Breast-Conserving Therapy for Triple-Negative Breast Cancer

Research Original Investigation PACIFIC COAST SURGICAL ASSOCIATION Breast-Conserving Therapy for Triple-Negative Breast Cancer Alexandra Gangi, MD; Alice Chung, MD; James Mirocha, MS; Douglas Z. Liou, MD; Trista Leong, MA; Armando E. Giuliano, MD IMPORTANCE The aggressive triple-negative phenotype of breast cancer (negative for estrogen and progesterone receptors and v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2 [ERBB2] [formerly human epidermal growth factor receptor 2 (HER2)]) is considered by some investigators to be a relative contraindication to breast-conserving therapy. OBJECTIVES To compare outcomes of breast-conserving therapy for patients with triple-negative breast cancer () with those of patients with the luminal A, luminal B, and ERBB2 subtypes. DESIGN, SETTING, AND PARTICIPANTS Prospective database review at an academic tertiary medical center with a designated breast cancer center. We included 181 consecutive patients ages 29 to 8 years with stages I to III invasive breast cancer who underwent breast-conserving therapy at a single institution from January 1, 2, through May 3, 212. Of these patients, 234 (12.6%) had ; 1341 (72.4%), luminal A subtype; 212 (11.%), luminal B subtype; and 64 (3.%), ERBB2-enriched subtype. EXPOSURE Breast-conserving therapy. MAIN OUTCOMES AND MEASURES The primary outcome measure was local recurrence (LR). Secondary outcome measures included regional recurrence, distant recurrence, and overall survival. RESULTS Triple-negative breast cancer was associated with younger age at diagnosis (6 vs years; P =.1), larger tumors (2.1 vs 1.8 cm; P <.1), more stage II vs I cancer (42.1% vs 33.6%; P =.), and more G3 tumors (86.4% vs 28.4%; P <.1) compared with the non- subtypes. Multivariable analysis showed that did not have a significantly increased risk of LR compared with the luminal A (hazard ratio, 1.4 [9% CI,.6-3.3]; P =.43), luminal B (1.6 [.-.2]; P =.43), and ERBB2 (1.1 [.2-.2]; P =.87) subtypes. Only tumor size was a significant predictor of LR (hazard ratio, 4.7 [9% CI, 1.6-14.3]; P =.6). Predictors of worse overall survival included tumor size, grade, and stage and subtype. CONCLUSIONS AND RELEVANCE Breast-conserving therapy for is not associated with increased LR compared with non- subtypes. However, the phenotype correlates with worse overall survival. Breast-conserving therapy is appropriate for patients with. JAMA Surg. 214;149(3):22-28. doi:1.1/jamasurg.213.337 Published online January 1, 214. Author Affiliations: Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California (Gangi, Chung, Liou, Giuliano); Department of Biostatistics, Cedars-Sinai Medical Center, Los Angeles, California (Mirocha); Department of Health Information, Cedars-Sinai Medical Center, Los Angeles, California (Leong). Corresponding Author: Armando E. Giuliano, MD, Department of Surgery, Cedars-Sinai Medical Center, 31 N San Vicente Blvd, Ste 311, Los Angeles, CA 948 (armando.giuliano@cshs.org). 22 jamasurgery.com

Breast-Conserving Therapy for Original Investigation Research Breast cancers are characterized by a wide spectrum of clinical, pathologic, and molecular features. Various well-established tumor markers have been used to determine prognosis and response to therapy, including molecular biomarkers allowing for the identification of distinct subtypes of breast cancer. The most common and useful classification is based on the expression of estrogen receptors (ERs), progesterone receptors (PRs), and v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2 (ERBB2) (formerly human epidermal growth factor receptor 2 [HER2]). 1-4 Triple-negative breast cancers (s) are those that lack or only minimally express ERs, PRs, and ERBB2. Triplenegative breast cancers account for approximately 1% to 2% of newly diagnosed breast cancers and tend to exhibit a more aggressive clinical behavior, a metastatic pattern, and poor prognosis compared with other subtypes.,6 Although targeted therapies have been developed for tumors that express ERs, PRs, or ERBB2, treatment for tumors that lack these markers remains challenging. The lack of targeted therapy and the aggressive nature of s have resulted in controversy as to whether breastconserving therapy (BCT) is appropriate treatment for these tumors. Several large randomized clinical trials demonstrate equivalent overall survival (OS) for patients undergoing mastectomy compared with those undergoing BCT; however, none included an analysis of molecular subtypes or. 7,8 For patients with who undergo BCT, many investigators suggest that local recurrence (LR), regional recurrence (RR), and distant metastasis are increased and that OS is decreased compared with the outcomes of patients with non- subtypes. 9-12 Given the aggressive nature of, one can reasonably question whether BCT is appropriate. The purpose of this study was to compare outcomes between patients with and non- who underwent BCT to determine whether LR is increased in patients. Methods This study was performed with the approval of the institutional review board of Cedars-Sinai Medical Center. Informed consent was waived for this retrospective review of a prospective database. We reviewed a prospectively maintained database of patients undergoing evaluation and treatment for breast cancer from January 1, 2, through May 3, 212. Women ages 18 through 8 years with newly diagnosed stages I through III breast cancer were identified. Approximately 2 surgeons performed the procedures that qualified for inclusion in this study. The surgeons did not follow a standardized surgical management protocol. Men, patients undergoing neoadjuvant chemotherapy or mastectomy, and patients with fewer than 9 days of follow-up were excluded from the study. In addition, patients with positive margins were excluded. Most surgeons considered margins to be negative if the tumor-free margin was larger than 1 mm; some surgeons were content if no tumor cells were found at the ink of the surgical specimen on pathologic review. Of the remaining patients, we included only those for whom ER, PR, and ERBB2 status were available. We identified a total study sample of 181 patients. Patients were then categorized according to tumor phenotypic subtype using the presence or absence of tumor markers. Specifically, tumors were classified into luminal A (positive for ER or PR and negative for ERBB2), luminal B (positive for ER or PR and ERBB2), ERBB2 (negative for ER and PR and positive for ERBB2), and (negative for all 3 markers) subtypes based on immunohistochemical identification of these markers on biopsied or excised specimens. A positive ERBB2 marker was defined as immunohistochemical identification (ERBB2 receptor protein on the surface of cells in the breast cancer tissue sample) of 3+ and/or amplified (ratio, >2.) expression of ERBB2 on fluorescence in situ hybridization. Patient and tumor characteristics examined included age at diagnosis, tumor size, histologic subtype, grade, stage, lymph node status, adjuvant systemic treatment, and adjuvant radiotherapy. As is standard practice, conventional whole-breast radiotherapy with opposing tangents was used in nearly all patients. Most patients with invasive cancer at our institution receive a boost dose of radiotherapy to the primary site. The primary outcome measure was LR. Secondary outcome measures included RR, distant recurrence (DR), and OS. As is standard practice, most of the patients were followed up with biannual mammography for 2 years and then annual mammography and physical examination thereafter. Time to recurrence was calculated from the date of diagnosis to the date of recurrence. Survival was calculated from the date of diagnosis to the date of death or the most recent follow-up for surviving patients. Differences on normally distributed variables across the 4 cancer subtypes were assessed by analysis of variance and Tukey post hoc tests. Differences on nonnormally distributed numerical variables across the 4 subtypes were assessed by the Kruskal-Wallis test and Wilcoxon rank sum post hoc tests. Differences between and non- on normally distributed variables were assessed by the independentsamples t test. Differences between and non- on nonnormally distributed numerical variables were assessed by the Wilcoxon rank sum test. Differences on dichotomous variables were assessed by the χ 2 test or the Fisher exact test, as appropriate. Overall survival and freedom from recurrence were estimated by the Kaplan-Meier method and compared across groups by the log-rank test. Hazard ratios (HRs) and their 9% confidence intervals were estimated using Cox proportional hazards regression models. Multivariable Cox models were used to estimate the association of with the risk of death and recurrence, adjusting for potentially confounding variables. Time to recurrence for the Cox models was truncated at years. Candidate predictors in the Cox models for recurrence were age (<, to <, and years), tumor size (<2, 2 to <, and cm), stage, and grade. Subtype (comparing with each other subtype) was the main predictor of interest. A preliminary Cox survival model revealed a very large HR for patients years or older vs those younger than years (HR, 7. [9% CI, 3.6-13.4]). Thus, separate multivariable Cox survival models were estimated in patients younger than years and years or older. Candidate predictors in the Cox survival model for patients younger than years were age (< jamasurgery.com JAMA Surgery March 214 Volume 149, Number 3 23

Research Original Investigation Breast-Conserving Therapy for Table 1. Patient and Tumor Characteristics Subtype a P Value Characteristic (n = 234) [12.6%] (n = 1341) [72.4%] (n = 212) [11.%] ERBB2 Enriched (n = 64) [3.%] All vs Non- Age at diagnosis, mean (SD), y 6.1 (14.).2 (12.) 6.9 (12.7) 6.2 (12.4) <.1.1 Tumor size, median (range), cm 1.9 (.2-9.) 1. (.1-16) 1.7 (.1-8.) 1.8 (.2-9.4) <.1 <.1 Size distribution, No. (%) T1 (2. cm) 121 (1.9) 897 (66.9) 127 (9.9) 36 (6.3) T2 (>2. to 4.9 cm) 13 (44.2) 2 (3.) 78 (36.8) 26 (.6) <.1 <.1 T3 (. cm) 9 (3.9) 42 (3.1) 7 (3.3) 2 (3.1) Histology, No. (%) Ductal only 218 (93.2) 18 (79.) 188 (88.7) 61 (9.3) Lobular only 2 (.9) 12 (9.) 6 (2.8) Ductal and lobular 7 (3.) 18 (11.8) 16 (7.) 3 (4.7) <.1 <.1 Unknown/other 7 (3.) 4 (.3) 2 (.9) Pathologic stage, No. (%) I 12 (1.3) 81 (63.) 118 (.7) 33 (1.6) II 98 (41.9) 439 (32.7) 77 (36.3) 27 (42.2) <.1 <.1 III 16 (6.8) 1 (3.8) 17 (8.) 4 (6.3) Grade, No. (%) G1 (2.1) 387 (28.9) 24 (11.3) G2 21 (9.1) 629 (46.9) 77 (36.3) 8 (12.) G3 22 (86.3) 299 (22.3) 11 (1.9) 3 (82.8) <.1 <.1 Unknown 6 (2.6) 26 (1.9) 1 (.) 3 (4.7) Lymph node status, No. positive/total No. 67/22 (3.) 3/123 (24.3) 9/194 (3.4) 21/ (3.).4.1 dissected (%) Treatment, No. receiving/no. eligible (%) Adjuvant chemotherapy 183/214 (8.) 44/1164 (38.2) 124/19 (6.3) 1/ (8.) <.1 <.1 Radiotherapy 21/213 (94.4) 1/1116 (9.) 16/18 (89.2) 48/3 (9.6).26.48, triple-negative breast cancer. Not all categories total numbers in column headings owing to missing data. Percentages have been rounded and may not sum to. and years), tumor size, stage, and grade; candidate predictors in the Cox survival model for the group years or older were age (numerical), tumor size, stage, and grade. Subtype (comparing with each other subtype) was the main predictor of interest in both age models. We used a 2-sided. significance level throughout. Analyses were performed with commercially available statistical software (SAS, version 9.2; SAS Institute, Inc). Results We identified 181 patients who received BCT and had complete data for ER, PR, and ERBB2 status. Tumors in 234 patients (12.6%) were ; 1341 (72.4%), luminal A subtype; 212 (11.%), luminal B subtype; and 64 (3.%), ERBB2-enriched subtype. All patients were followed up for at least 9 days after diagnosis, with a median follow-up of (interquartile range, 33-98) months. Patient demographic and tumor data are reported in Table 1. Most of the patients were years or older (74.7%), with the mean age slightly higher in the luminal A group (.2 years) compared with the luminal B (6.9 years), (6.1 years), and ERBB2 (6.2 years) groups (P <.1). All patients had stage I (1122 [.6%]), stage II (641 [34.6%]), or stage III (91 [4.9%]) disease at presentation. Among the 4 subtypes, we found a substantial difference in tumor size (P <.1), histopathologic type (P <.1), pathologic grade (P <.1), and stage (P <.1). When compared with non- patients, patients were younger at diagnosis (mean [SD] age, 6.1 [14.] vs 9.6 [12.6] years; P =.1) and had a larger tumor size (2.1 [1.3] vs 1.8 [1.3] cm; P <.1). In addition, s were more frequently high grade (P <.1), were stage II or III vs stage I (P <.1), and had predominantly infiltrating ductal histologic type tumors (P <.1). Overall, 26.2% of patients had node-positive disease. Of the subtypes, ERBB2 had the strongest association with nodal positivity (3.%) compared with (3.%) or the luminal A (24.3%) or luminal B (3.4%) subtypes (P =.4). When comparing with non- patients, lymph node positivity was not significantly different (3.% vs 2.%; P =.1). Patients were treated with adjuvant systemic therapy and/or radiotherapy. Overall, 49.3% of patients received chemotherapy, whereas 91.2% received radiotherapy. Patients with (8.%) and the ERBB2 subtype (8.%) were more likely to receive chemotherapy compared with patients with the lu- 24 JAMA Surgery March 214 Volume 149, Number 3 jamasurgery.com

Breast-Conserving Therapy for Original Investigation Research Figure 1. Kaplan-Meier Estimates of Freedom From Local Recurrence Figure 2. Kaplan-Meier Estimates of Freedom From Regional Recurrence Log-rank P =.13 Log-rank P <.1 2 2 1 2 3 4 receptor 2 [HER2]);, triple-negative breast cancer. Cancer subtypes are 1 2 3 4 receptor 2 [HER2]);, triple-negative breast cancer. Cancer subtypes are Table 2. Multivariable Hazard Model for Local Recurrence at Years a Grade 2 vs 1 1.7 (.-6.3).41 Grade 3 vs 1 3.4 (.9-12.6).6 T2 vs T1 1.6 (.8-3.2).2 T3 vs T1 4.7 (1.6-14.3).6 vs luminal A 1.4 (.6-3.3).43 vs luminal B 1.6 (.-.2).43 vs 1.1 (.3-.2).87 HR, hazard ratio;, triple-negative breast cancer. minal B (6.3%) and especially the luminal A (38.2%) subtypes (P <.1). A total of 143 (8.8%) patients did not receive radiotherapy. Of these, 12 patients had and 16 had luminal A, 2 had luminal B, and had ERBB2 tumor subtypes. Within the group, 8 patients had comorbid conditions that precluded them from receiving radiotherapy, and 4 patients refused radiotherapy although it was recommended. Within the luminal A and B groups, patients had smaller tumors and were generally older with comorbid conditions and therefore did not receive radiotherapy. Within the ERBB2 group, 2 patients refused the treatment; 3 had significant comorbidities, and although radiotherapy was recommended, they declined. Most of the patients in all groups received adjuvant whole-breast radiotherapy or accelerated partialbreast radiotherapy (94.1% vs 3.8%). Forty-six LRs were observed among the entire study population, including 11 (4.7%) in the group, 8 (12.%) in the ERBB2 group, 23 (1.7%) in the luminal A group, and 4 (1.9%) in the luminal B group. Kaplan-Meier estimated freedom from LR at years was 93% for the, 96% for ERBB2, 9% for luminal A, and 96% for luminal B (P =.13) groups. Figure 1 shows Kaplan-Meier curves for LR for Table 3. Multivariable Cox Model for Regional Recurrence at Years a Stage II vs I.2 (1.7-1.8).4 Stage III vs I 8.3 (1.8-37.4).6 vs luminal A 1.3 (.4-4.9).68 vs luminal B.4 (.1-1.8).2 vs.2 (.-.7).2 HR, hazard ratio;, triple-negative breast cancer. patients who underwent BCT stratified by subtype. On multivariable analysis for LR, did not have a significantly increased risk compared with the luminal A (HR, 1.4 [9% CI,.6-3.3]; P =.43), the luminal B (1.6 [.-.2]; P =.43), or the ERBB2 (1.1 [.3-.2]; P =.87) subtype. Based on multivariable analysis, larger size T3 vs T1 classification (HR, 4.7 [9% CI, 1.6-14.3]; P =.6) was the only significant independent predictor of LR (Table 2). We observed a total of 21 RRs, including 3 (1.3%) in the, 4 (6.3%) in the ERBB2, 9 (.7%) in the luminal A, and (2.4%) in the luminal B groups. Kaplan-Meier estimated freedom from RR at years was 98% for the, 84% for the ERBB2, 98% for the luminal A, and 96% for the luminal B groups (P <.1) (Figure 2). Multivariable analysis revealed that stage II vs I (HR,.2 [9% CI, 1.7-1.8]; P =.4) and stage III vs I (8.3 [1.8-37.4]; P =.6) were significant predictors of RR (Table 3). Also, was protective for risk of RR, compared with the ERBB2 subtype (HR,.2 [9% CI,.-.7]; P =.2). Distant recurrences were the most frequent recurrences seen among all patients, with a total of 66 patients presenting with metastatic disease after BCT. Of these, 21 (9.%) were in the group, (7.8%) in the ERBB2 group, 31 (2.3%) in the luminal A group, and 9 (4.2%) in the luminal B jamasurgery.com JAMA Surgery March 214 Volume 149, Number 3 2

Research Original Investigation Breast-Conserving Therapy for Figure 3. Kaplan-Meier Estimates of Freedom From Distant Recurrence 2 Log-rank P <.1 1 2 3 4 receptor 2 [HER2]);, triple-negative breast cancer. Cancer subtypes are Table 4. Multivariable Hazard Model for Distant Recurrence at Years a Stage II vs I 1.8 (.8-3.9).16 Stage III vs I.4 (2.2-13.4) <.1 T2 vs T1 3. (1.6-7.4).1 T3 vs T1. (2.-1.6).1 G3 vs G1 and G2 1. (.8-2.9).18 vs luminal A 2. (1.4-4.4).1 vs luminal B 1.6 (.7-3.6).22 vs.8 (.3-2.2).67 HR, hazard ratio;, triple-negative breast cancer. group. Kaplan-Meier estimated freedom from DR at years was 8% for the, 88% for the ERBB2, 9% for luminal A, and 92% for luminal B (P <.1) groups (Figure 3). A more advanced stage (III vs I; HR,.4 [9% CI, 2.2-13.4]; P <.1) and larger tumor (T3 vs T1,. [2.-1.6]; P =.1) were associated with an increased risk of DR (Table 4). Among subtypes, patients were at increased risk for DR compared with patients with the luminal A subtype (HR, 2. [9% CI, 1.4-4.4]; P =.1) but not those with the luminal B or ERBB2 subtypes. A total of 113 deaths occurred. Patients older than years were excluded from the multivariable analysis of OS because of their higher risk of death (HR, 7. [9% CI, 3.-13.2]). Predictors of worse OS included being years or older vs younger than years (HR, 2.2 [9% CI, 1.3-3.9]; P =.), stage III vs I disease (2.8 [1.3-6.]; P =.7), T2 vs T1 classification (1.9 [1.1-3.4]; P =.3), and T3 vs T1 classification (4.2 [1.8-9.9]; P =.1). Furthermore, was associated with worse OS compared with the luminal A (HR, 3. [9% CI, 2.2-.7]; P <.1) and luminal B (3.7 [1.7-8.2]; P =.1) subtypes (Table ). Kaplan-Meier analysis of OS is shown in Figure 4. Table. Multivariable Hazard Model for Overall Survival at Years a Age vs < y 2.2 (1.3-3.9). Stage II vs I 1.2 (.7-2.1).3 Stage III vs I 2.8 (1.3-6.).7 T2 vs T1 1.9 (1.1-3.4).3 T3 vs T1 4.2 (1.8-9.9).1 vs luminal A 3. (2.2-.7) <.1 vs luminal B 3.7 (1.7-8.2).1 vs 1.3 (.6-3.). HR, hazard ratio;, triple-negative breast cancer. Figure 4. Kaplan-Meier Estimates of Overall Survival 2 1 2 3 4 Discussion Log-rank P <.1 receptor 2 [HER2]);, triple-negative breast cancer. Cancer subtypes are Breast cancer subtypes are known to have phenotypic diversity with regard to tumor aggressiveness and response to therapy. 3 Triple-negative breast cancer specifically is challenging to treat because it lacks a targeted treatment approach, is associated with a poor prognosis, and, in some studies, has an increased risk of LR. 13-1 This study validates that patients are younger, present with tumors of a higher grade and larger size, and present at a more advanced stage compared with non- patients. The study also validates that OS is worse among this group of patients. These findings are consistent with the current literature, which indicates that the triple-negative subtype is generally more aggressive, with worse prognosis overall.,16,17 Although breast cancer patients undergoing BCT have longterm outcomes equivalent to those of patients treated with mastectomy, significant debate remains regarding BCT as an appropriate treatment of. 8,18 Several investigators 1,19,2 26 JAMA Surgery March 214 Volume 149, Number 3 jamasurgery.com

Breast-Conserving Therapy for Original Investigation Research have reported results evaluating locoregional recurrence (LRR) related to the breast cancer subtype. Some studies 11,12,21 have included only patients who have undergone BCT, whereas others include patients who have undergone mastectomy. Rates for LR after BCT in these studies have ranged from 4% to 2% for patients compared with 3% to 14% for non- patients, suggesting higher LRR in patients. 19 Data regarding rates of LRR for patients are incongruent. Arvold et al 22 reviewed 1434 patients who underwent BCT and determined that 171 patients had a significantly higher risk of LR compared with patients with other subtypes (adjusted HR, 3.9; P =.1). A similar but smaller study by Nguyen et al 9 found that, of the 793 patients who underwent BCT, the patients had a dramatically increased risk for LR (adjusted HR, 7.1; P =.9). Additional studies 1-12,2,21 have demonstrated that the LRR rate after BCT was significantly greater in compared with the other subtypes. In contrast, Haffty et al 23 and Freedman et al 24 found no significant differences in LR rates for patients treated with BCT for vs non-. In the study by Haffty et al, 23 117 patients had and 36 had non-, with no appreciable difference in -year breast relapse free survival between the 2 groups (83% vs 83%; differences were not significant). When comparing 73 patients who had received BCT by subtype, Freedmanetal 24 found no significant difference in LRR related to the subtypes (2.3% in ER- or PR-positive subtypes; 4.6% in ER- and PR-negative and ERBB2-positive subtypes, and 3.2% in ; P =.36). The present study validates that BCT is appropriate for patients with and supports the findings of Haffty et al, 23 Freedman et al, 24 and others 6 who have shown no increase in LRR for patients with. Our study is particularly relevant to widespread practice. The large numbers of surgeons in the US have different practice patterns, and a variety of adjuvant systemic therapies and radiotherapy are prescribed. Our study is particularly relevant to widespread practice because of the large number of US surgeons, each with different practice patterns, who treat these patients and the variety of standard adjuvant systemic therapies and radiotherapy that are prescribed widely in the United States. On multivariable analysis, after adjusting for tumor size and grade, no significant difference was found in risk of in-breast LR among subtypes. Indeed, few LRs were seen in any group. The use of adjuvant systemic chemotherapy may contribute to the low rate of LRR seen in this study because chemotherapy was routinely used for patients with no significant comorbidities. Furthermore, the only predictive variable for statistically significant risk of LR was a T3 tumor. This finding suggests that is not associated with increased risk for LR after BCT. Similarly, an increased risk for RR was not seen in patients but in patients with the ERBB2 subtype and stages II and III cancers. However, the multivariable analysis is of limited value with so few RR. Conclusions Triple-negative breast cancer is associated with worse OS and an increased risk for DR. However, this study validates the lack of a significant risk for LR in patients who undergo BCT. Despite the aggressive nature of, the triple-negative phenotype does not lead to a significantly increased risk of LRR compared with the non- phenotype in patients undergoing BCT. Breast-conserving therapy is appropriate for patients and should be routinely offered. ARTICLE INFORMATION Accepted for Publication: May 17, 213. Published Online: January 1, 214. doi:1.1/jamasurg.213.337. Author Contributions: Drs Gangi and Giuliano had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Gangi, Giuliano. Acquisition of data: Gangi, Chung, Liou, Leong, Giuliano. Analysis and interpretation of data: Gangi, Chung, Mirocha, Giuliano. Drafting of the manuscript: Gangi, Chung, Mirocha. Critical revision of the manuscript for important intellectual content: Gangi, Chung, Mirocha, Liou, Giuliano. Statistical analysis: Gangi, Mirocha. Obtained funding: Giuliano. Administrative, technical, and material support: Giuliano. Study supervision: Chung, Giuliano. Conflict of Interest Disclosures: None reported. Funding/Support: This study was supported by the Fashion Footwear Charitable Foundation of New York, Inc, Associates for Breast and Prostate Cancer Studies, the Avon Foundation, the Margie and Robert E. Petersen Foundation, and Linda and Jim Lippman. Role of the Sponsor: The funding sources had no role in the design and conduct of the study; collection, management, analysis, or interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Previous Presentation: This study was presented as a poster at the 84th Annual Meeting of the Pacific Coast Surgical Association; February 17, 213; Kauai, Hawaii, and is published after peer review and revision. REFERENCES 1. Wiechmann L, Sampson M, Stempel M, et al. Presenting features of breast cancer differ by molecular subtype. Ann Surg Oncol. 29;16(1):27-271. 2. Perou CM. Molecular stratification of triple-negative breast cancers. Oncologist. 211;16(suppl 1):61-7. 3. Sørlie T, Wang Y, Xiao C, et al. Distinct molecular mechanisms underlying clinically relevant subtypes of breast cancer: gene expression analyses across three different platforms. BMC Genomics. 26;7:127. doi:1.1186/1471-2164-7-127. 4. 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Breast cancer subtype approximated by estrogen receptor, progesterone receptor, and HER-2 is associated with local and distant recurrence after breast-conserving therapy. J Clin Oncol. 28;26(14):2373-2378. 1. Panoff JE, Hurley J, Takita C, et al. Risk of locoregional recurrence by receptor status in breast cancer patients receiving modern systemic therapy and post-mastectomy radiation. Breast Cancer Res Treat. 211;128(3):899-96. jamasurgery.com JAMA Surgery March 214 Volume 149, Number 3 27

Research Original Investigation Breast-Conserving Therapy for 11. Zaky SS, Lund M, May KA, et al. The negative effect of triple-negative breast cancer on outcome after breast-conserving therapy. Ann Surg Oncol. 211;18(1):288-286. 12. Meyers MO, Klauber-Demore N, Ollila DW, et al. Impact of breast cancer molecular subtypes on locoregional recurrence in patients treated with neoadjuvant chemotherapy for locally advanced breast cancer.ann Surg Oncol. 211;18(1):281-287. 13. Foulkes WD, Smith IE, Reis-Filho JS. Triple-negative breast cancer. N Engl J Med. 21;363(2):1938-1948. 14. Gabos Z, Thoms J, Ghosh S, et al. The association between biological subtype and locoregional recurrence in newly diagnosed breast cancer. Breast Cancer Res Treat. 21;124(1):187-194. 1. Zhang P, Xu BH, Ma F, et al. Treatment outcomes and clinicopathologic characteristics of advanced triple-negative breast cancer patients [in Chinese]. Zhonghua Zhong Liu Za Zhi. 211;33():381-384. 16. Hattangadi-Gluth JA, Wo JY, Nguyen PL, et al. Basal subtype of invasive breast cancer is associated with a higher risk of true recurrence after conventional breast-conserving therapy. Int J Radiat Oncol Biol Phys. 212;82(3):118-1191. 17. Fulford LG, Reis-Filho JS, Ryder K, et al. Basal-like grade III invasive ductal carcinoma of the breast: patterns of metastasis and long-term survival. Breast Cancer Res. 27;9(1):R4. doi:1.1186/bcr1636. 18. Toft DJ, Cryns VL. Minireview: basal-like breast cancer: from molecular profiles to targeted therapies. Mol Endocrinol. 211;2(2):199-211. 19. Lowery AJ, Kell MR, Glynn RW, Kerin MJ, Sweeney KJ. Locoregional recurrence after breast cancer surgery: a systematic review by receptor phenotype. Breast Cancer Res Treat. 212;133(3):831-841. 2. Solin LJ, Hwang W-T, Vapiwala N. Outcome after breast conservation treatment with radiation for women with triple-negative early-stage invasive breast carcinoma. Clin Breast Cancer. 29;9(2):96-. 21. Montagna E, Bagnardi V, Rotmensz N, et al. Breast cancer subtypes and outcome after local and regional relapse. Ann Oncol.212;23(2):324-331. 22. Arvold ND, Taghian AG, Niemierko A, et al. Age, breast cancer subtype approximation, and local recurrence after breast-conserving therapy. J Clin Oncol. 211;29(29):388-3891. 23. Haffty BG, Yang Q, Reiss M, et al. Locoregional relapse and distant metastasis in conservatively managed triple negative early-stage breast cancer. J Clin Oncol. 26;24(36):62-67. 24. Freedman GM, Anderson PR, Li T, Nicolaou N. Locoregional recurrence of triple-negative breast cancer after breast-conserving surgery and radiation.cancer. 29;11():946-91. 28 JAMA Surgery March 214 Volume 149, Number 3 jamasurgery.com