original reports
Local Recurrence After Breast-Conserving
Therapy in Patients With Multiple Ipsilateral
Breast Cancer: Results From ACOSOG
Z11102 (Alliance)
Judy C. Boughey, MD1; Kari M. Rosenkranz, MD2; Karla V. Ballman, PhD3; Linda McCall, MS4; Bruce G. Haffty, MD5;
Laurie W. Cuttino, MD6; Charlotte D. Kubicky, MD7; Huong T. Le-Petross, MD8; Armando E. Giuliano, MD9;
Kimberly J. Van Zee, MS, MD10; Kelly K. Hunt, MD8; Olwen M. Hahn, MD11; Lisa A. Carey, MD12; and Ann H. Partridge, MD, MPH13
abstract
PURPOSE Breast-conserving therapy (BCT) is the preferred treatment for unifocal breast cancer (BC). The
oncologic safety of BCT for multiple ipsilateral breast cancer (MIBC) has not been demonstrated in a prospective
study. ACOSOG Z11102 (Alliance) is a phase II, single-arm, prospective trial designed to evaluate oncologic
outcomes in patients undergoing BCT for MIBC.
PATIENTS AND METHODS Women age 40 years and older with two to three foci of biopsy-proven cN0-1 BC were
eligible. Patients underwent lumpectomies with negative margins followed by whole breast radiation with boost
to all lumpectomy beds. The primary end point was cumulative incidence of local recurrence (LR) at 5 years with
an a priori rate of clinical acceptability of ,8%.
RESULTS Among 270 women enrolled between November 2012 and August 2016, there were 204 eligible
patients who underwent protocol-directed BCT. The median age was 61 years (range, 40-87 years). At a median
follow-up of 66.4 months (range, 1.3-90.6 months), six patients developed LR for an estimated 5-year cumulative incidence of LR of 3.1% (95% CI, 1.3 to 6.4). Patient age, number of sites of preoperative biopsy–
proven BC, estrogen receptor status and human epidermal growth factor receptor 2 status, and pathologic T and
N categories were not associated with LR risk. Exploratory analysis showed that the 5-year LR rate in patients
without preoperative magnetic resonance imaging (MRI; n 5 15) was 22.6% compared with 1.7% in patients
with a preoperative MRI (n 5 189; P 5 .002).
CONCLUSION The Z11102 clinical trial demonstrates that breast-conserving surgery with adjuvant radiation that
includes lumpectomy site boosts yields an acceptably low 5-year LR rate for MIBC. This evidence supports BCT
as a reasonable surgical option for women with two to three ipsilateral foci, particularly among patients with
disease evaluated with preoperative breast MRI.
J Clin Oncol 41:3184-3193. © 2023 by American Society of Clinical Oncology
ASSOCIATED
CONTENT
Appendix
Protocol
Author affiliations
and support
information (if
applicable) appear
at the end of this
article.
Accepted on February
17, 2023 and
published at
ascopubs.org/journal/
jco on March 28,
2023: DOI https://doi.
org/10.1200/JCO.22.
02553
INTRODUCTION
Breast-conserving therapy (BCT) is the preferred treatment option for patients with early breast cancer (BC) after
several successful prospective trials demonstrated its
safety compared with mastectomy.1-3 However, mastectomy has remained the most common surgery for patients
with multiple ipsilateral breast cancer (MIBC). This is
based on data from retrospective studies that reported
higher rates of local recurrence (LR) in patients with MIBC
in comparison with patients with unifocal disease in an era
before current diagnostic and therapeutic advances.4-8
In recent years, significant progress has been made in
BC management. Advances include better imaging
techniques to more accurately detect additional tumors
and define extent of disease, more effective systemic
therapy and radiation therapy, and enhancements in
surgery and pathology. These developments decreased LR and improved overall survival. These improvements provide a rationale for re-evaluating the
safety of BCT for patients with MIBC. Several retrospective papers published in the era of modern diagnostic modalities and tailored treatments report LR
rates after BCT for MIBC similar to those in the unifocal
population. A systematic review of papers published
from 1988 to 2015 identified 24 retrospective studies
including 3,537 women with MIBC undergoing BCT.9
BCT yielded LR rates similar to mastectomy in several
studies, but their retrospective nature, poor quality
study designs, and lack of power to definitely declare
equivalent LR rates for BCT and mastectomy have
limited utilization of BCT in the setting of MIBC.
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Breast Conservation in MIBC
CONTEXT
Key Objective
This is a prospective single-arm study to evaluate whether the local recurrence (LR) rate with breast-conserving surgery
followed by whole breast radiation with radiation boost to lumpectomy sites at 5 years is ,8%.
Knowledge Generated
Five-year estimated LR rate with breast-conserving therapy (lumpectomy plus radiation) in patients with multiple ipsilateral
breast cancer was acceptable at 3.1%. Factors that may affect LR are the use of preoperative breast magnetic resonance
imaging and, in estrogen receptor–positive breast cancer, the use of adjuvant endocrine therapy. A majority of patients
enrolled in the trial were postmenopausal with estrogen receptor–positive/human epidermal growth factor receptor 2–
negative breast cancer and had two sites of disease.
Relevance (K.D. Miller)
A mastectomy is not automatically required for patients with multiple tumors in the same breast. Breast conserving surgery
can be offered to selected patients with a low risk of LR.*
*Relevance section written by JCO Senior Deputy Editor Kathy D. Miller, MD.
The American College of Surgeons Oncology Group
(ACOSOG)/Alliance for Clinical Trials in Oncology Z11102
(Alliance) clinical trial was designed to prospectively assess
LR rates after BCT for patients with MIBC. We have previously reported secondary end points of this trial, including
the conversion to mastectomy rate, cosmetic outcome, and
radiation feasibility.10-12 The primary end point for this trial is
LR as a first event. LR is defined as histologic evidence of
ductal carcinoma in situ (DCIS) or invasive BC in the ipsilateral breast or chest wall. The trial was designed as a
single-arm phase II clinical trial with a prespecified safety
threshold to assess whether the LR rate at 5 years in women
with MIBC who undergo BCT is clinically acceptable. On
the basis of prior retrospective reports showing a 12-year LR
rate in unifocal BC of 10%13,14 and a 5-year LR rate in MIBC
of 5.1%-11%,15,16 a clinically acceptable 5-year LR rate for
BCT was defined to be ,8%.
PATIENTS AND METHODS
The ACOSOG Z11102 (Alliance) clinical trial is a prospective single-arm trial that enrolled women age 40 years
and older diagnosed with two or three foci of biopsy-proven
BC who were interested in pursuing breast-conserving
surgery. At least one of the sites of biopsy-proven disease had to be invasive BC, and the additional site(s) could
be DCIS or invasive BC. The maximum single largest tumor
dimension allowed (by preoperative imaging) was 5 cm.
The original Protocol (online only) required 3 cm of normal
tissue between the sites of disease on imaging, and this was
decreased to 2 cm with an amendment in September 2013.
Disease extent was limited to two quadrants of the breast.
Patients with cN0 or cN1 disease were eligible. All patients
had preoperative mammogram and/or ultrasound, and the
original protocol required a preoperative breast magnetic
resonance imaging (MRI). The preoperative breast MRI
was made optional with an amendment in May 2015 to
enhance accrual. Patients with prior or concurrent contralateral disease, known BRCA mutation, or current breast
implants were excluded. Initially, enrollment was required
before surgery, but in May 2015, postoperative enrollment of
patients with MIBC treated with lumpectomy was allowed.
Neoadjuvant systemic therapy was prohibited. Patients were
treated with lumpectomy (either through one or multiple
incisions), and negative margins were required. Oncoplastic
closure was allowed. Margin negativity was originally defined
as 2 mm and amended to no tumor on ink in October 2014
after changes in national SSO-ASTRO guidelines.17 Axillary
surgery was required and could be performed with sentinel
lymph node surgery or axillary lymph node dissection at the
discretion of the treating surgeon.
The protocol required adjuvant whole breast radiation with a
boost to the lumpectomy bed of each site of disease,
initiated #8 weeks after the last dose of cytotoxic chemotherapy or #10 weeks after lumpectomy or re-excision of
margins if cytotoxic therapy was not administered. The boost
was limited to two quadrants of the breast only. The addition
of nodal radiation fields was at the discretion of the treating
radiation oncologist. Radiation was delivered to the whole
breast at 45-50 Gy in standard daily fractions of 1.8-2.0 Gy. A
boost of 10-16 Gy in 2.0-Gy daily fractions to each tumor bed
was mandatory.12 The protocol required that $90% of the
lumpectomy planning target volume receive $90% of the
boost prescription dose. Not more than 50% of the target
breast tissue was to receive over 60 Gy.
Adjuvant endocrine therapy (tamoxifen or an aromatase
inhibitor) was recommended for patients with estrogen receptor (ER)– and/or progesterone receptor–positive tumors.
Targeted anti-human epidermal growth factor receptor 2
(HER2) therapy was recommended for patients with HER2positive tumors receiving adjuvant chemotherapy. Final
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3185
Boughey et al
decisions regarding adjuvant systemic therapy were left to
the discretion of the treating medical oncologist. Patients
were monitored every 6 months and had annual bilateral
mammogram until 5 years after completion of radiation. All
patients provided informed consent. The trial was IRBapproved at each site, and the trial was registered on
ClinicalTrials.gov (identifier: NCT01556243) and supported
by NCI grants to the Alliance for Clinical Trials in Oncology:
U10CA180821 and U10CA180882.
Total patients enrolled (N = 270)
Not evaluable for primary end point
Ineligible
Converted to mastectomy
Unable to achieve negative margins
Withdrew consent before first follow-up
(n = 66)
(n = 34)
(n = 14)
(n = 2)
(n = 16)
Statistical Considerations
The primary end point of Z11102 is the cumulative incidence of LR, defined as histologic evidence of DCIS or invasive BC in the ipsilateral breast or chest wall. Patient death,
distant BC recurrence, and nodal/regional BC recurrence
are competing risks. The primary analysis was to determine if
there is evidence that the 5-year LR rate is ,8%; this would
be achieved if the 95% CI for the 5-year LR rate is entirely
below 8%. The target sample size was 200 patients, and over
accrual was allowed to account for ineligible patients, patients who withdrew before consent, patients who converted
to mastectomy, and patients who were found to have a single
contiguous area of malignancy at final pathology. A sample
size of 200 yielded a half-width of 0.033 for the 95% CI
associated with the estimate of the 5-year LR rate. The
cumulative incidence of LR was estimated in the competing
risk framework as described by Marubini and Valsecchi18
with a point estimate and corresponding 95% CI. Cox proportional hazard models were used to determine the association between patient and disease baseline variables and
LR, which was estimated by the point estimate and corresponding 95% CI for the hazard ratio (HR). Data were frozen
on May 25, 2022. Analyses were performed using SAS
version 9.4 and R version 4.2.1.
RESULTS
Patient and Disease Characteristics
The ACOSOG Z11102 (Alliance) clinical trial was activated in
July 2012 and closed to accrual in August 2016. There were
270 women enrolled across 78 sites, of whom 34 were
ineligible, 14 converted to mastectomy, two did not achieve
negative margins, and 16 withdrew before their first follow-up
(Fig 1). This analysis includes 204 patients who were eligible
and completed breast-conserving surgery. Of the 204 patients, 193 completed protocol-directed radiation and 11 did
not meet the protocol radiation requirement or came off
study without providing information on radiation treatment.
In addition, two patients did not have axillary surgery.
Table 1 shows the patient and disease characteristics of the
study cohort overall and those enrolled before versus after
the May 15, 2015, amendment, which allowed postoperative enrollment and removed the requirement for preoperative MRI. The median patient age was 61 years (range,
40-87 years). The majority of patients had two foci of
disease (197 patients). Seven patients had three sites of
Patients evaluable for primary end point (n = 204)
FIG 1. Flow diagram of patients enrolled on Z11102.
disease. The median shortest distance between lesions on
imaging was 4.0 cm (range, 2.0-15.0 cm). Lesions were
resected by a single lumpectomy in 61 (29.9%) and via a
multiple lumpectomy approach in 143 (70.1%). Clinical T
category was cT1 in 121 patients (59.3%) and cT2 in 83
patients (40.7%). Clinical N category was clinically nodenegative in 195 patients (95.6%) and clinically nodepositive disease in nine patients (4.4%).
Tumor receptor status for ER and HER2 was available on
at least one of the sites of biopsy-proven invasive disease
in 203 cases. Of the 23 patients with HER21 disease, 13
received HER2-directed therapy, three did not receive
adjuvant HER2-directed therapy, and for seven, it is not
known whether they received HER2-directed therapy.
Of the 197 cases with two sites of disease, 148 had two
sites of invasive disease and the receptor status was the
same in both lesions in 124 cases (83.8%); 117 had
estrogen receptor–positive (ER1)/HER2– disease, six had
HER21 disease, and one had estrogen receptor–negative
(ER–)/HER2– disease. The receptor status between the
two lesions differed in 23 cases. For 21 patients, one
lesion was ER1/HER2–, of which the second lesion was
HER21 in nine patients, ER–/HER2– in four patients, and
missing tumor biology in eight patients. One patient had
one HER21 lesion and one ER–/HER2– lesion, and one
patient had a HER21 lesion with missing tumor biology
for the other lesion. There were 49 patients who had one
site of invasive disease and one site of DCIS. Of the seven
cases with three sites of disease, five had three sites of
invasive disease, one had two sites of invasive and one site
of DCIS, and one had one site of invasive and two sites of
DCIS, and all tumors with available receptor status were
ER1/HER2–.
We further classified patients by the most aggressive tumor
subtype across the invasive lesions for which receptor status
was available: ER–/HER2– was deemed prognostically worse
than HER21, which, in turn, was worse than ER1/HER2–
disease. This classification yielded 167 patients (83.5%)
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Volume 41, Issue 17
Breast Conservation in MIBC
TABLE 1. Patient and Tumor Characteristics of Patients Enrolled on Z11102 Clinical Trial
Characteristic
Preamendment 5 (n 5 103)
Postamendment 5 (n 5 101)
Total (n 5 204)
103
101
204
Age at registration, years
No.
Mean (SD)
60.70 (10.3)
61.51 (10.2)
61.10 (10.2)
Median
60.0
61.0
61.0
Q1-Q3
52.0-69.0
55.0-69.0
53.0-69.0
Range
40.0-87.0
41.0-86.0
40.0-87.0
Race, No. (%)
White
90 (87.4)
Black
Asian
American Indian/Alaska Native
1 (1.0)
Unknown/not reported
86 (85.1)
176 (86.3)
10 (9.7)
8 (7.9)
18 (8.8)
2 (1.9)
1 (1.0)
3 (1.5)
0
0
6 (5.9)
1 (0.5)
6 (2.9)
Ethnicity, No. (%)
Hispanic or Latino
3 (2.9)
5 (5.0)
8 (3.9)
Not Hispanic or Latino
94 (91.3)
91 (90.1)
185 (90.7)
Unknown/not reported
6 (5.8)
5 (5.0)
11 (5.4)
2
100 (97.1)
97 (96.1)
197 (96.6)
3
3 (2.9)
4 (4.0)
7 (3.4)
No. of malignant lesions at registration, No. (%)
Shortest distance between lesions on imaging
No.
Mean (SD)
102
100
202
4.1 (2.3)
4.7 (2.3)
4.4 (2.3)
Median
3.4
4.5
4.0
Q1-Q3
2.5-5.0
2.8-5.8
2.5-5.4
Range
2.0-14.0
2.0-15.0
2.0-15.0
T1
61 (59.2)
60 (59.4)
121 (59.3)
T2
42 (40.8)
41 (40.6)
83 (40.7)
N0
99 (96.1)
96 (95.0)
195 (95.6)
N1
4 (3.9)
5 (5.0)
9 (4.4)
All ductal
68 (66.0)
51 (50.5)
119 (58.3)
All lobular
5 (4.9)
11 (10.9)
16 (7.8)
DCIS/ductal
23 (22.3)
23 (22.8)
46 (22.5)
DCIS/lobular
1 (1.0)
4 (4.0)
5 (2.5)
Ductal/lobular
6 (5.8)
12 (11.9)
18 (8.8)
Clinical T category, No. (%)
Clinical N category, No. (%)
Histology, No. (%)
Highest histologic grade on biopsy, No. (%)
G1 (low)
27 (26.2)
26 (25.7)
53 (26.0)
G2 (intermediate)
45 (43.7)
51 (50.5)
96 (47.1)
G3 (high)
29 (28.2)
23 (22.8)
52 (25.5)
2 (1.9)
1 (1.0)
3 (1.5)
GX (grade cannot be assessed)
(continued on following page)
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3187
Boughey et al
TABLE 1. Patient and Tumor Characteristics of Patients Enrolled on Z11102 Clinical Trial (continued)
Preamendment 5 (n 5 103)
Characteristic
Postamendment 5 (n 5 101)
Total (n 5 204)
Tumor biology, No. (%)
ER1/HER2–
83 (83.0)
ER–/HER2–
HER21 (any ER)
Missing
84 (84.0)
167 (83.5)
5 (5.0)
5 (5.0)
10 (5.0)
12 (12.0)
11 (11.0)
23 (11.5)
3
1
4
Axillary surgery, No. (%)
SLN surgery
87 (84.5)
ALND
85 (84.2)
172 (84.3)
4 (3.9)
6 (5.9)
10 (4.9)
11 (10.7)
9 (8.9)
20 (9.8)
1 (1.0)
1 (1.0)
2 (1.0)
1
30 (30.7)
31 (29.1)
61 (29.9)
2
73 (64.4)
65 (70.9)
138 (67.6)
3
0 (5.0)
SLN surgery and ALND
No axillary surgery
No. of lumpectomies, No. (%)
5 (100.0)
5 (2.4)
Pathologic T category, No. (%)
T1
80 (77.7)
77 (76.2)
157 (77.0)
T2
22 (21.4)
23 (22.8)
45 (22.1)
T3
1 (1.0)
1 (1.0)
2 (1.0)
N0
81 (78.6)
77 (76.2)
158 (77.5)
N1
17 (16.5)
20 (19.8)
37 (18.1)
N2
1 (1.0)
3 (3.0)
4 (2.0)
N3
3 (2.9)
0 (0.0)
3 (1.5)
NX
1 (1.0)
1 (1.0)
2 (1.0)
Pathologic N category, No. (%)
Adjuvant chemotherapy regimen
None
67
Anthracycline-based, No. (%)
78
145
1 (2.8)
1 (4.4)
Taxane-based, No. (%)
22 (61.1)
17 (73.9)
39 (66.1)
Anthracycline- and taxane-based, No. (%)
10 (27.8)
4 (17.4)
14 (23.7)
3 (8.3)
1 (4.4)
4 (6.8)
No
103 (100.0)
75 (74.3)
178 (87.3)
Yes
0 (0.0)
26 (25.7)
26 (12.7)
Others, No. (%)
2 (3.4)
Postoperative enrollment, No. (%)
Abbreviations: ALND, axillary lymph node dissection; DCIS, ductal carcinoma in situ; ER, estrogen receptor; G, grade; HER2, human epidermal growth
factor receptor 2; N, node; Q1, quartile 1; Q3, quartile 3; SD, standard deviation; SLN, sentinel lymph node; T, tumor.
with ER1/HER2– disease, 23 patients (11.5%) with
HER21 disease, 10 patients (5.0%) with ER–/HER2–
disease, and four patients without information for classification. Adjuvant chemotherapy was given to 28.9% of
patients, and 89.7% of patients with any ER1 disease
received adjuvant endocrine therapy.
Disease Outcomes
At a median follow-up of 66.4 months (range, 1.3-90.6
months), six patients developed LR. The estimated incidence
of LR at 5 years was 3.1% (95% CI, 1.3 to 6.4). Figure 2 shows
the LR incidence curve. Of the six patients with LR, four had
in-breast tumor recurrence, one had an ipsilateral breast skin
recurrence, and one had a chest wall recurrence with an
intrapectoral mass. No patients developed a regional recurrence (with or without LR). Four patients developed distant
recurrence, none of whom had concurrent LR. The sites of
distant recurrence were bone only (two patients), bone and
bone marrow (one patient), and lungs (one patient). Six patients developed contralateral BC. Three patients developed
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Volume 41, Issue 17
Breast Conservation in MIBC
20
18
Events/Total
6/204
Median (95% CI)
NE (NE-NE)
16
LR (%)
14
12
10
8% clinically significant threshold
8
6
4
2
0
0
6
12
18
24
30
36
42
48
54
60
181
178
178
173
Time (months)
No. at risk:
204
202
196
193
191
188
184
FIG 2. Cumulative incidence of LR after breast-conserving surgery with whole breast radiation in multiple
ipsilateral breast cancer. Shaded region is the 95% confidence interval for the cumulative incidence curve. LR,
local recurrence; NE, not estimable.
non-BC malignancies (one gastric cancer, one lung cancer,
and one ovarian cancer), and eight patients have died (seven
non–breast-related and one related to BC).
Four of the 167 patients with ER1/HER2– disease developed
LR for a 5-year estimated LR rate of 2.6% (95% CI, 1 to 6.8).
None of the 23 patients with HER21 disease developed LR,
one of the 10 patients with ER–/HER2– disease developed LR
(5-year estimated LR rate of 10.0%; 95% CI, 1.5 to 52.7), and
one patient with missing tumor biology developed LR. Six of
the 197 patients with two lesions developed LR for an estimated 5-year risk of LR of 3.3% (95% CI, 1.5 to 7.2). None of
the seven patients with three lesions of biopsy-proven BC have
developed LR.
For the 20 patients with ER1 disease who did not receive
adjuvant endocrine treatment, the 5-year LR incidence was
12.5% (two LR events) compared with a 5-year LR incidence of 1.9% (three LR events) for patients who received
adjuvant endocrine therapy (HR, 7.7; 95% CI, 1.3 to 43.3).
Use of adjuvant chemotherapy was not associated with LR
(HR, 0.75; 95% CI, 0.1 to 4.1).
Breast MRI was obtained in 189 patients (92.6%), and 15
patients (7.4%) did not have a preoperative breast MRI.
Clinical, tumor, and treatment characteristics did not significantly differ between the 189 patients with preoperative breast
MRI and the 15 without MRI; five of the patients without MRI
were enrolled postoperatively. Mammogram/ultrasound followed by MRI was performed in 171 patients, and the MRI
identified a malignant lesion not seen on mammogram/
ultrasound in 72 patients (42.1%). Three patients with a
preoperative MRI and three patients without a preoperative
MRI developed LR. The estimated 5-year LR rate in patients
with a preoperative breast MRI was 1.7% (95% CI, 0.6 to 5.2)
and was 22.6% (95% CI, 7.9 to 55.1) in patients without a
breast MRI (HR, 13.49; 95% CI, 2.72 to 66.90; P 5 .002).
Table 2 shows the results of univariable analyses of the association between patient, disease, and pathology characteristics with LR. Pathologic tumor category (T2/3 v T1), pathologic
nodal status (pN1 v pN0), and any close margin (defined as
margin ,2 mm) were associated with higher LR risk, but these
were not statistically significant. Patient age, number of cancer
lesions, single versus multiple lumpectomy approach, and
tumor histology (invasive ductal v invasive lobular/mixed carcinoma) were not significantly associated with LR incidence.
DISCUSSION
The ACOSOG Z11102 (Alliance) prospective, single-arm,
clinical trial estimates that breast-conserving surgery followed by adjuvant radiation with lumpectomy site boosts for
women with MIBC yields a 5-year LR rate of 3.1%. This is
below the a priori determined clinically acceptable
threshold of 8% and provides evidence that breast conservation is an oncologically effective treatment option for
patients with two to three ipsilateral foci of BC.
The LR rate in Z11102 is lower than what had been observed in reports of BCT-treated patients with MIBC published in the 1980s and the early 1990s. These studies
reported significantly higher risk of LR in women with two or
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Boughey et al
TABLE 2. Factors Associated With LR After Breast-Conserving Therapy for Multiple Ipsilateral Breast Cancer
Estimated Rate of
LR at 5 Years (95% CI)
Characteristic
All patients (n 5 204)
Patients With LR, No.
HR (95% CI)
P
6
Patient age, years
.96
#60 (n 5 100)
3.2 (1.1 to 9.7)
3
1.00 (ref)
.60 (n 5 104)
3.2 (1.0 to 9.6)
3
0.96 (0.19 to 4.75)
Bilateral MRI performed
.002
Yes (n 5 189)
1.7 (0.6 to 5.2)
3
1.00 (ref)
22.6 (7.9 to 55.1)
3
13.49 (2.72 to 66.90)
3.3 (1.5 to 7.2)
6
NE
0
0
NE
2.6 (1.0 to 6.8)
4
NE
10.0 (1.5 to 52.7)
1
NE
0
0
NE
T0/Tis/T1 (n 5 157)
2.1 (1.0 to 6.4)
3
1.00 (ref)
T2/T3 (n 5 47)
7.2 (2.4 to 20.5)
3
3.44 (0.70 to 17.07)
No (n 5 15)
No. of sites of breast cancer at registration
2 (n 5 197)
3 (n 5 7)
NE
Tumor biology
NE
ER1/HER2– (n 5 167)
ER–/HER2– (n 5 10)
HER21 (any ER) (n 5 23)
Pathologic T category
.13
Pathologic N category
.10
N0 (n 5 158)
2.1 (1.0 to 6.3)
3
1.00 (ref)
N11 (n 5 44)
7.8 (2.6 to 22.2)
3
3.87 (0.78 to 19.18)
Margin status
.21
Negative (n 5 174)
2.5 (1.0 to 6.5)
4
1.00 (ref)
Close (n 5 30)
7.5 (2.0 to 26.5)
2
3.00 (0.55 to 16.35)
Ductal (n 5 165)
3.3 (1.4 to 7.7)
5
1.00 (ref)
Lobular/mixed (n 5 39)
3.0 (0.5 to 19.1)
1
0.84 (0.10 to 7.22)
1 (n 5 61)
1.6 (0.3 to 11.8)
1
1.00 (ref)
2 or 3 (n 5 143)
3.9 (1.7 to 9.0)
5
2.25 (0.26 to 19.28)
Tumor histology
.87
No. of lumpectomies
.46
Adjuvant chemotherapy
.74
Yes (n 5 59)
3.8 (1.0 to 14.2)
2
1.00 (ref)
No (n 5 145)
3.0 (1.2 to 7.8)
4
0.75 (0.14 to 4.09)
1.9 (0.6 to 5.6)
3
1.00 (ref)
12.5 (3.3 to 41.5)
2
7.72 (1.29 to 43.31)
Adjuvant endocrine therapy in ER1 disease (n 5 195)
Yes (n 5 175)
No (n 5 20)
.025
Abbreviations: ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; HR, hazard ratio; LR, local recurrence; MRI, magnetic resonance
imaging; N, node; NE, not estimable; ref, reference; T, tumor.
more synchronous breast lesions compared with those with
unifocal disease.4-6,19,20 More recent retrospective studies
have reported rates of LR with breast conservation therapy
in patients with MIBC, which are more consistent with the
recurrence rates seen in unifocal disease and those seen in
this study.7,16,19,21 Gentilini et al16 reviewed 476 patients with
MIBC treated with BCT between 1997 and 2002. The 5-year
LR rate was 5.1%.16 This study found that HER21 disease
and ER–/PR– disease were associated with higher LR rates
(HR, 3.2 and 2.7, respectively). The Z11102 study excluded
patients treated with neoadjuvant therapy, and thus, the
number of patients with HER21 or ER– disease was small
and too low for statistical comparison although the 5-year
estimated LR rate of 10% in ER–/HER2– disease was
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Breast Conservation in MIBC
numerically higher than that for ER1/HER2– disease as
would be expected in unifocal disease. None of the 23
patients with HER21 disease in the Z11102 trial developed
LR by 5 years. The discrepancy between our data and the
Gentilini cohort may reflect advances in HER2-targeting
systemic therapy, which have been widely adopted since
the time of the Gentilini study.
Previous studies have demonstrated that MRI detects
additional areas of concern in the breast in 13%-75% of
patients undergoing MRI after diagnosis of unifocal BC,22,23
with a meta-analysis reporting a rate of 16%.24 In Z11102,
MRI was the method of detection of the second or third
focus of disease (not seen on mammogram or ultrasound)
in 42% of cases. Use of MRI does carry potential risk as it
has a significant false-positive rate, incurs cost, and has
been shown to increase rate of mastectomy.25-28
The initial Z11102 protocol required preoperative MRI, and
in May 2015, an amendment made patients without a
preoperative MRI eligible. Only 15 patients on the trial did
not have an MRI; however, three of the six LRs occurred in
this group, resulting in a significantly higher 5-year LR rate
in the small cohort of patients without preoperative breast
MRI. The cohort of patients without MRI is too small to draw
definitive conclusions. The observation may reflect a
greater disease burden in patients with multiple tumors
detected by diagnostic mammogram and ultrasound rather
than on staging MRI, but the study is underpowered to
determine this. Patients with higher-risk disease detected
on staging MRI might have been counseled toward or opted
for mastectomy and not enrolled on the trial. The Z11102
data suggest that patients who are diagnosed with two or
more malignant lesions in the breast and who are considering breast conservation may benefit from breast MRI to
evaluate for the extent of disease and any additional lesions
to determine candidacy for breast conservation.
The findings from this study should be interpreted in the
context of certain limitations. First, the study was limited to
female patients. Although BCT is appropriate to consider for
men with BC, the generally smaller breast size may be a
limiting factor for breast conservation in men with MIBC; for
this reason, male patients were excluded from this trial.
Second, patients requiring preoperative systemic therapy
were excluded, and thus, there were relatively few patients
with three lesions, cN1 disease, or HER21 or TNBC leaving
some concern about generalizing findings to these higher-risk
subpopulations. Third, our findings regarding patients who did
not undergo a preoperative MRI are limited by small numbers
hampering definitive recommendations in this regard. Finally,
although the 5-year follow-up is reassuring, longer-term followup particularly for LR in ER1 disease is warranted.
After closure of the study to accrual and while awaiting
maturation of the data for primary end point, secondary
end points of the Z11102 trial have been reported. These
publications addressed several theoretical concerns
regarding the safety and feasibility of BCT for MIBC. The
majority of patients successfully completed radiation
with protocol adherent plans that included whole breast
radiation and a boost to all lumpectomy sites (195 of the
236 patients enrolled).12 Higher absolute radiation boost
volume was associated with higher rates of grade 21
acute dermatitis although relative boost volume was not.
Neither absolute nor relative boost volume were associated with worse overall cosmesis.2
The Z11102 data also affirm the ability to perform breast
conservation for MIBC without prohibitively high rates of
margin re-excision or conversion to mastectomy, with
67.6% of patients achieving a margin-negative excision in
a single operation and only 7.1% converting to a mastectomy because of persistently positive margins.10 Furthermore, cosmetic outcome after breast conservation, per
patient-reported outcome surveys, was good or excellent in
the majority of cases (70.6%), with only a minority of
patients (15.3%) undergoing oncoplastic reconstruction.11
Several other groups have also subsequently confirmed
the cosmetic feasibility of BCT for MIBC with oncoplastic
reconstruction.29-31
To our knowledge, the Z11102 trial is the only known
prospective study of BCT for MIBC. The MIAMI trial was
designed and activated in the United Kingdom as a randomized prospective trial aiming to assess the clinical safety
of multiple lumpectomies combined with therapeutic
mammaplasty compared with the standard of mastectomy in
MIBC. Recruitment to this randomized trial was challenging
with only four of the first 20 patients who were eligible for the
trial agreeing to participate, and the study was closed in
October 2020 because of accrual challenges.32,33
At the St Gallen Consensus Conference in 2013, the
majority viewed MIBC as a relative but not absolute
contraindication to breast conservation.34 At the 15th St
Gallen International Breast Cancer Conference 4 years
later in 2017, the panel endorsed breast conservation for
both multifocal and multicentric BCs with the caveats that
negative margins need to be obtained, adjuvant radiation
needs to be given, and adequate cosmesis needs to be
feasible.35 The Z11102 results provide prospective evidence to support this consensus guideline.
With the current advances in the diagnosis and management of BC including high-quality digital imaging,
targeted surgical resection, increasingly elegant pathologic assessment of margins, and continuously improving
systemic therapy and radiation therapy, the LR rates in
eligible women with MIBC treated with breast-conserving
surgery and radiation are acceptably low and similar to
those seen in unifocal BC supporting the use of BCT in
select patients with MIBC. This broadening of indications
for BCT greatly benefits this growing population of patients
as breast conservation is associated with better patient
satisfaction and potentially improved survival.36-39
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3191
Boughey et al
AFFILIATIONS
CLINICAL TRIAL INFORMATION
1
NCT01556243
Mayo Clinic, Rochester, MN
2
Dartmouth Hitchcock Medical Center, Dartmouth College—Norris
Cotton Cancer Center, Lebanon, NH
3
Alliance Statistics and Data Management Center, Weill Cornell
Medicine, New York, NY
4
Alliance Statistics and Data Management Center, Duke University,
Durham, NC
5
Rutgers Cancer Institute of New Jersey, New Brunswick, NJ
6
Sarah Cannon Cancer Center, Richmond, VA
7
Oregon Health and Science University, Legacy Good Samaritan Hospital
and Medical Center, Portland, OR
8
University of Texas MD Anderson Cancer Center, Houston, TX
9
Cedars-Sinai Medical Center, Los Angeles, CA
10
Memorial Sloan Kettering Cancer Center, New York, NY
11
Alliance for Clinical Trials in Oncology Operations Office, Chicago, IL
12
UNC Lineberger Comprehensive Cancer Center, Chapel Hill, NC
13
Dana-Farber/Partners Cancer Care, Boston, MA
CORRESPONDING AUTHOR
Judy C. Boughey, MD, Mayo Clinic, 200 1st St SW, Rochester, MN
55905; e-mail: Boughey.judy@mayo.edu.
DISCLAIMER
The content is solely the responsibility of the authors and does not
necessarily represent the official views of the National Institutes of
Health.
EQUAL CONTRIBUTION
J.C.B. and K.M.R. contributed equally to this work and are co-first
authors.
PRIOR PRESENTATION
Presented at the San Antonio Breast Cancer Symposium (SABCS), San
Antonio, TX, December 6-10, 2022; and at the Society of Surgical
Oncology (SSO), Boston, MA, March 22-25, 2023.
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF
INTEREST
Disclosures provided by the authors are available with this article at DOI
https://doi.org/10.1200/JCO.22.02553.
DATA SHARING STATEMENT
Deidentified patient data may be requested from Alliance for Clinical
Trials in Oncology via concepts@alliancenctn.org if data are not publicly
available. A formal review process includes verifying the availability of
data, conducting a review of any existing agreements that might have
implications for the project, and ensuring that any transfer is in
compliance with the IRB. The investigator will be required to sign a data
release form prior to transfer.
AUTHOR CONTRIBUTIONS
Conception and design: Judy C. Boughey, Kari M. Rosenkranz, Karla V.
Ballman, Bruce G. Haffty, Laurie W. Cuttino, Charlotte D. Kubicky, Kelly
K. Hunt, Olwen M. Hahn, Lisa A. Carey
Administrative support: Judy C. Boughey, Ann H. Partridge
Provision of study materials or patients: Judy C. Boughey, Bruce G. Haffty,
Armando E. Giuliano, Kimberly J. Van Zee, Kelly K. Hunt
Collection and assembly of data: Judy C. Boughey, Kari M. Rosenkranz,
Linda McCall, Laurie W. Cuttino, Charlotte D. Kubicky, Armando E.
Giuliano, Kimberly J. Van Zee, Kelly K. Hunt, Olwen M. Hahn
Data analysis and interpretation: Judy C. Boughey, Kari M. Rosenkranz,
Karla V. Ballman, Linda McCall, Bruce G. Haffty, Laurie W. Cuttino,
Charlotte D. Kubicky, Kelly K. Hunt, Ann H. Partridge
Manuscript writing: All authors
Final approval of manuscript: All authors
Accountable for all aspects of the work: All authors
ACKNOWLEDGMENT
A list of the participating institutional networks in this study are listed in
Appendix 1 (online only).
SUPPORT
Supported by the National Cancer Institute of the National Institutes of
Health under Award Nos. U10CA180821 and U10CA180882 (to the
Alliance for Clinical Trials in Oncology), UG1CA189869, UG1CA232760,
UG1CA233180, UG1CA233290, UG1CA233323, UG1CA233329, and
UG1CA233373 (https://acknowledgments.alliancefound.org).
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37. van Maaren MC, de Munck L, de Bock GH, et al: 10 year survival after breast-conserving surgery plus radiotherapy compared with mastectomy in early breast
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38. Hartmann-Johnsen OJ, Karesen R, Schlichting E, et al: Survival is better after breast conserving therapy than mastectomy for early stage breast cancer: A
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n n n
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AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Local Recurrence After Breast-Conserving Therapy in Patients With Multiple Ipsilateral Breast Cancer: Results From ACOSOG Z11102 (Alliance)
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted.
Relationships are self-held unless noted. I 5 Immediate Family Member, Inst 5 My Institution. Relationships may not relate to the subject matter of this manuscript.
For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.
Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).
Judy C. Boughey
Honoraria: UpToDate, PeerView, PER
Consulting or Advisory Role: CairnSurgical, Symbiosis (Inst)
Research Funding: Lilly (Inst)
Patents, Royalties, Other Intellectual Property: Patent pending—Methods and
Materials for Assessing Chemotherapy Responsiveness and Treating Cancer
(Inst)
Karla V. Ballman
This author is an Editorial Board Member for Journal of Clinical Oncology.
Journal policy recused the author from having any role in the peer review of this
manuscript.
Consulting or Advisory Role: Takeda, Agenus
Patents, Royalties, Other Intellectual Property: Prostate cancer signature
patent (Inst)
Expert Testimony: Janssen Oncology, Sanofi, Mylan
Bruce G. Haffty
This author is a Deputy Editor for Journal of Clinical Oncology. Journal policy
recused the author from having any role in the peer review of this manuscript.
Laurie W. Cuttino
Employment: HCA Healthcare
Leadership: HCA Healthcare
Stock and Other Ownership Interests: HCA Healthcare
Kelly K. Hunt
Consulting or Advisory Role: Armada Health Care, Merck, AstraZeneca
Research Funding: Lumicell (Inst), CairnSurgical (Inst), Lilly (Inst)
Olwen M. Hahn
Employment: Solaris Health
Leadership: Via Oncology
Stock and Other Ownership Interests: Teleflex Medical, Novavax
Honoraria: Cardinal Health
Consulting or Advisory Role: Pfizer, HMP
Travel, Accommodations, Expenses: Cardinal Health
Lisa A. Carey
Research Funding: NanoString Technologies (Inst), Seattle Genetics (Inst),
Veracyte (Inst), AstraZeneca (Inst)
Uncompensated Relationships: Novartis (Inst), Genentech/Roche (Inst),
GlaxoSmithKline (Inst), Lilly, Seattle Genetics
Open Payments Link: https://openpaymentsdata.cms.gov/physician/179671
Ann H. Partridge
Patents, Royalties, Other Intellectual Property: I receive small royalty payments
for coauthoring the breast cancer survivorship section of UpToDate
Open Payments Link: https://openpaymentsdata.cms.gov/physician/835197
No other potential conflicts of interest were reported.
Armando E. Giuliano
Stock and Other Ownership Interests: Blacklight Surgical
Honoraria: Merck/Schering Plough
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Volume 41, Issue 17
Breast Conservation in MIBC
APPENDIX 1. ALLIANCE FOUNDATION
The following institutional networks participated in this study: Aurora
NCI Community Oncology Research Program, Milwaukee, WI;
Shamsuddin Virani; UG1CA190140; Avera Cancer Institute, Sioux
Falls, SD; Bay Area Tumor Institute NCORP, Oakland, CA; Lisa
Bailey; UG1CA189817; Beaumont NCI Community Oncology Research Program; Cancer Research Consortium of West Michigan
NCORP, Grand Rapids, MI; Kathleen Yost; UG1CA189971; Cancer
Research for the Ozarks NCORP, Springfield, MO; Jay Carlson;
UG1CA189822; Carolinas Medical Center/Levine Cancer Institute,
Charlotte, NC; Richard White; Cedars-Sinai Medical Center, Los
Angeles, CA; Armando Giuliano; Dana-Farber/Partners Cancer Care
LAPS, Boston, MA; Harold Burstein; UG1CA233180; Dartmouth
College—Norris Cotton Cancer Center LAPS, Lebanon, NH; Konstantin Dragnev; UG1CA233323; Delaware/Christiana Care NCI
Community Oncology Research Program, Newark, DE; Gregory
Masters; UG1CA189819; Doctor’s Hospital of Laredo, Laredo, TX;
Gary Unzeitig; Duke University—Duke Cancer Institute LAPS,
Durham, NC; Jeffrey Crawford; UG1CA233253; Eastern Maine
Medical Center Cancer Care, Brewer, ME; Sarah Sinclair; Froedtert
and the Medical College of Wisconsin LAPS, Milwaukee, WI; Tina
Yen; UG1CA233198; Heartland Cancer Research NCORP, Decatur,
IL; Bryan Faller; UG1CA189830; Indiana University—Melvin and
Bren Simon Cancer Center LAPS, Indianapolis, IN; Iowa-Wide
Oncology Research Coalition NCORP, Des Moines, IA; Joshua
Lukenbill; UG1CA189816; Lankenau Medical Center, Wynnewood,
PA; John Devlin; Mayo Clinic LAPS, Rochester, MN; Steven Alberts;
UG1CA232760; MedStar Franklin Square Medical Center/Weinberg
Cancer Institute, Baltimore, MD; Memorial Sloan-Kettering Cancer
Center LAPS, New York, NY; Michael Morris; UG1CA233290; Metro
Minnesota Community Oncology Research Consortium, Saint Louis
Park, MN; Daniel Anderson; UG1CA189863; Michigan Cancer
Research Consortium NCORP, Ann Arbor, MI; Tareq Al Baghdadi;
UG1CA189971; Morton Plant Hospital, Clearwater, FL; Peter Blumencranz; New Mexico Minority Underserved NCORP, Albuquerque, NM; Zoneddy Dayao; UG1CA189856; Northern Indiana
Cancer Research Consortium; Northwell Health NCORP, Lake
Success, NY; Jonathan Kolitz; Northwest NCI Community Oncology
Research Program; Oregon Health and Science University, Portland, OR; Brett Sheppard; Saint Elizabeth Healthcare Edgewood,
Edgewood, KY; Daniel Flora; The James Graham Brown Cancer
Center at University of Louisville, Louisville, KY; Robert Martin; UC
San Diego Moores Cancer Center, La Jolla, CA; Lyudmila Bazhenova; UNC Lineberger Comprehensive Cancer Center LAPS, Chapel
Hill, NC; Matthew Milowsky; UG1CA233373; UPMC Hillman Cancer
Center LAPS, Pittsburgh, PA; Matthew Schuchert; UG1CA233184;
University of Miami Miller School of Medicine-Sylvester Cancer
Center, Miami, FL; Ronald Benveniste; University of Oklahoma
Health Sciences Center LAPS, Oklahoma City, OK; Adam Asch;
UG1CA233193; University of Rochester, Rochester, NY; Kristin
Skinner; University of Texas MD Anderson Cancer Center LAPS,
Houston, TX; Kelly Hunt; UG1CA233329; University of Texas
Southwestern Medical Center LAPS, Dallas, TX; Ann Leitch;
UG1CA233302; University of Utah—Huntsman Cancer Institute
LAPS, Salt Lake City, UT; Howard Colman; UG1CA233178; University of Vermont and State Agricultural College, Burlington, VT;
Peter Kaufman; University of Wisconsin Carbone Cancer Center
LAPS, Madison, WI; Lee Wilke; UG1CA233277; VCU Massey Cancer
Center Minority Underserved NCORP, Richmond, VA; Zhijian Chen;
UG1CA189869; Washington University—Siteman Cancer Center
LAPS, Saint Louis, MO; Nancy Bartlett; UG1CA233339; William
Beaumont Hospital-Royal Oak, Royal Oak, MI; Andrew Muskovitz;
and Wisconsin NCI Community Oncology Research Program,
Marshfield, WI; Matthias Weiss; UG1CA189956.
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