Prognosis for Patients With Metastatic Breast Cancer Who Achieve a No-Evidence-of-Disease Status After Systemic or Local Therapy

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1 Prognosis for Patients With Metastatic Breast Cancer Who Achieve a -Evidence-of-Disease Status After Systemic or Local Therapy Andrew J. Bishop, MD 1 ; Joe Ensor, PhD 2 ; Stacy L. Moulder, MD 3 ; Simona F. Shaitelman, MD 1 ; Mark A. Edson, MD, PhD 1 ; Gary J. Whitman, MD 4 ; Sandra Bishnoi, PhD 5 ; Karen E. Hoffman, MD 1 ; Michael C. Stauder, MD 1 ; Vicente Valero, MD 3 ; Thomas A. Buchholz, MD 1 ; Naoto T. Ueno, MD 3 ; Gildy Babiera, MD 6 ; and Wendy A. Woodward, MD, PhD 1 BACKGROUND: This study sought to determine outcomes for patients with metastatic breast cancer (MBC) with no evidence of disease (NED) after treatment and to identify factors predictive of outcomes once the status of NED was attained. METHODS: This study reviewed 570 patients with MBC who were consecutively treated between January 2003 and December Ninety patients (16%) attained NED, which was defined as a complete metabolic response on positron emission tomography or sclerotic healing of bone metastases on computed tomography or magnetic resonance imaging. The median follow-up for patients attaining NED was 100 months (range, months). RESULTS: The 3- and 5-year overall survival (OS) rates were 44% and 24%, respectively, for the entire group and 96% and 78%, respectively, for those attaining NED. According to a landmark analysis, NED status was significantly associated with survival at 2 (P <.001; hazard ratio [HR], 0.23; 95% confidence interval [CI], ) and 3 years (P <.001; HR, 0.20; 95% CI, ). From the time of NED, the median survival was 102 months (range, months) with 5-year OS and progression-free survival (PFS) rates of 77% and 40%, respectively. According to a multivariate analysis, human epidermal growth factor receptor 2 positivity was significantly associated with OS in comparison with estrogen receptor positivity (P 5.02; HR, 0.44; 95% CI, ), and trastuzumab use was significantly associated with PFS (P 5.007; HR, 0.48; 95% CI, ). Thirty-one patients (34%) with NED remained in remission at the last follow-up. CONCLUSIONS: MBC patients who attain the status of NED have significantly prolonged survival with a durable response to therapy. Ultimately, this study provides essential outcome data for clinicians and patients living with MBC. Cancer 2015;121: VC 2015 American Cancer Society. KEYWORDS: breast cancer, complete response, metastatic, no evidence of disease (NED), survival, targeted therapy. INTRODUCTION Among patients with metastatic breast cancer (MBC), there is a unique subset with disease that shows a sustainable, complete response to therapies that are offered. 1-5 Prior studies have reported that 5% to 10% of patients with MBC survive for more than 5 years, and 2% to 5% survive for more than 10 years, with many achieving complete responses to therapy despite having had limited options for systemic therapy when those studies were performed. 6,7 This albeit uncommon but distinctive subset challenges the belief that MBC is universally fatal. 8,9 Counseling no-evidence-of-disease (NED) patients with MBC about outcomes and expectations is challenging because the time to recurrence after the achievement of NED, predictors of shorter NED intervals, and the possibility of achieving NED for a second time have not been well studied. From the patient s perspective, this uncertainty is psychologically distressing Studies suggest that a lack of insight into disease status and prognosis can lead to poorer outcomes among patients with advanced or incurable cancer, with psychological consequences including increased mistrust and feelings of abandonment. 12,13 Furthermore, the cancer-free implication of an NED status is clearly a strongly desired outcome for any patient with MBC, and validation of the frequency with which this status occurs is influential. Corresponding author: Wendy A. Woodward, MD, PhD, Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 97, Houston, TX 77030; wwoodward@mdanderson.org 1 Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas; 2 Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas; 3 Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas; 4 Department of Diagnostic Radiology, The University of Texas MD Anderson Cancer Center, Houston, Texas; 5 Department of Electrical and Computer Engineering, Rice University, Houston, Texas; 6 Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas Christine F. Wogan, MS (The University of Texas MD Anderson Cancer Center) provided valuable editorial assistance for this article. Wogan did not receive additional compensation for her assistance beyond that of her normal salary for employment. DOI: /cncr.29681, Received: June 4, 2015; Revised: August 10, 2015; Accepted: August 19, 2015, Published online September 8, 2015 in Wiley Online Library (wileyonlinelibrary.com) 4324 Cancer December 15, 2015

2 NED After Metastatic Breast Cancer/Bishop et al The few studies that report outcomes for patients with MBC who have achieved a complete response are retrospective reviews of patients treated with older chemotherapeutic regimens and often include only patients with locoregional recurrences, which are biologically different from M1 disease. 7,14,15 Therefore, in an era in which long-term survival may be more achievable for patients with MBC because of the use of modern systemic therapies and more aggressive local treatments, we sought to identify and characterize a subset of patients with MBC who attain NED status to assess their outcomes versus those of patients who do not attain NED status and to identify potential predictors of more durable complete responses. MATERIALS AND METHODS Patients We identified 570 patients with histologically confirmed MBC who were consecutively treated at The University of Texas MD Anderson Cancer Center and presented between January 2003 and December Patients had either de novo MBC or initial stage III disease with distant recurrences that appeared during that interval. All staging studies were prescribed in accordance with National Comprehensive Cancer Network recommendations. Medical records were reviewed in detail after approval had been obtained from our institutional review board. The site of the first distant metastasis was categorized by organ involvement (eg, lung vs liver vs bone); patients were coded as having mixed disease if more than 1 organ was involved. NED Subset Patients who had an interval of no clinical or radiographic evidence of disease were identified. The frequency and modality of radiographic imaging were at the discretion of the treating physician. NED was defined as a complete response according to the Response Evaluation Criteria in Solid Tumors on computed tomography (CT) and/or a complete metabolic response on positron emission tomography (PET)/CT interpreted as NED by the reading radiologist. In the setting of bone metastasis, sclerotic bone lesions on CT were considered to have had a complete response if they were confirmed to be metabolically inactive on PET/CT or without radiotracer uptake on a bone scan. Patients for whom the review and interpretation of images by MD Anderson radiologists were not available were not classified as having NED. Follow-Up and Statistical Analysis The median follow-up intervals from the date of distant metastatic disease were 27 months for all patients (range, months) and 100 months (range, months) for patients with NED. Descriptive statistics were used to evaluate baseline characteristics, and categorical data were analyzed with Fisher s exact test and chi-squared analyses. Survival times were calculated from the date of distant metastatic disease. Additional survival times were calculated for the NED subset from the date of NED to the first occurrence of the considered event. NED intervals were calculated from the radiographic date of NED to the time of progression. The Kaplan-Meier method was used to estimate overall survival (OS) for the entire cohort and progression-free survival (PFS) for the NED subset (last reviewed July 9, 2014). The time to NED was analyzed with the methods of Fine and Gray 16 ; for patients who did not achieve NED, death was treated as a competing risk. Log-rank tests were applied to assess for equality across groups for all analyses. A 2-sided significance level of 5% was used for analysis. The Cox proportional hazard model was used for univariate and multivariate analyses to assess the potential influence of patient, tumor, and other factors on the endpoints. The multivariate assessment was performed in a stepwise fashion, with only factors having a P value.05 included in the model. Estimated hazard ratios (HRs) were reported when they were significant (P.05). IBM SPSS Statistics 22 and SAS/STAT were used for data analysis. RESULTS Patient Characteristics: All Patients Patient and tumor characteristics are summarized in Table 1. Ninety patients with MBC (16%) attained an NED status. The median time to NED among those who attained it was 11 months (range, 1-43 months). Patients with NED were more likely to have a normal body mass index (BMI; ie, kg/m 2 ; P <.001), have estrogen receptor (ER) positive or human epidermal growth factor receptor 2 (HER2) positive tumors (P <.001), present with de novo stage IV disease (P 5.04), and have single sites of metastasis (P <.001) in comparison with the non-ned group. Patients attaining NED were also more likely to have undergone PET/CT imaging than patients not attaining NED (P <.001). The majority of the PET/CT scans for patients attaining NED (78%) were used to confirm a complete metabolic response in lymph nodes, in sclerotic bone lesions, or in residual posttherapy tissue on CT. Cancer December 15,

3 TABLE 1. Patient and Disease Characteristics TABLE 1. Continued Variable All Patients (n 5 570) NED (n 5 90) t NED (n 5 480) P Variable All Patients (n 5 570) NED (n 5 90) t NED (n 5 480) P Follow-up time, mo Median Range Age, y Median Range Age categories, <35 y 49 (9) 10 (11) 39 (8) y 244 (43) 40 (44) 204 (43) y 229 (40) 36 (40) 193 (40) >70 y 48 (8) 4 (4) 44 (9) Sex, Female 568 (100) 90 (100) 478 (99).54 Male 2 (0) 0 (0) 2 (1) Race, Caucasian 367 (64) 68 (76) 299 (62).14 Black 115 (20) 11 (12) 104 (22) Hispanic 64 (11) 8 (9) 56 (12) Asian 19 (3) 3 (3) 16 (3) Other 5 (1) 0 (0) 5 (1) Menopausal status, Premenopausal 255 (45) 50 (56) 205 (43).08 Postmenopausal 309 (54) 40 (44) 269 (56) Unknown 6 (1) 0 (0) 6 (1) Body mass index, kg/m 2 Median Range Body mass index categories, Underweight 8 (1) 0 (0) 8 (2) <.001 rmal 151 (26) 40 (44) 111 (23) Overweight 169 (30) 25 (28) 144 (30) Obese 230 (40) 25 (28) 205 (43) Unknown 12 (2) 0 (0) 12 (2) Disease stage at diagnosis, IIIA 74 (13) 11 (11) 63 (13).17 IIIB 124 (22) 16 (18) 108 (23) IIIC 48 (8) 3 (3) 45 (9) IV 324 (57) 60 (67) 264 (55) Stage IV, At diagnosis 324 (57) 60 (67) 264 (55).04 At recurrence 246 (43) 30 (33) 216 (45) Inflammatory at diagnosis, Yes 103 (18) 16 (18) 88 (18) (82) 74 (82) 393 (82) Histology, Invasive ductal 441 (77) 71 (79) 271 (77).94 Invasive lobular 44 (8) 6 (7) 38 (8) Mixed 34 (6) 6 (7) 28 (6) Sarcoma 10 (2) 2 (2) 8 (2) Other 11 (2) 2 (2) 9 (2) NOS 30 (5) 3 (3) 27 (6) Receptor status, ER1/HER2 250 (44) 44 (49) 206 (43) <.001 HER (28) 37 (41) 124 (26) TNBC 122 (21) 7 (8) 115 (24) Unknown 37 (6) 2 (2) 35 (7) Site of first distant metastasis, Bone 144 (25) 28 (31) 116 (24) <.001 Lung 39 (7) 9 (10) 30 (6) Liver 64 (11) 19 (21) 45 (9) Brain 17 (3) 0 (0) 17 (4) LN/contralateral breast 59 (10) 17 (19) 42 (9) Other (eg, skin or pleura) 15 (3) 0 (0) 15 (3) Mixed (2) 232 (41) 17 (19) 215 (45) PET scan used for response, Yes 91 (16) 32 (36) 59 (12) < (84) 58 (64) 421 (88) Obtained NED status, Yes 90 (16) 480 (84) Abbreviations: ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; LN, lymph node; NED, no evidence of disease; NOS, not otherwise specified; PET, positron emission tomography; TNBC, triplenegative breast cancer. Survival and Predictors of Survival: All Patients For the entire group of 570 patients, the 1-, 3-, and 5-year actuarial OS rates were 77%, 44%, and 24%, with a median survival time of 31 months (Fig. 1). Several patient and tumor characteristics influenced survival. Patients with a normal BMI had longer median survival times than patients who were overweight (BMI kg/m 2 ) or obese (BMI 30 kg/ m 2 ;40vs32vs24months,P <.001). Patients who had de novo MBC had longer median survival times than patients who initially had stage III disease but later had distant recurrence (38 vs 19 months, P <.001). Furthermore, for patients who initially presented with stage III disease, the stage subtype predicted median survival upon metastatic recurrence (23 months for stage IIIA vs 9 months for stage IIIC, P <.001;Fig.1).Inthemultivariate analysis, several significant factors associated with better OS included presenting with de novo stage IV disease (P <.001; HR, 0.45) and having local therapy of the primary (P 5.04; HR, 0.76) followed by adjuvant radiation therapy (P <.001; HR, 0.55; Table 2). A second multivariate model was constructed with NED as a time-dependent covariate; in that model, NED status was nonsignificant. According to a multivariate landmark analysis, attaining NED status was significantly associated with survival at 2 (P <.001; HR, 0.23; 95% confidence interval [CI], ) and 3 years (P <.001; HR, 0.20; 95% CI, ). Factors Associated With Attaining NED To identify factors that affect the likelihood of attaining an NED status, we used cumulative incidence plots to analyze the time to NED, with an HR < 1.0 representing variables that were less likely to be linked with NED (Table 3). After adjustments for confounders, the variables that remained 4326 Cancer December 15, 2015

4 NED After Metastatic Breast Cancer/Bishop et al TABLE 2. Multivariate Analysis of Factors Associated With Overall Survival Variable P HR 95% CI Race nblack Black < Body mass index: continuous Stage at presentation III IV < Receptor status ER1 HER TNBC < Site of DM Mixed Bone < Lung < Liver Brain/other Adjuvant hormones for primary Yes Local therapy of primary Yes Adjuvant RT to primary Yes < Abbreviations: CI, confidence interval; DM, distant metastasis; ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; HR, hazard ratio; RT, radiation therapy; TNBC, triple-negative breast cancer. associated with a decreased likelihood of NED in the multivariate analysis were overweight (P 5.01; HR, 0.52) and obesity according to the BMI (P 5.001; HR, 0.43) and triple-negative breast cancer (TNBC; P 5.005; HR, 0.32), whereas presenting with de novo MBC (P <.001; HR, 2.49), having a single metastatic site versus multiple sites (all P 0.01; HR, 2.0), and having undergone local treatment of the primary tumor (P <.001; HR, 4.1) were associated with an increased likelihood of NED (Table 3). Figure 1. Kaplan-Meier curves depicting survival from the time of distant metastasis: (A) survival of all patients, (B) survival of patients attaining NED versus those not attaining NED, and (C) survival based on the presenting stage (P <.001). NED indicates no evidence of disease. Relapse and Treatment Characteristics: NED Subgroup Among the 90 patients who attained an NED status, 31 (34% of the NED cohort and 5% of the entire population) had NED at the last follow-up. Twenty-seven patients (30%) continued to have NED after the first remission. Among the 63 patients who had recurrent disease, 20 attained NED for a second time, and 16 of those patients had a second relapse. Within the subset of patients with NED, few differences were found between patients who had recurrent disease after NED and those who did not (Table 4), particularly in the number of sites of involvement (P 5.87) or the number of distant metastases (P 5.22). Cancer December 15,

5 TABLE 3. Univariate Analysis and Multivariate Analysis of Factors Associated With the Time to Evidence of Disease With the Methods of Fine and Gray Univariate Analysis Multivariate Analysis Variable P HR a 95% CI P HR a 95% CI Age at metastatic diagnosis: continuous Race nblack Black Body mass index rmal Overweight Obese < Menopausal status Premenopausal Postmenopausal Disease stage at presentation III IV < Receptor status ER1 HER TNBC Adjuvant chemotherapy for primary Yes Adjuvant hormones for primary Yes Local therapy for primary Yes < < Site of DM Mixed Liver < < Lung Bone < Brain/other Abbreviations: CI, confidence interval; DM, distant metastasis; ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; HR, hazard ratio; TNBC, triple-negative breast cancer. a Cumulative incidence plots were used. An HR < 1.0 represents variables that are less likely to be linked with NED. Among those attaining an NED status for the first time, 67 patients (74%) received chemotherapy as part of the treatment of MBC to obtain an NED status; this included taxanes (n 5 45 or 67%), platinum-based agents (n 5 38 or 57%), and doxorubicin (n 5 24 or 36%). Fifty-one of those patients (76%) received combination chemotherapy, whereas 16 received single-agent therapy, typically with microtubule inhibitors (n 5 11) or capecitabine (n 5 3). Fifty-five patients (61%) received hormone therapy (HT), and all 37 of the patients with HER2-positive disease (41%) received trastuzumab (Table 4). Thirty-five patients (39%) had local treatment of distant disease, with 16 (46%) receiving radiation therapy (median dose, 50 Gy; range, Gy) and 19 receiving surgery. The most common distant sites treated with surgery were the liver (n 5 8), bone (n 5 5), and lung (n 5 4). Among the patients attaining an NED status for a second time, 5 were treated with local therapy alone (radiation therapy, 4; surgery, 1), 4 received combination local and systemic treatment, and 11 were treated with systemic therapy (chemotherapy, 4; HT, 3; combination, 4). Maintenance Therapy After NED Status After attaining NED, nearly all patients (n 5 84 or 93%) continued maintenance therapy. Of the 65 patients with ER-positive disease, 55 (85%) received maintenance HT (whereas 6 received trastuzumab and 3 received chemotherapy). Thirty-seven of those patients (67%) either discontinued HT at the time of recurrence (n 5 16) or switched to a different HT (n 5 21). Nine patients continued maintenance HT indefinitely despite retaining their NED status, and 9 patients discontinued HT after a 4328 Cancer December 15, 2015

6 NED After Metastatic Breast Cancer/Bishop et al TABLE 4. Characteristics of Patients Attaining NED Who Did or Did t Have a Recurrence Variable NED (n 5 90) Recurrence (n 5 27) Recurrence (n 5 63) P Follow-up time, mo Median Range Time to NED status, mo Median Range Duration of NED status, mo Median Range Stage IV, At diagnosis 60 (67) 19 (70) 41 (65).63 At recurrence 30 (33) 8 (30) 22 (35) Inflammatory at diagnosis, Yes 16 (18) 1 (4) 15 (24) (82) 26 (96) 48 (76) Receptor status, ER1/HER2 44 (49) 10 (37) 34 (54).23 HER21 37 (41) 15 (56) 22 (35) TNBC 7 (8) 1 (4) 6 (10) Unknown 2 (2) 1 (4) 1 (2) Number of sites involved, 1 73 (81) 23 (85) 50 (79) (13) 3 (11) 9 (14) 3 4 (4) 1 (4) 3 (5) 4 1 (1) 0 (0) 1 (2) Number of metastases, 1 26 (29) 7 (26) 19 (30).22 2 or 3 14 (16) 7 (26) 7 (11) 4 30 (33) 6 (22) 24 (38) Lymph nodes 20 (22) 7 (26) 13 (21) Recurrence site after NED status, Same as previous DM 14 (16) New site 49 (76) Treatment of DM to achieve NED status, Local treatment Yes 35 (39) 13 (48) 22 (35) (61) 14 (52) 41 (65) Systemic (chemotherapy/ab) Yes 67 (74) 23 (85) 44 (70) (26) 4 (15) 19 (30) Hormone therapy Yes 55 (61) 14 (52) 41 (65) (39) 13 (48) 22 (35) Trastuzumab use Yes 37 (41) 15 (56) 22 (35) (59) 12 (44) 41 (65) Abbreviations: Ab, antibody; DM, distant metastasis; ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; NED, no evidence of disease; TNBC, triple-negative breast cancer. median of 60 months (range, months); this resulted in 4 relapses. Of the 37 HER2-positive patients, 34 received maintenance (post-ned) trastuzumab (the 3 others received HT). Trastuzumab was commonly continued until cardiac toxicity was documented. The median duration of use was 61 months (range, months), with 7 patients discontinuing at the time of recurrence and 12 continuing beyond their first relapse. Six patients remained on trastuzumab (median use, 120 months) with a continued NED status, and 9 patients discontinued trastuzumab use; this resulted in 3 relapses. A total of 15 patients also received maintenance chemotherapy, most commonly capecitabine (n 5 8) or paclitaxel (n 5 4) and often in combination with trastuzumab or HT. Three of the patients receiving maintenance chemotherapy had TNBC, whereas the other 4 patients with TNBC did not receive any maintenance. Outcomes and Predictors: NED Subgroup The 1-, 3-, and 5-year OS rates from the time of metastasis for the NED subgroup were 100%, 96%, and 78%, respectively (Fig. 1). tably, patients who attained NED had longer median survival times (112 vs 24 months for those not attaining NED, P <.001), although direct comparisons are biased because of the guaranteed time. From the time of NED, the median survival was 102 months (range, months). For patients attaining NED, the probability of survival was as follows: 98% at 1 year (95% CI, 91%-99%), 89% at 3 years (95% CI, 80%-94%), 77% at 5 years (95% CI, 67%-85%), and 39% at 10 years (95% CI, 24%-54%). Having either HER2-positive (median not reached) or ER-positive disease (90 vs 23 months for TNBC, P <.001) was significantly associated with longer survival from the time of NED. In the multivariate analysis, age (continuous; P 5.03; HR, 0.97; 95% CI, ), HER2-positive disease (vs ER-positive disease, P 5.02; HR, 0.44; 95% CI, ), and TNBC (vs ERpositive disease, P <.001; HR, 7.35; 95% CI, ) remained significantly associated with OS from the time of NED. The PFS rates (after NED) at 1, 3, and 5 years were 87%, 54%, and 40%, respectively (Fig. 2). The median PFS time after the initial NED status was 41 months (range, months), and the median interval from recurrence to a second NED status was 12 months (range, 4-31 months). The only patient-, tumor-, or treatmentrelated characteristics that were associated with PFS after NED were the receptor status (58 months for HER2- positive disease vs 35 months for ER-positive disease vs 13 months for TNBC, P 5.02), inflammatory breast cancer at presentation (28 vs 45 months, P 5.02), and trastuzumab use (73 vs 31 months, P 5.01; Fig. 2). Although not Cancer December 15,

7 Figure 2. Kaplan-Meier curves of progression-free survival from the time of NED: (A) all patients and (B) patients stratified by trastuzumab use (P 5.01). statistically significant, directed local therapy for distant metastases resulted in a numerically longer median PFS time (58 vs 31 months, P 5.17). In the multivariate analysis, trastuzumab use (P 5.007; HR, 0.48; 95% CI, ) and inflammatory breast cancer (P 5.005; HR, 2.34; 95% CI, ) remained significant predictors of PFS. DISCUSSION In this large retrospective study, we investigated characteristics of patients with MBC in the modern era of targeted systemic treatment. Sixteen percent of our group of 570 patients attained NED. A normal BMI, an ER-positive tumor, de novo MBC, a single site of metastatic disease, and local treatment of the primary tumor were all associated with attaining NED. Once they had attained NED, most patients remained on maintenance therapy, and importantly, patients who attained NED had a 77% probability of surviving 5 years, with many having durable remissions that were associated with trastuzumab use. Ultimately, this study provides valuable outcome and prognostic information for the practicing clinician and the patients living with MBC. The proportion of patients with MBC who attained NED after they had been treated from 2003 through 2005 (16%) was similar to the proportion in older studies, including an MD Anderson series of almost 1600 patients, in which reported complete response rates were 11% to 17%, although arguable advances in imaging may affect this direct comparison. 7,15,17 The similarity in these complete response rates between different treatment eras suggests that perhaps some subset of MBC is biologically more susceptible to treatment despite newer therapies. However, Greenberg et al 7 noted that only 3% of their patients retained their NED status at 5 years, whereas 12% (66 patients) did in our cohort. Therefore, even though initially obtaining a complete response may not depend on the use of newer agents, the higher rate of NED at 5 years in this modern series suggests that newer agents have an important role in maintaining the durability of the response. Because of the uncertain outcome among patients who attain NED, this series provides critical prognostic information for patients and their caregivers. We observed a 77% probability of survival at 5 years from the time of NED, which is notably high in light of the pessimistic view often associated with metastatic disease. This may be in part due to trastuzumab, an agent with a demonstrated survival benefit for patients with HER2-positive MBC. 18 For patients who attain NED, trastuzumab may be important in suppressing micrometastases, as suggested by the association between HER2-positive disease and OS and by the association between its use and PFS. Also, a higher proportion of patients who retained their NED status received this agent. Interestingly, NED status was an independent predictor of survival at 2 and 3 years. This series also suggests that with increasing targets and with the use of targeted therapy, there may be a higher proportion of MBC patients maintaining NED. Therefore, research will become increasingly necessary to better define this subset. For instance, the biologic behavior of MBC is diverse and undoubtedly influences the ability to attain an NED status. Similarly to the findings of Dawood et al, 19 in the entire cohort, we observed superior survival for patients 4330 Cancer December 15, 2015

8 NED After Metastatic Breast Cancer/Bishop et al with de novo MBC (which also was associated with achieving an NED status) versus patients with stage III disease that recurred distantly. Distantly recurrent MBC is possibly chemoresistant because of exposure to previous adjuvant treatment, in contrast to chemotherapy-naive de novo MBC. Although plausible, this theory does not adequately explain our observation that among patients who presented originally with stage III disease, the initial presenting substage (eg, IIIA vs IIIB vs IIIC) predicted the ultimate outcome at the time of metastasis. Regardless of the cause of this observation, the biologic corollary may be the subject of future preclinical and clinical studies and may suggest that de novo MBC should be considered a unique entity with respect to recurrent stage IV disease. Similar questions pertain to our observation that 1 site of disease was associated with a higher likelihood of NED and improved survival, regardless of the number of tumor deposits within the visceral organ or bone. A recent study of more than 700 patients noted the same association between survival and the number of organs containing metastases; in that study, for each additional site of disease, the risk of death increased by 18%. 20 Although this approach to categorizing tumor burden may be simplistic because of the heterogeneity among MBC patients, there is no standard classification system. Furthermore, although the prognostic benefit of single-organ involvement is not included in the classic definition of oligometastatic disease, perhaps the number of organs involved is a surrogate of tumor plasticity. Because acquiring the capacity for organ-specific colonization has a temporal component, multivisceral involvement may indicate that micrometastatic disease has been present for longer periods, and this leads to a poorer outcome. Also, genetic diversity is required to colonize dissimilar organ microenvironments; this diversification may promote the emergence of a clonogenic population resistant to therapy and lead to poorer outcomes when multiple sites are involved. 21 Despite some uncertainty about the explanation, our observation that single-organ involvement portends better outcomes suggests that clinicians may need to expand their definition of oligometastatic disease for MBC. We attempted to thoroughly analyze a large cohort of consecutively treated patients with MBC in the modern era with access to targeted therapy. One important question is whether our results are generalizable. Because our clinicians use treatment schemes similar to those recommended by the National Comprehensive Cancer Network and the 5-year survival rate observed among our MBC patients is similar to that reported with Surveillance, Epidemiology, and End Results data (24% vs 25%), there is evidence supporting the idea that our experience does correspond to that of the general MBC population. Despite the strengths of our study, several limitations must be considered when one is interpreting the results. First, as is true for any retrospective study, an inherent bias was present. Second, several studies have implicated the performance status as being a major prognostic factor in MBC; we did not have access to these data to incorporate them into our survival model. Third, we also did not have information on the therapeutic approach used to treat metastatic disease among patients who did not attain an NED status, and this limits our ability to comment on treatment approaches that may result in a higher incidence of NED or on how many lines of therapy it took to attain NED. Despite these limitations, our results are highly provocative; future prospective studies and large database studies should be used to further validate and explore our results. In conclusion, the results of our study indicate that patients with MBC who attain an NED status have significantly prolonged survival with a durable response to therapy. Ultimately, this study provides findings to encourage further research into this subset of patients with MBC, and it provides a backbone of outcome data for clinicians to use when they are counseling patients who attain complete responses to treatment about potential outcomes. FUNDING SUPPORT This study was supported in part by Cancer Center Support (Core) grant CA to The University of Texas MD Anderson Cancer Center. CONFLICT OF INTEREST DISCLOSURES Simona F. Shaitelman reports a grant from Elekta outside the submitted work. REFERENCES 1. Cheng YC, Ueno NT. Improvement of survival and prospect of cure in patients with metastatic breast cancer. Breast Cancer. 2012;19: Dawood S, Broglio K, Gonzalez-Angulo AM, et al. Trends in survival over the past two decades among white and black patients with newly diagnosed stage IV breast cancer. J Clin Oncol. 2008;26: Giordano SH, Buzdar AU, Smith TL, et al. Is breast cancer survival improving? Cancer. 2004;100: Pagani O, Senkus E, Wood W, et al. International guidelines for management of metastatic breast cancer: can metastatic breast cancer be cured? J Natl Cancer Inst. 2010;102: Palumbo R, Sottotetti F, Riccardi A, et al. Which patients with metastatic breast cancer benefit from subsequent lines of treatment? 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