoRx
Le Bouedec, Geissler, et al
2006(Le Bouedec, Geissler et al. 2006)
• 74 pts T1T2T3N0N1 POST neo
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• SLN 68/74 (92%) then ALND
• Mets in 30/68 (44%) i.e. Neg 56%
• False neg 14% But if clinically neg N0 pre RX then accuracy 100% and
FN 0%
• In 32 N1 patients accuracy 83% FN 25%
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Reitsamer, Peintinger, et al (2003)(Reitsamer, Peintinger et al. 2003)
30 Patients Stage II or III, Rx Neoadj Chemo
Attempted SLN with completion ALND
SLN 26 of 30 (86.7%) (could not ID SLN in 4 (13.3%)
SLN accurate 25 of 26 (96.2%)
11 pts Neg SLN and Neg ALND
6 pts Pos SLN and Pos ALND
8 pts SLN pos and the only Pos node (~30%)
1 pt false-neg (1/15 = 6.7%)
Cohen, Breslin, et al (2000)(Cohen, Breslin et al. 2000)
38 pts, stage II or III treated with neoadjuvant chemo
SLN attempted then ALND
If SLN neg then all other nodes 3 add’l levels + IHC
SLN ID in 31 (82%) and accurate 28 (90%)
3 False neg
4 of 20 “neg” SLN with add’l studies + for occult mets (20%)
Kinoshita, Takasugi, et al, 2006(Kinoshita, Takasugi et al. 2006)
Post neo 77 pts Stage II and III
Clinically node neg post Rx
SLN then ALND
SLN ID 72 of 77 (93.5%)
69 of 72 accurate (95.8%)
3 of 27 False Neg (11%)
Mamounas, Brown et al
NSABP B-27(Mamounas, Brown et al. 2005)
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428 pts
SLN then ALND
SLN ID 89% with isotope
+SLN the only + node in 56% (70 of 125)
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• Of 218 Neg SLN nonsent + 15 => False neg 11%
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Kuerer, Sahin, et al (1999)(Kuerer, Sahin et al. 1999)
191 pts “cyto +” ALN => neoadj chemo
Surgery ALND
43 pts ALND “neg” re-eval confirmed Neg (add’l 1112 sections/half IHC)
=>43 of 191 “+” converted to neg (23%) by neoadj chemo
Of those 43, 11 were N1 and 32 were N2
If Converted to Neg: 5 yr surv = 87%
If Residual Positive: 5 yr surv = 51%
If Occult Positive (10%): 5 yr = 75%
Proposed: maybe consider SLN
POST-NEO PTS
SLN
SLN ID
False Neg
SLN
Accurate
Le Bouedec 74 PTs
2006
SL/ALND
68
(92%)
14%
If cN0 pre
0%
83%
100%
Reitsamer
30
2003
SLN/ALND
Cohen
38
2000
SLN/ALND
26
86%
25/26
96%
31
82%
28/30
90%
Kinoshita
77
2006
SLN/ALND
B-27
428
72/77
93%
3/27
11%
89%
11%
SLN only+
8/30
30%
72/77
96%
70/125
56%
SLN before Neo adjuvant
Van Rijk, Nieweg, et al 2006(van Rijk, Nieweg et al. 2006)
• Reviewed 18 studies SLN after neoRX, SLN ID 89%, FN 10%
Then studied:
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SLN in 25 T2 pre RX
If pre SLN + then ALND after neoadj
10 pos SLN=>post Rx ALND=> 4 pts add’l nodes pos in compl ALND
14 SLN Neg pts=> no completion ALND =>no recurrence 18 mo
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Kahn, Sabel, et al 2005(Khan, Sabel et al. 2005)
91 patients pre neo axillary staging
Pre neo SLN Bx path Neg 58% (53 pts)
Pre neo Pos by US FNA or SLN 42% (38 pts)
These 38 pts then Neo=>then ALND
33 of these SLN attempted, found 32 (97%)
33% of these Node Negative on ALND
Residual disease 22 patients
“False negative” 1 pt (4.5%)
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Cox,Cox, et al., 2006(Cox, Cox et al. 2006)
89 pts (42 palp or image+ histo proven; 47 cN0)
47 cN0 SLN preRX
82 of 89 + nodes
7 (8%) of 89 neg SLN=>no completion ALND (no recurrence in25 mo)
24 (27%) pCR axilla; 26% grp 1 and 33% grp 2
Demonstrated improved prognosis, avoided ALND 15%, improved
staging 53%
Comparison
Jones, Zabicki, et al., 2005(Jones, Zabicki et al. 2005)
• SLN ID rates better pre than post 100% vs 80.6%
• Recommend SLN in cN0 pre Rx and question its use post neo
Proposed
• If accuracy is important to the overall treatment planning and
sequencing, then pre-treatment workup requires staging the axilla. If
clinically + or US + then Bx; if cN0 and US/N0 Then SLN Bx pretreatment
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• If pre-treatment SLN is negative (with good mapping and careful
assessment), then leave the axilla alone post treatment.
• If pre-treatment SLN or US/FNA are positive, then post treatment
ALND with SLN ID.
• If post treatment axillary status is important in defining added
treatment then repeat SLN and complete ALND with additional levels
in non-SLNs if the SLN is positive.
Next Question: IBTR
The increased use of breast conservation therapy will continue to increase
the number of patients who present with ipsilateral in breast recurrence
(perhaps as high as 1-2% per year). In this setting prior axillary
interventions (ALND or SLN Bx) have generally been performed. These
“recurrences” represent both true recurrences (same site) and new primaries.
In many of these patients the implication of node metastases, or lack thereof,
should be equivalent to the original setting. If knowledge of the nodal status
is therapeutically important, then reassessment is required. This may be
particularly important in “late” recurrences that are more likely to be true
new primaries. A number of studies have looked at the question of “repeat
nodal evaluations”.
Dinan, Nagle, et al 2005(Dinan, Nagle et al. 2005)
• 16 pts second IBTR
• Lymphoscintigraphy pos 69%
• Ipsi ax, contra ax, supraclav (ipsi and contra)
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Intra, Trifiro, et al, 2005(Intra, Trifiro et al. 2005)
79 pts recurrent disease prior SLN 18 pts cN0 ~ 26 mo after initial Dx/Rx
Pre op ID SLN 100% with lymphoscintigrapy and SLN removed average
1.3
SLN pos in 2 patients
At 12 mo no recurrences in pts SLN Neg w/o ALND
Re-operative SLN
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Taback, Nguyen, et al 2006(Taback, Nguyen et al. 2006)
15 pts prior Rx BCT with IBTR and prior SLN or ALND
Preop Lymphoscintig + 11 (73%)
3 contralat ax, 5 ipsilat ax, 2 IM, 2 SC, 2 Intra pect
Intraop ID 11 of 14, Mets in 3; 2 contralat ax and 1 ipsilat ax
Individual Reports
• Milardovic 2006 Epigastric node(Milardovic, Castellon et al. 2006)
• Jackson 2006 IBTR prior neg now Pos SLN single pt(Jackson, Kim et al.
2006)
• Agarwal 2005 Two pts prior BCT with ALND => IBTR => SLN
contralateral +. SLN neg X 2(Agarwal, Heron et al. 2005)
Newman 2006(Newman, Cimmino et al. 2006)
• 14 LRR (10 previous ALND, 2 SLN, 2 no ax surg)
• SLN ID 90% no mets, non ipsilat drainage in 65%
Proposed
• With IBTR and prior Ax RX SLN ID (a neo-SLN) is possible ~ 70%
of the time, but the potential sites are many. Therefore
lymphoscintigraphy and planning SLN Bx are justified if a change in
therapy would occur; e.g. 1) If a positive ipsi- or contra- lateral
axillary neo-SLN would then lead to ALND. 2) If a positive neo-SLN
would lead to an increase in Chemo Rx or Rad Rx. (For internalmammary and supraclavicular nodes minimal data is available, but
Chemo or Radiation are probably the only useful interventions if
nodes are proven positive.)
References:
Agarwal, A., D. E. Heron, et al. (2005). "Contralateral uptake and metastases in
sentinel lymph node mapping for recurrent breast cancer." J Surg Oncol 92(1): 48.
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BACKGROUND AND OBJECTIVES: Sentinel lymph node mapping as a
constitutive component in the staging process for invasive breast cancer
continues to gain acceptance. We have identified two patients with
recurrent invasive breast cancer in whom contralateral sentinel lymph
node uptake and metastases, respectively, were detected. Such findings
have not been previously reported in our review of the medical literature
between 1966 and October 2004. METHODS: Sentinel lymph node
mapping was performed on two patients with recurrent invasive breast
cancer at our institution. At the time of their index diagnosis, both had
received breast conserving surgery and an axillary lymph node dissection
with post-operative radiotherapy (RT). All lymph nodes and margins of
resection were without tumor. Both patients remained with no evidence of
disease for years until routine serial screening mammography was
interpreted as suspicious. Each underwent a stereotactic biopsy of the
ipsilateral breast corresponding to the mammographic abnormality.
Pathology confirmed invasive ductal carcinoma. Both patients refused the
recommended salvage mastectomy. PRINCIPAL RESULTS: During a
second attempt at breast conservation, sentinel lymph node mapping-which is typically contraindicated for patients with prior axillary surgery-revealed contralateral axillary uptake for both patients. The respective
contralateral sentinel node was excised with pathology revealing no tumor
in one case, and a microscopic focus of metastatic carcinoma in the
second case. MAJOR CONCLUSION: Some patients may benefit from
sentinel lymph node mapping prior to salvage mastectomy. Identifying
uptake in a contralateral sentinel lymph node may change the multidisciplinary management of recurrent invasive breast cancer to include a
contralateral axillary dissection, chemotherapy, and/or RT to the
contralateral axilla.
Arnould, L., M. Gelly, et al. (2006). "Trastuzumab-based treatment of HER2positive breast cancer: an antibody-dependent cellular cytotoxicity mechanism?"
Br J Cancer 94(2): 259-67.
This study evaluated by immunohistochemistry (IHC) immune cell
response during neoadjuvant primary systemic therapy (PST) with
trastuzumab in patients with HER2-positive primary breast cancer. In all,
23 patients with IHC 3+ primary breast cancer were treated with
trastuzumab plus docetaxel. Pathological complete and partial responses
were documented for nine (39%) and 14 (61%) patients, respectively.
Case-matched controls comprised patients treated with docetaxel-based
PST without trastuzumab (D; n=23) or PST without docetaxel or
trastuzumab (non-taxane, non-trastuzumab, NT-NT; n=23). All surgical
specimens were blind-analysed by two independent pathologists, with
immunohistochemical evaluation of B and T lymphocytes, macrophages,
dendritic cells and natural killer (NK) cells. Potential cytolytic cells were
stained for Granzyme B and TiA1. HER2 expression was also evaluated in
residual tumour cells. Trastuzumab treatment was associated with
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significantly increased numbers of tumour-associated NK cells and
increased lymphocyte expression of Granzyme B and TiA1 compared with
controls. This study supports an in vivo role for immune (particularly NK
cell) responses in the mechanism of trastuzumab action in breast cancer.
These results suggest that trastuzumab plus taxanes lead to enhanced
NK cell activity, which may partially account for the synergistic activity of
trastuzumab and docetaxel in breast cancer.
Breslin, T. M., L. Cohen, et al. (2000). "Sentinel lymph node biopsy is accurate
after neoadjuvant chemotherapy for breast cancer [In Process Citation]." J Clin
Oncol 18(20): 3480-6.
PURPOSE: Sentinel lymph node (SLN) biopsy has proved to be an
accurate method for detecting nodal micrometastases in previously
untreated patients with early-stage breast cancer. We investigated the
accuracy of this technique for patients with more advanced breast cancer
after neoadjuvant chemotherapy. PATIENTS AND METHODS: Patients
with stage II or III breast cancer who had undergone doxorubicin-based
neoadjuvant chemotherapy before breast surgery were eligible.
Intraoperative lymphatic mapping was performed with peritumoral
injections of blue dye alone or in combination with technetium-labeled
sulfur colloid. All patients were offered axillary lymph node dissection.
Negative sentinel and axillary nodes were subjected to additional
processing with serial step sectioning and immunohistochemical staining
with an anticytokeratin antibody to detect micrometastases. RESULTS:
Fifty-one patients underwent SLN biopsy after neoadjuvant chemotherapy
from 1994 to 1999. The SLN identification rate improved from 64.7% to
94.1%. Twenty-two (51.2%) of the 43 successfully mapped patients had
positive SLNs, and in 10 of those 22 patients (45.5%), the SLN was the
only positive node. Three patients had false-negative SLN biopsy; that is,
the sentinel node was negative, but at least one nonsentinel node
contained metastases. Additional processing revealed occult
micrometastases in four patients (three in sentinel nodes and one in a
nonsentinel node). CONCLUSION: SLN biopsy is accurate after
neoadjuvant chemotherapy. The SLN identification improved with
experience. False- negative findings occurred at a low rate throughout the
series. This technique is a potential way to guide the axillary treatment of
patients who are clinically node negative after neoadjuvant chemotherapy.
Chung, M. A., T. DiPetrillo, et al. (2002). "Treatment of the axilla by tangential
breast radiotherapy in women with invasive breast cancer." Am J Surg 184(5):
401-2.
BACKGROUND: The objective of this study was to determine if standard
tangential breast radiation covered the sentinel lymph node in women with
invasive breast cancer. METHODS: Women with invasive breast cancer
treated by lumpectomy, radiotherapy and sentinel node biopsy at our
institution were included in this study if the sentinel lymph node site had
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been marked with a clip. Plain films were used to determine if the clip fell
within the tangential fields. RESULTS: Between April 1999 and May 2001,
36 women with invasive breast cancer treated by lumpectomy, sentinel
lymph node biopsy and breast radiation were identified. Median age was
56 years (range 34 to 80) with a median tumor size of 1.1 cm (range 0.3 to
2.9 cm). The clip marking the sentinel lymph node fell within the tangential
fields in 34 of 36 (94%) of the patients. The radiation dose to the clip area
was greater than 4,400 cGy in 50% of those calculated by threedimensional techniques. CONCLUSIONS: The sentinel lymph node is
located within classic tangential fields in the overwhelming majority of
women with invasive breast cancer. The extent of the radiation fields, and
ultimately the final dose, may need to be modified if the intent is for
prophylactic treatment.
Cohen, L. F., T. M. Breslin, et al. (2000). "Identification and evaluation of axillary
sentinel lymph nodes in patients with breast carcinoma treated with neoadjuvant
chemotherapy." Am J Surg Pathol 24(9): 1266-72.
Sentinel lymph node (SLN) biopsy has been shown to predict axillary
metastases accurately in early stage breast cancer. Some patients with
locally advanced breast cancer receive preoperative (neoadjuvant)
chemotherapy, which may alter lymphatic drainage and lymph node
structure. In this study, we examined the feasibility and accuracy of SLN
mapping in these patients and whether serial sectioning and keratin
immunohistochemical (IHC) staining would improve the identification of
metastases in lymph nodes with chemotherapy-induced changes. Thirtyeight patients with stage II or III breast cancer treated with neoadjuvant
chemotherapy were included. In all patients, SLN biopsy was attempted,
and immediately afterward, axillary lymph node dissection was performed.
If the result of the SLN biopsy was negative on initial hematoxylin and
eosin-stained sections, all axillary nodes were examined with three
additional hematoxylin and eosin sections and one keratin IHC stain.
SLNs were identified in 31 (82%) of 38 patients. The SLN accurately
predicted axillary status in 28 (90%) of 31 patients (three false negatives).
On examination of the original hematoxylin and eosin-stained sections, 20
patients were found to have tumor-free SLNs. With the additional sections,
4 (20%) of these 20 patients were found to have occult lymph node
metastases. These metastatic foci were seen on the hematoxylin and
eosin staining and keratin IHC staining. Our findings indicate that lymph
node mapping in patients with breast cancer treated with neoadjuvant
chemotherapy can identify the SLN, and SLN biopsy in this group
accurately predicts axillary nodal status in most patients. Furthermore,
serial sectioning and IHC staining aid in the identification of occult
micrometastases in lymph nodes with chemotherapy-induced changes.
Cox, C. E., J. M. Cox, et al. (2006). "Sentinel node biopsy before neoadjuvant
chemotherapy for determining axillary status and treatment prognosis in locally
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advanced breast cancer." Ann Surg Oncol 13(4): 483-90.
BACKGROUND: Treatment of locally advanced breast cancer with
neoadjuvant chemotherapy assesses an in vivo tumor response while
increasing breast conservation. Axillary clearance of nodal disease after
treatment defines prognostic stratification. Our study objective was to
show that sentinel node staging before treatment can optimize
posttreatment prognostic stratification in clinically N0 patients. METHODS:
Eighty-nine patients with locally advanced breast cancer were treated with
neoadjuvant chemotherapy. Of these, 42 (47%) clinically palpable or
image-detected nodes (cN+) were histologically confirmed before
treatment (group 1), and 47 (53%) patients without palpable lymph nodes
(cN0) had a sentinel lymph node (SLN) biopsy before treatment (group 2).
Survival analysis was conducted with the Kaplan-Meier method.
RESULTS: In groups 1 and 2, 82 (92%) of 89 patients had node-positive
disease before treatment. Seven (8%) of 89 had negative SLNs and no
completion axillary lymph node dissection, 24 (27%) patients had a
complete pathologic axillary response (pCRAX; 11 [26%] of 42 in group 1
and 13 [33%] of 40 in group 2), and 58 (65%) of 89 had residual disease
in the axilla. Breast-conserving therapy was applied to 27 (30%) of 89
patients. The seven SLN-negative patients had no axillary recurrence at
25 months, and pCRAX patients had a significantly higher overall survival
than patients with residual disease. CONCLUSIONS: This study validates
the prognostic stratification of patients with a complete pathologic axillary
response to neoadjuvant chemotherapy. The addition of SLN biopsy to
cN0 patients before treatment increased accurate nodal staging by 53%,
eliminated completion axillary lymph node dissection in 15%, and
demonstrated an improved prognosis in 28% of pCRAX patients. SLN
biopsy before treatment provides accurate staging of cN0 patients; allows
acquisition of standard treatment markers, prognostic biomarkers, and
microarray analysis; and affords prognostic stratification after treatment.
Dinan, D., C. E. Nagle, et al. (2005). "Lymphatic mapping and sentinel node
biopsy in women with an ipsilateral second breast carcinoma and a history of
breast and axillary surgery." Am J Surg 190(4): 614-7.
BACKGROUND: Women with a history of breast and axillary surgery may
demonstrate aberrant lymphatic drainage caused by disrupted lymphatic
channels. Lymphoscintigraphy may be valuable in evaluation and staging
of an ipsilateral second breast carcinoma. METHODS: We conducted a
retrospective review of 16 women treated for a second ipsilateral breast
carcinoma who underwent breast lymphoscintigraphy and intraoperative
lymphatic mapping. Drainage patterns were compared with pathologic and
operative findings. RESULTS: Lymphoscintigraphy succeeded in 69% of
patients and demonstrated widely varied drainage patterns including
ipsilateral axillary and supraclavicular as well as contralateral axillary and
supraclavicular basins. No trend between successful lymphatic mapping
and multiple clinical and pathologic measures was seen. CONCLUSIONS:
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In women with a second ipsilateral breast carcinoma and history of
previous breast and axillary surgery, lymphoscintigraphy is feasible.
Drainage patterns vary widely including across the midline of the thorax.
Preoperative lymphoscintigraphy may be useful to ensure inclusion of
potential sentinel nodes within the operative field.
Dowlatshahi, K., M. Fan, et al. (1999). "Occult metastases in the sentinel lymph
nodes of patients with early stage breast carcinoma: A preliminary study [see
comments]." Cancer 86(6): 990-6.
BACKGROUND: Thirty percent of lymph node negative patients with
operable breast carcinoma experience disease recurrence within 10
years. Retrospective serial sectioning of axillary lymph nodes has
revealed undetected metastases in 9-30% of these patients. These occult
metastases have been shown to have an adverse effect on survival. Serial
sectioning (SS) is impractical for all axillary lymph nodes harvested from
Levels I and II, but it is feasible if applied only to sentinel lymph nodes.
METHODS: Sentinel lymph nodes from 52 patients with invasive breast
carcinoma were cut at 2 mm intervals, fixed in 10% formalin, and
embedded in paraffin. Sections were taken from the blocks, stained with
hematoxylin and eosin (H & E), and compared with cytokeratin-stained
sections taken at 0.25 mm intervals throughout the entire blocks.
RESULTS: Tumor metastases were found in 6 patients (12%) when the
sentinel lymph nodes were sectioned at 2 mm intervals and stained with H
& E, compared with 30 patients (58%) when the same lymph nodes were
serially sectioned at 0.25 mm intervals and stained with cytokeratin. Of 24
patients whose metastases were detected by SS and cytokeratin staining,
12 had isolated tumor cells and 12 had colonies of several thousand
malignant cells. CONCLUSIONS: Routine histologic examination of
axillary lymph nodes, including sentinel lymph nodes, in cases of breast
carcinoma significantly underestimates lymph node metastases. This
deficiency may be overcome by SS of the entire lymph nodes and staining
with a specific monoclonal antibody. The percentage of patients found to
have colonies of cells that were missed by routine sectioning corresponds
closely to the percentage of "lymph node negative" patients who would be
expected to relapse. The true clinical significance of these occult
metastases will be determined by long term follow-up. [See editorial on
pages 905-7, this issue.] Copyright 1999 American Cancer Society.
Fant, J. S., M. D. Grant, et al. (2003). "Preliminary outcome analysis in patients
with breast cancer and a positive sentinel lymph node who declined axillary
dissection." Ann Surg Oncol 10(2): 126-30.
BACKGROUND: This retrospective study was designed to provide a
preliminary outcome analysis in patients with positive sentinel nodes who
declined axillary dissection. METHODS: A review was conducted of
patients who underwent lumpectomy and sentinel lymph node excision for
invasive disease between January 1998 and July 2000. Those who were
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found to have sentinel lymph node metastasis without completion axillary
dissection were selected for evaluation. Follow-up included physical
examination and mammography. RESULTS: Thirty-one patients were
identified who met inclusion criteria. Primary invasive cell types included
infiltrating ductal carcinoma, infiltrating lobular carcinoma, and mixed
cellularity. Most primary tumors were T1. Nodal metastases were
identified by hematoxylin and eosin stain and immunohistochemistry.
Twenty-seven of the metastases were microscopic (<2 mm), and the
remaining four were macroscopic. All patients received adjuvant systemic
therapy. With a mean follow-up of 30 months, there have been no patients
with axillary recurrence on physical examination or mammographic
evaluation. CONCLUSIONS: We have presented patients with sentinel
lymph nodes involved by cancer who did not undergo further axillary
resection and remain free of disease at least 1 year later. This preliminary
analysis supports the inclusion of patients with subclinical axillary disease
in trials that randomize to observation alone.
Fisher, B., J. H. Jeong, et al. (2002). "Twenty-five-year follow-up of a randomized
trial comparing radical mastectomy, total mastectomy, and total mastectomy
followed by irradiation." N Engl J Med 347(8): 567-75.
BACKGROUND: In women with breast cancer, the role of radical
mastectomy, as compared with less extensive surgery, has been a matter
of debate. We report 25-year findings of a randomized trial initiated in
1971 to determine whether less extensive surgery with or without radiation
therapy was as effective as the Halsted radical mastectomy. METHODS:
A total of 1079 women with clinically negative axillary nodes underwent
radical mastectomy, total mastectomy without axillary dissection but with
postoperative irradiation, or total mastectomy plus axillary dissection only
if their nodes became positive. A total of 586 women with clinically positive
axillary nodes either underwent radical mastectomy or underwent total
mastectomy without axillary dissection but with postoperative irradiation.
Kaplan-Meier and cumulative-incidence estimates of outcome were
obtained. RESULTS: No significant differences were observed among the
three groups of women with negative nodes or between the two groups of
women with positive nodes with respect to disease-free survival, relapsefree survival, distant-disease-free survival, or overall survival. Among
women with negative nodes, the hazard ratio for death among those who
were treated with total mastectomy and radiation as compared with those
who underwent radical mastectomy was 1.08 (95 percent confidence
interval, 0.91 to 1.28; P=0.38), and the hazard ratio for death among those
who had total mastectomy without radiation as compared with those who
underwent radical mastectomy was 1.03 (95 percent confidence interval,
0.87 to 1.23; P=0.72). Among women with positive nodes, the hazard ratio
for death among those who underwent total mastectomy and radiation as
compared with those who underwent radical mastectomy was 1.06 (95
percent confidence interval, 0.89 to 1.27; P=0.49). CONCLUSIONS: The
14
findings validate earlier results showing no advantage from radical
mastectomy. Although differences of a few percentage points cannot be
excluded, the findings fail to show a significant survival advantage from
removing occult positive nodes at the time of initial surgery or from
radiation therapy.
Fuhrman, G. M., J. Gambino, et al. (2005). "5-year follow-up after sentinel node
mapping for breast cancer demonstrates better than expected treatment
outcomes." Am Surg 71(7): 564-9; discussion 569-70.
We conducted this study to provide one of the initial assessments of
treatment outcomes for breast cancer patients evaluated with sentinel
node mapping. All patients diagnosed with breast carcinoma, evaluated
with sentinel node mapping, and followed for 5 years were divided into
three groups depending on sentinel node(s) status. Group I (node
negative) included 91 patients, 77 with invasive cancer, and 7 lost to
follow-up. Of the remaining 70 patients, 3 (4.3%) suffered a distant
recurrence and died, 1 developed an in-breast recurrence, and 9 (12.9%)
developed a contralateral cancer during the study. Group II (IHC positive)
included 28 patients. One (3.6%) developed a distant recurrence and died
of breast cancer, and one developed a contralateral cancer during follow.
Group III (H&E positive) included 36 patients with 1 lost to follow-up. Five
patients (14.3%) died of breast cancer and two (5.7%) developed
contralateral carcinomas during follow-up. The most striking observation
was a lower than expected rate of distant recurrences in these patients
followed for 5 years after a diagnosis of breast cancer and staging with
sentinel node mapping. The ability to identify subtle nodal metastasis and
design appropriate systemic therapeutic strategies may explain this
finding.
Gervasoni, J. E., Jr., C. Taneja, et al. (2000). "Axillary dissection in the context of
the biology of lymph node metastases." Am J Surg 180(4): 278-83.
BACKGROUND: Modern breast surgery, as the primary treatment of
invasive breast carcinoma, has been evolving over the last century.
Aggressive radical surgery, which included chest wall resection, complete
axillary clearance and internal mammary node dissection, has slowly
changed to a less aggressive approach. This has been based on an
improved understanding of the biology of the disease. Over the years,
randomized prospective trials, performed at centers all over the world,
have demonstrated that axillary dissection does not impact on the overall
survival while it helps with loco-regional control of breast cancer. Its major
role, at the present time, is limited to staging and prognostication;
functions that are equally well served by the limited approach of a sentinel
node biopsy. SOURCES: This review is based on the available medical
literature involving the biology and organ specificity of the metastatic
process, not only in breast cancer but also in other malignancies. In
addition, studies pertaining to clinical breast cancer, and the role of
15
surgery in its treatment, were reviewed. The ongoing trials on the role of
sentinel node biopsy in the management of the clinically node negative
patients are discussed. CONCLUSIONS: This review covers the history,
pathophysiology, and clinical basis of the current role of axillary dissection
for invasive breast cancer. From the data presented we hope that the
medical community will agree that there is no therapeutic role for extended
axillary dissection at the current time.
Greco, M., R. Agresti, et al. (2000). "Breast cancer patients treated without
axillary surgery: clinical implications and biologic analysis." Ann Surg 232(1): 1-7.
Hennessy, B. T., G. N. Hortobagyi, et al. (2005). "Outcome after pathologic
complete eradication of cytologically proven breast cancer axillary node
metastases following primary chemotherapy." J Clin Oncol 23(36): 9304-11.
PURPOSE: Pathologic complete remission (pCR) of primary breast
tumors after primary chemotherapy (PCT) is associated with higher
relapse-free survival (RFS) and overall survival (OS) rates. The purpose of
this study was to determine long-term outcome in patients achieving pCR
of cytologically proven axillary lymph node (ALN) metastases. METHODS:
Patients with cytologically documented ALN metastases were treated in
five prospective PCT trials. After surgery, patients were subdivided into
those with and without residual ALN carcinoma. Survival was calculated
by the Kaplan-Meier method. RESULTS: Of 925 patients treated, 403
patients had cytologically confirmed ALN metastases. Eighty-nine patients
(22%) achieved ALN pCR after PCT. Compared with the group without
ALN pCR, 5-year OS and RFS were improved in patients achieving ALN
pCR (93% [95% CI, 87.5 to 98.5] and 87% [95% CI, 79.7 to 94.3] v 72%
[95% CI, 66.5 to 77.5] and 60% [95% CI, 54.1 to 65.9], respectively; P <
.0001). Residual primary tumor did not affect outcome of those with ALN
pCR. Combination anthracycline/taxane-based PCT resulted in
significantly more ALN pCRs, although outcome after ALN pCR was not
improved by taxanes. We constructed a nomogram demonstrating that
patients who do not benefit from neoadjuvant anthracyclines are unlikely
to benefit from subsequent taxanes. CONCLUSION: ALN pCR is
associated with an excellent prognosis, even with a residual primary
tumor, pointing to biologic differences between primary and metastatic
cells. ALN pCR represents an early surrogate marker of long-term
outcome. Response to initial PCT has important potential as a guide to
subsequent therapy.
Hess, K. R., K. Anderson, et al. (2006). "Pharmacogenomic predictor of
sensitivity to preoperative chemotherapy with paclitaxel and fluorouracil,
doxorubicin, and cyclophosphamide in breast cancer." J Clin Oncol 24(26): 423644.
PURPOSE: We developed a multigene predictor of pathologic complete
response (pCR) to preoperative weekly paclitaxel and fluorouracil-
16
doxorubicin-cyclophosphamide (T/FAC) chemotherapy and assessed its
predictive accuracy on independent cases. PATIENTS AND METHODS:
One hundred thirty-three patients with stage I-III breast cancer were
included. Pretreatment gene expression profiling was performed with
oligonecleotide microarrays on fine-needle aspiration specimens. We
developed predictors of pCR from 82 cases and assessed accuracy on 51
independent cases. RESULTS: Overall pCR rate was 26% in both
cohorts. In the training set, 56 probes were identified as differentially
expressed between pCR versus residual disease, at a false discovery rate
of 1%. We examined the performance of 780 distinct classifiers (set of
genes + prediction algorithm) in full cross-validation. Many predictors
performed equally well. A nominally best 30-probe set Diagonal Linear
Discriminant Analysis classifier was selected for independent validation. It
showed significantly higher sensitivity (92% v 61%) than a clinical
predictor including age, grade, and estrogen receptor status. The negative
predictive value (96% v 86%) and area under the curve (0.877 v 0.811)
were nominally better but not statistically significant. The combination of
genomic and clinical information yielded a predictor not significantly
different from the genomic predictor alone. In 31 samples, RNA was
hybridized in replicate with resulting predictions that were 97%
concordant. CONCLUSION: A 30-probe set pharmacogenomic predictor
predicted pCR to T/FAC chemotherapy with high sensitivity and negative
predictive value. This test correctly identified all but one of the patients
who achieved pCR (12 of 13 patients) and all but one of those who were
predicted to have residual disease had residual cancer (27 of 28 patients).
Huang, E. H., E. A. Strom, et al. (2006). "Comparison of risk of local-regional
recurrence after mastectomy or breast conservation therapy for patients treated
with neoadjuvant chemotherapy and radiation stratified according to a prognostic
index score." Int J Radiat Oncol Biol Phys 66(2): 352-7.
PURPOSE: We previously developed a prognostic index that stratified
patients treated with breast conservation therapy (BCT) after neoadjuvant
chemotherapy into groups with different risks for local-regional recurrence
(LRR). The purpose of this study was to compare the rates of LRR as a
function of prognostic index score for patients treated with BCT or
mastectomy plus radiation after neoadjuvant chemotherapy. METHODS:
We retrospectively analyzed 815 patients treated with neoadjuvant
chemotherapy, surgery, and radiation. Patients were assigned an index
score from 0 to 4 and given 1 point for the presence of each factor: clinical
N2 to N3 disease, lymphovascular invasion, pathologic size>2 cm, and
multifocal residual disease. RESULTS: The 10-year LRR rates were very
low and similar between the mastectomy and BCT groups for patients with
an index score of 0 or 1. For patients with a score of 2, LRR trended lower
for those treated with mastectomy vs. BCT (12% vs. 28%, p=0.28). For
patients with a score of 3 to 4, LRR was significantly lower for those
treated with mastectomy vs. BCT (19% vs. 61%, p=0.009).
17
CONCLUSIONS: This analysis suggests that BCT can provide excellent
local-regional treatment for the vast majority of patients after neoadjuvant
chemotherapy. For the few patients with a score of 3 to 4, LRR was >60%
after BCT and was <20% with mastectomy. If these findings are confirmed
in larger randomized studies, the prognostic index may be useful in
helping to select the type of surgical treatment for patients treated with
neoadjuvant chemotherapy, surgery, and radiation.
Intra, M., G. Trifiro, et al. (2005). "Second biopsy of axillary sentinel lymph node
for reappearing breast cancer after previous sentinel lymph node biopsy." Ann
Surg Oncol 12(11): 895-9.
BACKGROUND: Sentinel lymph node biopsy (SLNB) is a safe and
accurate axillary staging procedure for patients with primary operable
breast cancer. An increasing proportion of these patients undergo breastconserving surgery, and 5% to 15% will develop local relapses that
necessitate reoperation. Although a previous SLNB is often considered a
contraindication for a subsequent SLNB, few data support this concern.
METHODS: Between January 2000 and June 2004, 79 patients who were
previously treated at our institution with breast-conserving surgery and
who had a negative SLNB for early breast cancer developed, during
follow-up, local recurrence that was amenable to reoperation. Eighteen of
these patients were offered a second SLNB because of a clinically
negative axillary status an average of 26.1 months after the primary event.
RESULTS: In all 18 patients (7 with ductal carcinoma-in-situ and 11 with
invasive recurrences), preoperative lymphoscintigraphy showed an axillary
sentinel lymph node, with a preoperative identification rate of 100%, and 1
or more SLNs (an average of 1.3 per patient) were surgically removed.
Sentinel lymph node metastases were detected in two patients with
invasive recurrence, and a complete axillary dissection followed. At a
median follow up of 12.7 months, no axillary recurrences have occurred in
patients who did not undergo axillary dissection. CONCLUSIONS: Second
SLNB after previous SLNB is technically feasible and likely effective in
selected breast cancer patients. A larger population and longer follow-up
are necessary to confirm these preliminary data.
Jackson, B. M., S. Kim, et al. (2006). "Repeat operative sentinel lymph node
biopsy." Clin Breast Cancer 6(6): 530-2.
Because sentinel lymph node (SLN) biopsy continues to be used for
staging in patients with breast cancer, physicians treating these patients
will be faced with in-breast recurrences and new primary breast cancers in
the treated breast. Repeat operative SLN biopsy might be feasible in this
clinical scenario. This report describes the case of a patient with an
ipsilateral different-site, recurrent, infiltrating ductal carcinoma 14 months
after lumpectomy; negative SLN biopsy result; and radiation therapy, now
with a positive SLN biopsy result.
18
Jeruss, J. S., D. J. Winchester, et al. (2005). "Axillary recurrence after sentinel
node biopsy." Ann Surg Oncol 12(1): 34-40.
BACKGROUND: Sentinel node biopsy (SNB) has evolved as the standard
of care in the surgical staging of breast cancer. This technique is accurate
for surgical staging of axillary nodal disease. We hypothesized that axillary
recurrence after SNB is rare and that SNB may provide regional control in
patients with microscopic nodal involvement. METHODS: With institutional
review board approval, SNB was performed with peritumoral injection of
99mTc-labeled sulfur colloid. From 1996 to 2003, 1167 patients were
entered into a prospective cancer database after surgical therapy; 916
patients consented to long-term follow-up. Fifty-two patients (5.7%) did not
map successfully and were excluded, leading to a study population of 864
patients. The median follow-up was 27.4 months (range, 1-98 months).
RESULTS: The median number of sentinel nodes harvested was 2, and
633 (73%) patients had negative sentinel nodes. Thirty (4.7%) of those
sentinel node-negative patients underwent completion axillary dissection,
whereas 592 (94%) patients were followed up with observation. A total of
231 (27%) had positive sentinel nodes: 158 (68%) of these patients
underwent completion axillary dissection, and 73 (32%) were managed
with observation alone. Two (.32%) patients who were sentinel node
negative had an axillary recurrence; one of these patients had undergone
completion axillary dissection. No patient in the observed sentinel nodepositive group had an axillary recurrence (odds ratio, .37; P = .725).
CONCLUSIONS: On the basis of a median follow-up of 27.4 months,
axillary recurrence after SNB is extraordinarily rare regardless of nodal
involvement, thus indicating that this technique provides an accurate
measure of axillary disease and may impart regional control for patients
with node-positive disease.
Johansen, H., S. Kaae, et al. (1990). "Simple mastectomy with postoperative
irradiation versus extended radical mastectomy in breast cancer. A twenty-fiveyear follow-up of a randomized trial." Acta Oncol 29(6): 709-15.
From November 1951 to December 1957, all patients with untreated
breast cancer admitted to the Radium Centre in Copenhagen were
randomized before their operability was evaluated into two groups, if the
patients were operable, viz. simple mastectomy with postoperative x-ray
treatment or extended radical mastectomy. Twenty-five-year results are
presented, showing no difference in survival or recurrence-free survival of
the operable patients. Histological grading was performed in nearly all
cases. Patients with grade 1 tumours had a better survival than grades 2
and 3, but there was no difference in survival between the two treatment
groups, when histological grading was taken into account. Histological
node positive patients had more grades 2 and 3, tumours, whereas node
negative patients had more grade 1 than grades 2 and 3 tumours.
Premenopausal women had a significantly better survival than
postmenopausal in all stages.
19
Jones, J. L., K. Zabicki, et al. (2005). "A comparison of sentinel node biopsy
before and after neoadjuvant chemotherapy: timing is important." Am J Surg
190(4): 517-20.
BACKGROUND: Because neoadjuvant chemotherapy is being used more
frequently, the optimal timing of sentinel node biopsy (SNB) remains
controversial. We previously evaluated the predictive value of SNB before
neoadjuvant chemotherapy in clinically node-negative breast cancer. Our
identification rate of the sentinel node among 52 patients before
chemotherapy with a mean tumor size of 4 cm was 100%. In this study,
we compared the identification rates of SNB before and after neoadjuvant
chemotherapy and evaluated the false-negative rate of SNB after
chemotherapy. METHODS: A retrospective institutional database review
identified 36 women who underwent SNB after neoadjuvant chemotherapy
for breast cancer from 1999 to 2004. The initial clinical tumor size and
lymph node status, SNB pathology, axillary lymph node dissection
pathology, and residual pathologic tumor size were reviewed. RESULTS:
Sixteen of 36 patients had a clinically negative axilla before neoadjuvant
therapy. SNB after neoadjuvant therapy was successful in 29 patients
(80.6%), although 7 patients did not map (19.4%). Six of the 7 patients
who failed to map had a clinically positive axilla initially. Axillary disease
was found in 6 of 7 of these patients at dissection (85.7%). Of the 29
patients who mapped successfully, 13 (45%) were SNB negative, and 16
(55%) were SNB positive. Of the 13 SNB-negative patients, 2 had a
positive axillary lymph node dissection, yielding a false-negative rate of
11%. Thirteen patients who mapped had a clinically positive axilla before
therapy (45%). Of the 11 patients with true-negative SNBs, 7 (64%) were
clinically node negative at presentation. The initial tumor sizes on
examination ranged from 2 to 9 cm (mean, 5.0 cm), and residual
pathologic tumor sizes ranged from 0 to 6 cm (mean, 1.8 cm). Failure to
map correlated with a clinically positive axilla at presentation (100% vs
45%) but did not correlate with initial tumor size. CONCLUSIONS:
Sentinel node identification rates are significantly better when mapping is
performed before neoadjuvant chemotherapy (100% vs 80.6%), with
failure to map correlated with clinically positive nodal disease at
presentation and residual disease at axillary lymph node dissection.
Among patients who map successfully after chemotherapy, the falsenegative rate is high (11%). Given these findings, we currently
recommend SNB before neoadjuvant chemotherapy for clinically nodenegative patients, and raise concerns about the use of SNB after
neoadjuvant therapy in patients with an initially clinically positive axilla.
Karalak, A. and P. Homcha-Em (1999). "Occult axillary lymph node metastases
discovered by serial section in node-negative breast cancer." J Med Assoc Thai
82(10): 1017-9.
Serial sectioning of the axillary lymph nodes from lymph node-negative
20
breast cancer patients is presented. All patients were admitted between
1997-1998 and underwent mastectomy and axillary node dissection. The
histological examination revealed micrometastases in 5 (10%) of 50 breast
cancer subjects. The detection of these micrometastases in lymph nodes
may identify a high-risk node-negative population. The time and money
that was spent to detect the micrometastases was too high to perform it in
every case. The clinician should be aware of the occult micrometastases
in node-negative cases.
Kaufmann, P., C. E. Dauphine, et al. (2006). "Success of neoadjuvant
chemotherapy in conversion of mastectomy to breast conservation surgery." Am
Surg 72(10): 935-8.
Neoadjuvant chemotherapy (NC) in patients with breast cancer results in
high response rates and has been used with the purpose of reducing
tumor size and achieving breast conservation (BC) in individuals who
initially require mastectomy. Our objective is to determine the success of
NC in achieving BC in women who initially were not candidates for BC.
We conducted a cohort study of women with invasive breast cancer who
required mastectomy but desired BC surgery. Outcomes measured were
tumor response and rates of BC. Thirty-seven women had a mean age of
45 years. Mean tumor size was 51 mm, and 62 per cent were larger than
4 cm. Tumors were predominantly infiltrating ductal carcinoma (83.3%)
and high grade (62.2%). Cyclophosphamide, doxorubicin, and 5fluorouracil with or without taxotere were most commonly used (86%).
Complete clinical and pathologic responses were seen in 32.4 per cent
and 10.8 per cent of patients, respectively. BC was achieved in 56.7 per
cent of cases. Only initial tumor size predicted tumor regression and
success of BC (P = 0.014). Neither tumor histology nor biologic markers
predicted tumor response. In conclusion, NC is an effective alternative in
achieving tumor reduction and BC in selected patients who require
mastectomy but desire BC surgery.
Khan, A., M. S. Sabel, et al. (2005). "Comprehensive axillary evaluation in
neoadjuvant chemotherapy patients with ultrasonography and sentinel lymph
node biopsy." Ann Surg Oncol 12(9): 697-704.
BACKGROUND: There is ongoing debate regarding the optimal sequence
of sentinel lymph node (SLN) biopsy and neoadjuvant chemotherapy
(CTX) for breast cancer. We report the accuracy of comprehensive preneoadjuvant CTX and post-neoadjuvant CTX axillary staging via
ultrasound imaging, fine-needle aspiration (FNA) biopsy, and SLN biopsy.
METHODS: From 2001 to 2004, 91 neoadjuvant CTX patients at the
University of Michigan Comprehensive Cancer Center underwent axillary
staging by ultrasonography, ultrasound-guided FNA biopsy, SLN biopsy,
or a combination of these. RESULTS: Axillary staging was pathologically
negative by pre-neoadjuvant CTX SLN biopsy in 53 cases (58%); these
patients had no further axillary surgery. In 38 cases (42%), axillary
21
metastases were confirmed at presentation by either ultrasound-guided
FNA or SLN biopsy. These 38 patients underwent completion axillary
lymph node dissection (ALND) after delivery of neoadjuvant CTX. Followup lymphatic mapping was attempted in 33 of these cases, and the SLN
was identified in 32 (identification rate, 97%). One third of these cases
were completely node negative on ALND. Residual metastatic disease
was identified in 22 cases, and the SLN was falsely negative in 1 (4.5%).
CONCLUSIONS: Patients receiving neoadjuvant CTX can have accurate
axillary nodal staging by ultrasound-guided FNA or SLN biopsy. In cases
of documented axillary metastasis at presentation, repeat axillary staging
with SLN biopsy can document the post-neoadjuvant CTX nodal status.
This strategy optimizes pre-neoadjuvant CTX and post-neoadjuvant CTX
staging information by distinguishing the patients who are node negative
at presentation from those who have been downstaged to node negativity
and offers the potential for avoiding unnecessary ALNDs in both of these
patient subsets.
Kinoshita, T., M. Takasugi, et al. (2006). "Sentinel lymph node biopsy
examination for breast cancer patients with clinically negative axillary lymph
nodes after neoadjuvant chemotherapy." Am J Surg 191(2): 225-9.
BACKGROUND: The feasibility and accuracy of sentinel lymph node
(SLN) biopsy examination for breast cancer patients with clinically nodenegative breast cancer after neoadjuvant chemotherapy (NAC) have been
investigated under the administration of a radiocolloid imaging agent
injected intradermally over a tumor. In addition, conditions that may affect
SLN biopsy detection and false-negative rates with respect to clinical
tumor response and clinical nodal status before NAC were analyzed.
METHODS: Seventy-seven patients with stages II and III breast cancer
previously treated with NAC were enrolled in the study. All patients were
clinically node negative after NAC. The patients then underwent SLN
biopsy examination, which involved a combination of intradermal injection
over the tumor of radiocolloid and a subareolar injection of blue dye. This
was followed by standard level I/II axillary lymph node dissection.
RESULTS: The SLN could be identified in 72 of 77 patients (identification
rate, 93.5%). In 69 of 72 patients (95.8%) the SLN accurately predicted
the axillary status. Three patients had a false-negative SLN biopsy
examination result, resulting in a false-negative rate of 11.1% (3 of 27).
The SLN identification rate tended to be higher, although not statistically
significantly, among patients who had clinically negative axillary lymph
nodes before NAC (97.6%; 41 of 42). This is in comparison with patients
who had a positive axillary lymph node before NAC (88.6%; 31 of 35).
CONCLUSIONS: The SLN identification rate and false-negative rate were
similar to those in nonneoadjuvant studies. The SLN biopsy examination
accurately predicted metastatic disease in the axilla of patients with tumor
response after NAC and clinical nodal status before NAC. This diagnostic
technique, using an intradermal injection of radiocolloid, may provide
22
treatment guidance for patients after NAC.
Kuerer, H. M., A. A. Sahin, et al. (1999). "Incidence and impact of documented
eradication of breast cancer axillary lymph node metastases before surgery in
patients treated with neoadjuvant chemotherapy." Ann Surg 230(1): 72-8.
OBJECTIVE: To determine the incidence and prognostic significance of
documented eradication of breast cancer axillary lymph node (ALN)
metastases after neoadjuvant chemotherapy. SUMMARY BACKGROUND
DATA: Neoadjuvant chemotherapy is the standard of care for patients with
locally advanced breast cancer and is being evaluated in patients with
earlier-stage operable disease. METHODS: One hundred ninety-one
patients with locally advanced breast cancer and cytologically documented
ALN metastases were treated in two prospective trials of doxorubicinbased neoadjuvant chemotherapy. Patients had breast surgery with level I
and II axillary dissection followed by additional chemotherapy and
radiation treatment. Nodal sections from 43 patients who were originally
identified as having negative ALNs at surgery were reevaluated and
histologically confirmed to be without metastases. An additional 1112
sections from these lymph node blocks were obtained; half were stained
with an anticytokeratin antibody cocktail and analyzed. Survival was
calculated using the Kaplan-Meier method. RESULTS: Of 191 patients
with positive ALNs at diagnosis, 23% (43 patients) were converted to a
negative axillary nodal status on histologic examination (median number
of nodes removed = 16). Of the 43 patients with complete axillary
conversion, 26% (n = 11) had N1 disease and 74% (n = 32) had N2
disease. On univariate analysis, patients with complete versus incomplete
histologic axillary conversion were more likely to have initial estrogenreceptor-negative tumors, smaller primary tumors, and a complete
pathologic response in the primary tumor. The 5-year disease-free survival
rates were 87% in patients with preoperative eradication of axillary
metastases and 51% for patients with residual nodal disease after
neoadjuvant chemotherapy. Of the 39 patients with complete histologic
conversion for whom nodal blocks were available, occult nodal
metastases were found in additional nodal sections in 4 patients (10%). At
a median follow-up of 61 months, the 5- year disease-free survival rates
were 87% in patients without occult nodal metastases and 75% in patients
with occult nodal metastases. CONCLUSIONS: Neoadjuvant
chemotherapy can completely clear the axilla of microscopic disease
before surgery, and occult metastases are found in only 10% of patients
with a histologically negative axilla. The results of this study have
implications for the potential use of sentinel lymph node biopsy as an
alternative to axillary dissection in patients treated with neoadjuvant
chemotherapy.
Langer, I., W. R. Marti, et al. (2005). "Axillary recurrence rate in breast cancer
patients with negative sentinel lymph node (SLN) or SLN micrometastases:
23
prospective analysis of 150 patients after SLN biopsy." Ann Surg 241(1): 152-8.
OBJECTIVE: To assess the axillary recurrence rate in breast cancer
patients with negative sentinel lymph node (SLN) or SLN micrometastases
(>0.2 mm to <or=2.0 mm) after breast surgery and SLN procedure without
formal axillary lymph node dissection (ALND). SUMMARY
BACKGROUND DATA: Under controlled study conditions, the SLN
procedure proved to be a reliable method for the evaluation of the axillary
nodal status in patients with early-stage invasive breast cancer. Axillary
dissection of levels I and II can thus be omitted if the SLN is free of
macrometastases. The prognostic value and potential therapeutic
consequences of SLN micrometastases, however, remain a matter of
great debate. We present the follow-up data of our prospective SLN study,
particularly focusing on the axillary recurrence rate in patients with
negative SLN and SLN micrometastases. METHODS: In this prospective
study, 236 SLN procedures were performed in 234 patients with earlystage breast cancer between April 1998 and September 2002. The SLN
were marked and identified with 99m technetium-labeled colloid and blue
dye (Isosulfanblue 1%). The excised SLNs were examined by step
sectioning and stained with hematoxylin and eosin and
immunohistochemistry (cytokeratin antibodies Lu-5 or CK 22). Only
patients with SLN macrometastases received formal ALND of levels I and
II, while patients with negative SLN or SLN micrometastases did not
undergo further axillary surgery. RESULTS: The SLN identification rate
was 95% (224/236). SLN macrometastases were found in 33% (74/224)
and micrometastases (>0.2 mm to <or=2 mm) in 12% (27/224) of patients.
Adjuvant therapy did not differ between the group of SLN-negative
patients and those with SLN micrometastases. After a median follow-up of
42 months (range 12-64 months), 99% (222/224) of evaluable patients
were reassessed. While 1 patient with a negative SLN developed axillary
recurrence (0.7%, 1/122), all 27 patients with SLN micrometastases were
disease-free at the last follow-up control. CONCLUSIONS: Axillary
recurrences in patients with negative SLN or SLN micrometastases did not
occur more frequently after SLN biopsy alone compared with results from
the recent literature regarding breast cancer patients undergoing formal
ALND. Based on a median follow-up of 42 months-one of the longest so
far in the literature-the present investigation does not provide evidence
that the presence of SLN micrometastases leads to axillary recurrence or
distant disease and supports the theory that formal ALND may be omitted
in these patients.
Le Bouedec, G., B. Geissler, et al. (2006). "[Sentinel lymph node biopsy for
breast cancer after neoadjuvant chemotherapy: influence of nodal status before
treatment]." Bull Cancer 93(4): 415-9.
OBJECTIVES: To determine feasibility and accuracy of SLN biopsy in
locally advanced breast cancer treated by neoadjuvant chemotherapy.
MATERIALS AND METHODS: From April 2001 to December 2004, a
24
prospective series was constituted of 74 women with invasive breast
carcinoma T1T2T3N0N1 receiving neoadjuvant chemotherapy. The SLN
located was removed using subdermal periareolar injection of
radiolabelled nanocolloid and axillary lymph node dissection was
systematically performed. RESULTS: A SLN was identified in 68/74 (92%)
patients. It was metastatic in 30/68 cases (44%). The false negative (FN)
rate was 14% (5/35). In the subgroup of 42 patients clinically N(0) before
chemotherapy, accuracy was 100 %, and FN rate 0%, in the 32 N1,
accuracy was 83%, and FN rate 25%. CONCLUSIONS: SLN biopsy using
a single subdermal injection of radiolabelled nanocolloid in patients with a
breast cancer treated by neoadjuvant chemotherapy is technically feasible
and appears to be highly accurate in the subgroup of patients with a
clinically negative axilla breast cancer before treatment.
Lee, Y. J., P. Doliny, et al. (2004). "Docetaxel and cisplatin as primary
chemotherapy for treatment of locally advanced breast cancers." Clin Breast
Cancer 5(5): 371-6.
A phase II trial was designed to evaluate the effectiveness of
docetaxel/cisplatin as primary or neoadjuvant chemotherapy of locally
advanced breast carcinoma (LABC). Patients with newly diagnosed breast
cancers > or = 5 cm in size by palpation were treated with
docetaxel/cisplatin, both at 70 mg/m2 intravenously every 21 days for 4
courses. Upon completion of chemotherapy, all patients underwent
modified radical mastectomy with axillary nodal dissection. Pathologic
complete response (pCR) was defined as absence of any invasive
carcinoma in the breast. Standard AC (doxorubicin/cyclophosphamide) at
60 mg/m2 and 600 mg/m2, respectively, for 4 cycles was given as
adjuvant therapy to maximally eradicate occult distant disease. Between
March 1998 and October 2001, 57 women were entered onto this trial, 28
(49%) with inoperable T4 and inflammatory cancers. Pretreatment median
tumor size was 9 cm. Thirty-six patients (63%) had estrogen receptorpositive tumors and 10 patients (18%) had tumors with HER2
overexpression. All tumors became operable after neoadjuvant
chemotherapy. Pathologic complete response in the breast was achieved
in 15 patients (26%) and pCR in the breast and the axilla was achieved in
11 patients (20%). All neoadjuvant chemotherapy courses were
administered at full doses without treatment delays caused by toxicity. The
most common side effects were hyperglycemia, anemia, and mild
neuropathy. The results of this study suggest that the docetaxel/cisplatin
combination can be an effective and well-tolerated induction treatment of
LABC, even in very large mostly HER2-nonoverexpressing tumors.
Loibl, S., G. von Minckwitz, et al. (2006). "Surgical Procedures After Neoadjuvant
Chemotherapy in Operable Breast Cancer: Results of the GEPARDUO Trial."
Ann Surg Oncol.
BACKGROUND: Neoadjuvant chemotherapy can increase the rate of
25
breast-conserving surgery in patients with operable breast cancer.
However, uncertainty remains regarding surgical procedures and
predictors for successful breast-conserving surgery. METHODS: This
study was an analysis of surgical data of a representative data subset of
607 patients enrolled in the GEPARDUO study. This prospective,
multicenter, phase III study randomly assigned patients with operable
breast cancer (>/= 2 cm) to neoadjuvant 8-week dose-dense doxorubicin
plus docetaxel or a 24-week schedule of doxorubicin plus
cyclophosphamide followed by docetaxel (AC-DOC). RESULTS: Breast
conservation was attempted in 493 (81.2%) patients, but 43 patients
eventually required mastectomy, thus resulting in a breast-conserving
surgery rate of 74.1%. Breast-conserving re-excision was performed in 61
patients (12.4%). Factors associated with a significantly higher breastconserving surgery rate were a prechemotherapy tumor size </= 40 mm,
nonlobular histological characteristics, treatment with AC-DOC, clinical
response, postchemotherapy tumor size </= 20 mm, and treatment in a
larger center (>10 enrolled patients). Nonlobular histological
characteristics and intraoperative frozen-section analysis for margin
evaluation were associated with significantly lower reoperation rates (P =
.015). CONCLUSIONS: Breast conservation after neoadjuvant
chemotherapy is feasible in most patients with operable breast cancer. For
surgical planning, tumor characteristics and response to neoadjuvant
chemotherapy should be taken into account. Improved breast-imaging
modalities are necessary to improve detection of residual disease after
neoadjuvant chemotherapy, especially when breast cancer is of lobular
invasive histology. Margin assessment by intraoperative frozen-section
analysis is helpful to avoid reoperation. To achieve an optimal result, an
interdisciplinary surgical approach is important.
Louis-Sylvestre, C., K. Clough, et al. (2004). "Axillary treatment in conservative
management of operable breast cancer: dissection or radiotherapy? Results of a
randomized study with 15 years of follow-up." J Clin Oncol 22(1): 97-101.
PURPOSE: Axillary dissection is the standard management of the axilla in
invasive breast carcinoma. This surgery is responsible for functional
sequelae and some options are considered, including axillary
radiotherapy. In 1992, we published the initial results of a prospective
randomized trial comparing lumpectomy plus axillary radiotherapy versus
lumpectomy plus axillary dissection. We present an update of this study
with a median follow-up of 180 months (range, 12 to 221 months).
PATIENTS AND METHODS: Between 1982 and 1987, 658 patients with a
breast carcinoma less than 3 cm in diameter and clinically uninvolved
lymph nodes were randomly assigned to axillary dissection or axillary
radiotherapy. All patients underwent wide excision of the tumor and breast
irradiation. RESULTS: The two groups were similar for age, tumor-nodemetastasis system stage, and presence of hormonal receptors; 21% of the
patients in the axillary dissection group were node-positive. Our initial
26
results showed an increased survival rate in the axillary dissection group
at 5 years (P =.009). At 10 and 15 years, however, survival rates were
identical in both groups (73.8% v 75.5% at 15 years). Recurrences in the
axillary node were less frequent in the axillary dissection group at 15 years
(1% v 3%; P =.04). There was no difference in recurrence rates in the
breast or supraclavicular and distant metastases between the two groups.
CONCLUSION: In early breast cancers with clinically uninvolved lymph
nodes, our findings show that long-term survival does not differ after
axillary radiotherapy and axillary dissection. The only difference is a better
axillary control in the group with axillary dissection.
Low, J. A., A. W. Berman, et al. (2004). "Long-term follow-up for locally advanced
and inflammatory breast cancer patients treated with multimodality therapy." J
Clin Oncol 22(20): 4067-74.
PURPOSE: To determine long-term event-free (EFS) and overall survival
(OS) for patients with stage III breast cancer treated with combinedmodality therapy. PATIENTS AND METHODS: Between 1980 and 1988,
107 patients with stage III breast cancer were prospectively enrolled for
study at the National Cancer Institute and stratified by whether or not they
had features of inflammatory breast cancer (IBC). Patients were treated to
best response with cyclophosphamide, doxorubicin, methotrexate,
fluorouracil, leucovorin, and hormonal synchronization with conjugated
estrogens and tamoxifen. Patients with pathologic complete response
received definitive radiotherapy to the breast and axilla, whereas patients
with residual disease underwent mastectomy, lymph node dissection, and
radiotherapy. All patients underwent six additional cycles of adjuvant
chemotherapy. RESULTS: OS and EFS were obtained with a median live
patient follow-up time of 16.8 years. The 46 IBC patients had a median OS
of 3.8 years and EFS of 2.3 years, compared with 12.2 and 9.0 years,
respectively, in stage IIIA breast cancer patients. Fifteen-year OS survival
was 20% for IBC versus 50% for stage IIIA patients and 23% for stage IIIB
non-IBC. Pathologic response was not associated with improved survival
for stage IIIA or IBC patients. Presence of dermal lymphatic invasion did
not change the probability of survival in clinical IBC patients.
CONCLUSION: Fifteen-year follow-up of stage IIIA and inflammatory
breast cancer is rarely reported; IBC patients have a poor long-term
outlook.
Lymberis, S. C., P. K. Parhar, et al. (2004). "Pharmacogenomics and breast
cancer." Pharmacogenomics 5(1): 31-55.
Germline variants can be used to study breast cancer susceptibility as well
as the variable response to both drug and radiation therapy used in the
treatment of breast cancer. In addition to germline high-penetrance
mutations important in familial and hereditary breast cancer, a substantial
component of breast cancer risk can be attributed to the combined effect
of many low-risk germline polymorphisms involved in relevant pathways
27
like those of DNA repair, adhesion, carcinogen and estrogen metabolism.
Additionally, the identification of sequence variants in genes involved in
response to chemotherapy and radiation treatment, has created the
opportunity to apply genomics to individualized treatment. The continued
insight into the molecular pathways involved in drug and radiation
response has enabled progress in tailoring therapies in such a way as to
both maximize efficacy and minimize toxicity. Polymorphisms in genes
encoding drug-metabolizing enzymes, drug transporters and drug targets
can be used to predict toxicity and response to pharmacologic agents
used in breast cancer treatment. Similarly, germline variants in genes
involved in DNA repair, radiation-induced fibrosis and reactive oxygen
species may be used to predict response to radiation therapy. As a result,
pharmacogenomics is rapidly evolving to affect the entire spectrum of
breast cancer management, influencing both prevention and treatment
choices.
Mamounas, E. P., A. Brown, et al. (2005). "Sentinel node biopsy after
neoadjuvant chemotherapy in breast cancer: results from National Surgical
Adjuvant Breast and Bowel Project Protocol B-27." J Clin Oncol 23(12): 2694702.
PURPOSE: Experience with sentinel node biopsy (SNB) after neoadjuvant
chemotherapy is limited. We examined the feasibility and accuracy of this
procedure within a randomized trial in patients treated with neoadjuvant
chemotherapy. PATIENTS AND METHODS: During the conduct of
National Surgical Adjuvant Breast and Bowel Project trial B-27, several
participating surgeons attempted SNB before the required axillary
dissection in 428 patients. All underwent lymphatic mapping and an
attempt to identify and remove a sentinel node. Lymphatic mapping was
performed with radioactive colloid (14.7%), with lymphazurin blue dye
alone (29.9%), or with both (54.7%). RESULTS: Success rate for the
identification and removal of a sentinel node was 84.8%. Success rate
increased significantly with the use of radioisotope (87.6% to 88.9%)
versus with the use of lymphazurin alone (78.1%, P = .03). There were no
significant differences in success rate according to clinical tumor size,
clinical nodal status, age, or calendar year of random assignment. Of 343
patients who had SNB and axillary dissection, the sentinel nodes were
positive in 125 patients and were the only positive nodes in 70 patients
(56.0%). Of the 218 patients with negative sentinel nodes, nonsentinel
nodes were positive in 15 (false-negative rate, 10.7%; 15 of 140 patients).
There were no significant differences in false-negative rate according to
clinical patient and tumor characteristics, method of lymphatic mapping, or
breast tumor response to chemotherapy. CONCLUSION: These results
are comparable to those obtained from multicenter studies evaluating SNB
before systemic therapy and suggest that the sentinel node concept is
applicable following neoadjuvant chemotherapy.
28
Martelli, G., P. Boracchi, et al. (2005). "A randomized trial comparing axillary
dissection to no axillary dissection in older patients with T1N0 breast cancer:
results after 5 years of follow-up." Ann Surg 242(1): 1-6; discussion 7-9.
SUMMARY BACKGROUND DATA: Axillary dissection, an invasive
procedure that may adversely affect quality of life, used to obtain
prognostic information in breast cancer, is being supplanted by sentinel
node biopsy. In older women with early breast cancer and no palpable
axillary nodes, it may be safe to give no axillary treatment. We addressed
this issue in a randomized trial comparing axillary dissection with no
axillary dissection in older patients with T1N0 breast cancer. METHODS:
From 1996 to 2000, 219 women, 65 to 80 years of age, with early breast
cancer and clinically negative axillary nodes were randomized to
conservative breast surgery with or without axillary dissection. Tamoxifen
was prescribed to all patients for 5 years. The primary endpoints were
axillary events in the no axillary dissection arm, comparison of overall
mortality (by log rank test), breast cancer mortality, and breast events (by
Gray test). RESULTS: Considering a follow-up of 60 months, there were
no significant differences in overall or breast cancer mortality, or crude
cumulative incidence of breast events, between the 2 groups. Only 2
patients in the no axillary dissection arm (8 and 40 months after surgery)
developed overt axillary involvement during follow-up. CONCLUSIONS:
Older patients with T1N0 breast cancer can be treated by conservative
breast surgery and no axillary dissection without adversely affecting breast
cancer mortality or overall survival. The very low cumulative incidence of
axillary events suggests that even sentinel node biopsy is unnecessary in
these patients. Axillary dissection should be reserved for the small
proportion of patients who later develop overt axillary disease.
Milardovic, R., I. Castellon, et al. (2006). "Scintigraphic visualization of an
epigastric sentinel node in recurrent breast cancer after lumpectomy and
postoperative radiation therapy." Clin Nucl Med 31(4): 207-8.
Sentinel node imaging and biopsy have become standard procedures for
staging early breast cancer. Positive sentinel lymph node (SLN) biopsy
necessitates the need for axillary lymph node dissection (ALND). Failure
to visualize a sentinel lymph node in recurrent breast cancer after
treatment by surgery, chemotherapy, and high-dose postoperative
radiation therapy is almost the case in every patient. The reason for failure
to visualize the sentinel node is the fibrosis that follows high-dose
radiotherapy and blocks the lymphatics preventing spread of the tumor
cells to the lymph nodes. Alternative pathways for the drainage of lymph
from the breast are developed in these patients. We have previously
reported on the alternative pathways of lymphatics to the contralateral
axilla, supraclavicular area, and also reported on the development of
intramammary lymph nodes. In this report, we are presenting another
alternative pathway of lymphatics to the region of the epigastrium below
the lower end of the sternum.
29
Neuman, H., L. A. Carey, et al. (2006). "Axillary lymph node count is lower after
neoadjuvant chemotherapy." Am J Surg 191(6): 827-9.
BACKGROUND: Retrieval of fewer than 10 lymph nodes at axillary
dissection (ALND) for breast cancer can represent anatomic variation or
inadequate dissection. We postulated that despite aggressive ALND, a
lower lymph node count is more frequent after neoadjuvant chemotherapy.
METHODS: Patients who received neoadjuvant chemotherapy followed by
ALND were compared with patients who received surgery first. All patients
received a level I and II ALND at a single institution by one of the breast
surgeons. The number of nodes retrieved at ALND was dichotomized into
categories (< 10 and > or = 10), and compared using Fisher exact test.
RESULTS: A total of 143 neoadjuvant and 170 surgery-first patients were
studied. Patients treated with neoadjuvant chemotherapy were
significantly more likely to have fewer than 10 lymph nodes retrieved at
ALND than were the surgery-first patients (19/143 or 13% vs. 6/170 or 4%,
P = .003). CONCLUSIONS: A low lymph node count is more common in
patients after treatment with neoadjuvant chemotherapy and should not be
assumed to represent an incomplete ALND.
Newman, E. A., V. M. Cimmino, et al. (2006). "Lymphatic mapping and sentinel
lymph node biopsy for patients with local recurrence after breast-conservation
therapy." Ann Surg Oncol 13(1): 52-7.
BACKGROUND: Local recurrence (LR) after breast-conservation therapy
for breast cancer occurs in 10% to 15% of cases. A subset of these
represents biologically aggressive disease, yet prognostic features for
identifying this high-risk category are lacking. We hypothesized that
lymphatic mapping and sentinel lymph node biopsy would provide useful
information regarding dominant lymphatic drainage patterns of patients
with LR. METHODS: Breast cancer case records involving surgery for LR
at the University of Michigan from 2002 to 2004 were reviewed. The
lymphatic drainage patterns were compared with those of 117 patients
who underwent mapping for primary breast cancer. RESULTS: Fourteen
LR cases were identified (10 with initial axillary lymph node dissection, 2
with initial sentinel lymph nodes, and 2 with no axillary surgery at the time
of primary cancer treatment); lymphatic mapping was performed in 10.
The sentinel lymph node identification rate was 90%, the median number
of lymph nodes retrieved was 3, and no metastases were detected.
Significantly more cases of nonipsilateral axillary sentinel node drainage
were observed in mapping procedures performed for LR compared with
those for primary breast cancer (67% vs. 15%; P = .001).
CONCLUSIONS: Lymphatic mapping is feasible in patients undergoing
mastectomy for LR and is likely to identify aberrantly located sentinel
lymph nodes that would otherwise be overlooked with a conventional
completion mastectomy.
30
Reitsamer, R., F. Peintinger, et al. (2003). "Sentinel lymph node biopsy in breast
cancer patients after neoadjuvant chemotherapy." J Surg Oncol 84(2): 63-7.
BACKGROUND AND OBJECTIVES: Sentinel lymph node biopsy (SLNB)
is an accurate method for axillary staging in patients with early breast
cancer. The aim of this study was to evaluate the accuracy and the
feasibility of SLNB in breast cancer patients who had received
preoperative (neoadjuvant) chemotherapy. METHODS: Patients with
advanced breast cancer stage II or III who were treated with neoadjuvant
chemotherapy were included in the study. Sentinel lymph node (SLN)
identification and biopsy was attempted and performed, and axillary lymph
node dissection (ALND) was performed in the same surgical procedure
after SLNB. The histopathologic examination of the SLNs and the
dissected axillary lymph nodes was performed and nodal status was
compared. RESULTS: Thirty patients were included in the study. After
peritumoural injection of technetium-99m labelled human albumin and
subareolar subcutaneous injection of blue dye, the SLNs could be
identified in 26/30 patients (identification rate 86.7%). In 4/30 patients
(13.3%) SLNs could not be identified. In 25/26 patients (96.2%) SLNs
accurately predicted the axillary status. Eleven patients had negative
SLNs and negative nodes in ALND. Six patients had positive SLNs and
positive nodes in ALND. In eight patients SLNs only were positive and
nodes in ALND were negative. One patient had a false-negative SLNB,
calculating a false-negative rate of 6.7% (1/15). CONCLUSIONS: SLNB is
a well introduced technique for axillary staging in patients with early breast
cancer. The accuracy of SLNB after neoadjuvant chemotherapy is similar
to patients with primary surgery. SLNB could be an alternative to ALND in
a subgroup of patients after neoadjuvant chemotherapy, and therefore
could reduce morbidity due to surgery in those patients. Due to small
numbers of patients, further evaluation in this subset of patients is
required.
Rouzier, R., M. C. Mathieu, et al. (2004). "Breast-conserving surgery after
neoadjuvant anthracycline-based chemotherapy for large breast tumors." Cancer
101(5): 918-25.
BACKGROUND: Randomized trials comparing neoadjuvant versus
adjuvant chemotherapy show that primary chemotherapy allows more
frequent breast-preserving surgery even though no survival advantage
has been demonstrated. The aim of the current study was to determine
the predicting factors and the survival impact of breast conservation in
patients with large breast tumors treated with neoadjuvant chemotherapy.
METHODS: Between January 1987 and December 2001, 594 patients
with invasive T2-3 breast carcinoma who were ineligible for breastconserving surgery (the mean initial tumor diameter was 49 mm) were
treated with 3 or 4 courses of an anthracycline-based primary
chemotherapy, surgery, and radiotherapy. Various clinicopathologic
factors were tested as possible predicting factors of breast-preserving
31
surgery. Survival analyses were performed to determine the implications
of breast-conserving surgery on outcome. RESULTS: After primary
chemotherapy, 287 (48%) patients were eligible for breast-conserving
surgery and 307 patients underwent a mastectomy. Initial tumor diameter
> 5 cm, low histologic grade, lobular histology, and multicentricity were
independent predicting factors of breast conservation ineligibility in the
multivariate analysis (logistic regression). In the univariate survival
analysis, a failure of breast-preserving surgery was associated with a poor
outcome. Local disease recurrence-free survival rates were similar in
patients treated with lumpectomy and mastectomy. CONCLUSIONS: The
results reported in the current study suggested that initial diameter,
histologic type and grade, and multicentricity are potential
prechemotherapy predicting factors of breast conservation. When carefully
selected, patients treated with breast conservation had a risk of local
disease recurrence similar to the risk of chest wall disease recurrence
after mastectomy.
Schwartz, G. (2005). "Neoadjuvant induction chemotherapy." Minerva Ginecol
57(3): 327-48.
Neoadjuvant chemotherapy (NACT) and neoadjuvant hormonal therapy
(NAHT) have been adopted worldwide as appropriate, if not standard of
care, options of treatment for patients with locally advanced carcinoma of
the breast. The initial role of NACT was the conversion of so called
inoperable tumors into those for which mastectomy could now be
performed, irrespective of effect on overall survival outcome. As breast
conservation became accepted as an alternative to mastectomy in
selected patients, NACT often reduced tumor volume enough to allow
consideration of this option for these patients as well. Currently a majority
of patients undergoing NACT become candidates for breast conservation.
Clinical trial data, however, suggest that overall survival has not been
affected by NACT, although recent non randomized but prospective data
do document improved disease free and overall survival, as well as
decrease in local recurrence. The adoption of axillary lymphatic mapping
and sentinel lymph node biopsy (SLNB) in stage I/II, clinically N0 patients
has promoted the judicious use of SLNB in selected patients who have
undergone NACT, if the nodes are ''downstaged'' and are clinically
negative at the completion of NACT. SLNB in these patients remains
highly controversial, as does the application of NACT in patients with
smaller (T1, N1, or T2, N01) cancers. The optimal choice of drug regimens
for NACT is also controversial, i.e., both the drugs used and the duration
of treatment. Generally accepted approaches are usually the same as if
the drugs were given as adjuvant, rather than neoadjuvant, treatment.
Most investigators do agree that those patients who achieve a complete
pathological response (pCR, or absence of any invasive cancer in the final
specimen) to NACT do have an improved outcome, so that the
manipulation of treatment regimens by ongoing clinical trials is of utmost
32
importance in this regard. The recent observation of an increased rate of
pCR in patients with Herceptin added to the NACT regimen is, therefore,
an exciting advance and requires further investigation. The adoption of
NACT into treatment plans for women with earlier cancers is likely to
become even more ubiquitous if a higher likelihood of pCR can be
achieved, and as more and more women with smaller tumors (T1c)
become almost automatic candidates for adjuvant chemotherapy because
of tumor size, irrespective of node status. It is not difficult to imagine that
the majority of women with breast cancer will become candidates for
NACT as more information about tumor response and outcome data are
accumulated.
Taback, B., P. Nguyen, et al. (2006). "Sentinel lymph node biopsy for local
recurrence of breast cancer after breast-conserving therapy." Ann Surg Oncol
13(8): 1099-104.
BACKGROUND: Lymphatic mapping (LM) with sentinel lymph node (SLN)
biopsy has revolutionized the surgical staging of primary breast cancer,
but its utility and feasibility have not been established in patients with
ipsilateral breast tumor recurrence (IBTR) after breast-conserving surgery
(BCS) and radiation. METHODS: We reviewed our breast cancer
database to identify all patients who underwent preoperative
lymphoscintigraphy for IBTR and whose primary tumor had been
managed by BCS, SLN biopsy and/or axillary node dissection, and
adjuvant breast irradiation. RESULTS: Preoperative lymphoscintigraphy
identified migration to the regional nodal drainage basins in 11 (73%) of 15
patients, as follows: 5 ipsilateral axillary, 1 supraclavicular, 2 internal
mammary, 2 interpectoral, and 3 contralateral axillary. Two patients
demonstrated drainage to two nodal basins. In four patients, no drainage
was observed. Intraoperative LM with radioisotope plus blue dye identified
at least 1 SLN in 11 of 14 patients, and histopathologic evaluation
revealed metastasis in 3 patients (2 contralateral axillary and 1 ipsilateral
axillary). During preoperative lymphoscintigraphy, the radiocolloid
migration time tended to be longer and the drainage pathways more
variable than those associated with primary tumors. CONCLUSIONS:
LM/SLN biopsy can be successfully performed in patients with IBTR after
prior BCS, axillary surgical staging, and adjuvant radiation. This approach
illustrates variations in the lymphatic drainage of recurrent breast tumors
and may permit the identification of regional metastasis not noted with
conventional imaging techniques.
van Rijk, M. C., O. E. Nieweg, et al. (2006). "Sentinel node biopsy before
neoadjuvant chemotherapy spares breast cancer patients axillary lymph node
dissection." Ann Surg Oncol 13(4): 475-9.
BACKGROUND: Neoadjuvant chemotherapy in breast cancer patients is a
valuable method to determine the efficacy of chemotherapy and potentially
downsize the primary tumor, which facilitates breast-conserving therapy.
33
In 18 studies published about sentinel node biopsy after neoadjuvant
chemotherapy, the sentinel node was identified in on average 89%, and
the false-negative rate was on average 10%. Because of these mediocre
results, no author dares to omit axillary clearance just yet. In our institute,
sentinel lymph node biopsy is performed before neoadjuvant
chemotherapy. The aim of this study was to evaluate our experience with
this approach. METHODS: Sentinel node biopsy was performed before
neoadjuvant chemotherapy in 25 T2N0 patients by using
lymphoscintigraphy, a gamma ray detection probe, and patent blue dye.
Axillary lymph node dissection was performed after chemotherapy if the
sentinel node contained metastases. RESULTS: Ten patients had a
tumor-positive axillary sentinel node, and one patient had an involved
lateral intramammary node. Four patients had additional involved nodes in
the completion lymph node dissection specimen. The other 14 patients
(56%) had a tumor-negative sentinel node and did not undergo axillary
lymph node dissection. No recurrences have been observed after a
median follow-up of 18 months. CONCLUSIONS: Fourteen (56%) of the
25 patients were spared axillary lymph node dissection when the sentinel
node was found to be disease free. Performing sentinel node biopsy
before neoadjuvant chemotherapy seems successful and reliable in
patients with T2N0 breast cancer.
Villa, G., M. Gipponi, et al. (2000). "Localization of the sentinel lymph node in
breast cancer by combined lymphoscintigraphy, blue dye and intraoperative
gamma probe." Tumori 86(4): 297-9.
Axillary lymph node status represents the most important prognostic factor
in patients with operable breast cancer. A severe limitation of this
technique is the relatively high rate of false negative sentinel lymph nodes
(>5%). We studied 284 patients suffering from breast cancer; 264 had T1
tumors (16 T1a, 37 T1b and 211 T1c), while 20 had T2 tumors. All
patients underwent lymphoscintigraphy 18-h before surgery. At surgery,
0.5 mL of patent blue violet was injected subdermally, and the sentinel
lymph node (SN) was searched by gamma probe and by the dye method.
The surgically isolated SN was processed for intraoperative and delayed
examinations. The SN was successfully identified by the combined
radioisotopic procedure and patent blue dye technique in 278/284 cases
(97.9%). Analysis of the predictive value of the SN in relation to the status
of the axillary lymph nodes was limited to 191 patients undergoing
standard axillary dissection irrespective of the SN status. Overall, 63/191
(33%) identified SNs were metastatic, the SN alone being involved in
37/63 (58.7%) patients; a positive axillary status with negative SN was
found in 10/73 (13.7%) patients with metastatic involvement. In T1a-T1b
patients the SN turned out to be metastatic in 9/53 patients (17.0%). In 7/9
patients the SN was the only site of metastasis, while in 2/9 patients other
axillary lymph nodes were found to be metastatic in addition to the SN.
None of the 44 patients in whom the SN proved to be non-metastatic
34
showed any metastatic involvement of other axillary lymph nodes. Our
results demonstrate a good predictive value of SN biopsy in patients with
breast cancer; the predictive value was excellent in those subjects with
nodules smaller than 1 cm.
Viswambharan, J. K., D. Kadambari, et al. (2005). "Feasibility of breast
conservation surgery in locally advanced breast cancer downstaged by
neoadjuvant chemotherapy: a study in mastectomy specimens using simulation
lumpectomy." Indian J Cancer 42(1): 30-4.
BACKGROUND: The response of locally advanced breast cancer (LABC)
to neoadjuvant chemotherapy (NACT) offers these patients previously
treated by mastectomy, the chance for breast conservation. AIM: This
study aims to assess the feasibility of lumpectomy in patients with LABC
treated by NACT, with residual tumor < or =5 cm. SETTINGS, DESIGN:
Single group prospective study from August 2001 to June 2003 in a
teaching hospital. MATERIALS AND METHODS: Thirty patients with
LABC whose tumors reduced with NACT to 5 cm were included.
Simulation lumpectomy was performed on the mastectomy specimens to
achieve 1 to 2 cm clearance from tumor and hence margin negativity.
Multiple sections of the inked margin were studied. STATISTICAL
ANALYSIS: Margin positivity was correlated with patient factors. Chi
square test and Fisher's exact test used as appropriate. P value 0.05 was
considered significant. RESULTS AND CONCLUSIONS: After three
cycles of NACT, 4 patients (13%) had complete clinical response including
2 with complete pathological response. Twenty-two (73%) showed partial
response and 4, no response. Fourteen out of thirty (47%) had tumor
involvement of margins. Tumors with post-chemotherapy size> 4 cm were
margin positive in 10/13 (77%). Tumors with post-chemotherapy size>3
cm were margin positive in 13/24 (54%). Tumors with post-chemotherapy
size 3 cm were margin negative in 5/6 (83%). Pre-chemotherapy tumor
size and post-chemotherapy tumor size were significantly associated with
margin positivity (P=0.003). Tumors in the subareolar location had
significantly higher incidence of residual tumor in the nipple areola
complex. (P=0.04). Margin positivity of lumpectomy on downstaged
tumors can be reduced by removing the nipple areola complex in
subareolar tumors and by limiting breast conservation to tumors with postchemotherapy size < or =3 cm.
White, E. J. (2001). "Early" Breast Cancer: Axillary Controversies. Unpublished:
12.
Wolmark, N., J. Wang, et al. (2001). "Preoperative chemotherapy in patients with
operable breast cancer: nine-year results from National Surgical Adjuvant Breast
and Bowel Project B-18." J Natl Cancer Inst Monogr(30): 96-102.
National Surgical Adjuvant Breast and Bowel Project (NSABP) Protocol B18 was initiated in 1988 to determine whether four cycles of
35
doxorubicin/cyclophosphamide given preoperatively improve survival and
disease-free survival (DFS) when compared with the same chemotherapy
given postoperatively. Secondary aims included the evaluation of
preoperative chemotherapy in downstaging the primary breast tumor and
involved axillary lymph nodes, the comparison of lumpectomy rates and
rates of ipsilateral breast tumor recurrence (IBTR) in the two treatment
groups, and the assessment of the correlation between primary tumor
response and outcome. Initially published findings were based on a followup of 5 years; this report updates results through 9 years of follow-up.
There continue to be no statistically significant overall differences in
survival or DFS between the two treatment groups. Survival at 9 years is
70% in the postoperative group and 69% in the preoperative group (P
=.80). DFS is 53% in postoperative patients and 55% in preoperative
patients (P =.50). A statistically significant correlation persists between
primary tumor response and outcome, and this correlation has become
statistically stronger with longer follow-up. Patients assigned to
preoperative chemotherapy received notably more lumpectomies than
postoperative patients, especially among patients with tumors greater than
5 cm at study entry. Although the rate of IBTR was slightly higher in the
preoperative group (10.7% versus 7.6%), this difference was not
statistically significant. Marginally statistically significant treatment-by-age
interactions appear to be emerging for survival and DFS, suggesting that
younger patients may benefit from preoperative therapy, whereas the
reverse may be true for older patients.
Wong, J. S., A. Recht, et al. (1997). "Treatment outcome after tangential
radiation therapy without axillary dissection in patients with early-stage breast
cancer and clinically negative axillary nodes." Int J Radiat Oncol Biol Phys 39(4):
915-20.
PURPOSE: To determine the risk of nodal failure in patients with earlystage invasive breast cancer with clinically negative axillary lymph nodes
treated with two-field tangential breast irradiation alone, without axillary
lymph node dissection or use of a third nodal field. METHODS AND
MATERIALS: Between 1988 and 1993, 986 evaluable women with clinical
Stage I or II invasive breast cancer were treated with breast- conserving
surgery and radiation therapy. Of these, 92 patients with clinically negative
nodes received tangential breast irradiation (median dose, 45 Gy) followed
by a boost, without axillary dissection. The median age was 69 years
(range, 49-87). Eighty-three percent had T1 tumors. Fifty-three patients
received tamoxifen, 1 received chemotherapy, and 2 patients received
both. Median follow-up time for the 79 survivors was 50 months (range,
15-96). Three patients (3%) have been lost to follow-up after 20-32
months. RESULTS: No isolated regional nodal failures were identified.
Two patients developed recurrence in the breast only (one of whom had a
single positive axillary node found pathologically after mastectomy). One
patient developed simultaneous local and distant failures, and six patients
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developed distant failures only. One patient developed a contralateral
ductal carcinoma in situ, and two patients developed other cancers.
CONCLUSION: Among a group of 92 patients with early-stage breast
cancer (typically T1 and also typically elderly) treated with tangential
breast irradiation alone without axillary dissection, with or without systemic
therapy, there were no isolated axillary or supraclavicular regional failures.
These results suggest that it is feasible to treat selected clinically nodenegative patients with tangential fields alone. Prospective studies of this
approach are warranted.
Zurrida, S., R. Orecchia, et al. (2002). "Axillary radiotherapy instead of axillary
dissection: a randomized trial. Italian Oncological Senology Group." Ann Surg
Oncol 9(2): 156-60.
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