Local Recurrence After Breast-Conserving Therapy in Patients With Multiple Ipsilateral Breast Cancer: Results From ACOSOG Z11102 (Alliance)

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 = 15) was 22.6% compared with 1.7% in patients with a preoperative MRI (n = 189; P = .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.

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

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.

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.

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 HER2-positive tumors receiving adjuvant chemotherapy. Final 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 IRB-approved 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.

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.

FIG 1.

Flow diagram of patients enrolled on Z11102.

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 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 node-negative in 195 patients (95.6%) and clinically node-positive disease in nine patients (4.4%).

TABLE 1.

Patient and Tumor Characteristics of Patients Enrolled on Z11102 Clinical Trial

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 HER2+ 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 (ER+)/HER2– disease, six had HER2+ 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 ER+/HER2–, of which the second lesion was HER2+ in nine patients, ER–/HER2– in four patients, and missing tumor biology in eight patients. One patient had one HER2+ lesion and one ER–/HER2– lesion, and one patient had a HER2+ 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 ER+/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 HER2+, which, in turn, was worse than ER+/HER2– disease. This classification yielded 167 patients (83.5%) with ER+/HER2– disease, 23 patients (11.5%) with HER2+ 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 ER+ 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 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).

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.

Four of the 167 patients with ER+/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 HER2+ 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 ER+ 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 = .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.

TABLE 2.

Factors Associated With LR After Breast-Conserving Therapy for Multiple Ipsilateral Breast Cancer

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 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 HER2+ 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 HER2+ 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 numerically higher than that for ER+/HER2– disease as would be expected in unifocal disease. None of the 23 patients with HER2+ 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 HER2+ 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 follow-up particularly for LR in ER+ 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 2+ 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

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.

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

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)

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