Phase III Trial of Adjuvant Capecitabine After original reports Standard Neo-/Adjuvant Chemotherapy in Patients With Early Triple-Negative Breast Cancer (GEICAM/2003-11_CIBOMA/2004-01) Ana Lluch, PhD1,2,3; Carlos H. Barrios, MD4,5; Laura Torrecillas, MD6; Manuel Ruiz-Borrego, MD3,7; Jose Bines, MD, PhD5,8; Jose Segalla, MSc, MD5,9; Ángel Guerrero-Zotano, MD3,10; Jose A. Garcı́a-Sáenz, MD, PhD3,11; Roberto Torres, MD12; Juan de la Haba, MD, PhD2,3,13; Elena Garcı́a-Martı́nez, MD, PhD3,14; Henry L. Gómez, MD15,16; Antonio Llombart, MD, PhD3,17; Javier Salvador Bofill, MD3,18; José M. Baena-Cañada, PhD3,19; Agustı́ Barnadas, MD, PhD2,3,20; Lourdes Calvo, MD3,21; Laura Pérez-Michel, MD22; Manuel Ramos, MD3,23; Isaura Fernández, MD3,24; Álvaro Rodrı́guez-Lescure, MD, PhD3,25; Jesús Cárdenas, MD26; Jeferson Vinholes, MD, PhD5,27; Eduardo Martı́nez de Dueñas, MD, PhD3,28; Maria J. Godes, MD3,29; Miguel A. Seguı́, PhD3,30; Antonio Antón, MD3,31; Pilar López-Álvarez, MD3,32; Jorge Moncayo, MD33; Gilberto Amorim, MD5,34; Esther Villar, MD3,35; Salvador Reyes, MD36; Carlos Sampaio, MD5,37; Bernardita Cardemil, MD38; Maria J. Escudero, MD3; Susana Bezares, MD3; Eva Carrasco, MD3; and Miguel Martı́n, MD, PhD2,3,39; on behalf of GEICAM Spanish Breast Cancer Group, CIBOMA (Iberoamerican Coalition for Research in Breast Oncology), and LACOG (Latin American Cooperative Oncology Group) abstract PURPOSE Operable triple-negative breast cancers (TNBCs) have a higher risk of relapse than non-TNBCs with standard therapy. The GEICAM/2003-11_CIBOMA/2004-01 trial explored extended adjuvant capecitabine after completion of standard chemotherapy in patients with early TNBC. PATIENTS AND METHODS Eligible patients were those with operable, node-positive—or node negative with tumor 1 cm or greater—TNBC, with prior anthracycline- and/or taxane-containing chemotherapy. After central confirmation of TNBC status by immunohistochemistry, patients were randomly assigned to either capecitabine or observation. Stratification factors included institution, prior taxane-based therapy, involved axillary lymph nodes, and centrally determined phenotype (basal v nonbasal, according to cytokeratins 5/6 and/or epidermal growth factor receptor positivity by immunohistochemistry). The primary objective was to compare disease-free survival (DFS) between both arms. RESULTS Eight hundred seventy-six patients were randomly assigned to capecitabine (n = 448) or ob- servation (n = 428). Median age was 49 years, 55.9% were lymph node negative, 73.9% had a basal phenotype, and 67.5% received previous anthracyclines plus taxanes. Median length of follow-up was 7.3 years. DFS was not significantly prolonged with capecitabine versus observation [hazard ratio (HR), 0.82; 95% CI, 0.63 to 1.06; P = .136]. In a preplanned subgroup analysis, nonbasal patients seemed to derive benefit from the addition of capecitabine with a DFS HR of 0.53 versus 0.94 in those with basal phenotype ASSOCIATED (interaction test P = .0694) and an HR for overall survival of 0.42 versus 1.23 in basal phenotype (in- CONTENT teraction test P = .0052). Tolerance of capecitabine was as expected, with 75.2% of patients completing the See accompanying Editorial on page 179 planned 8 cycles. Data Supplement CONCLUSION This study failed to show a statistically significant increase in DFS by adding extended capecitabine Protocol to standard chemotherapy in patients with early TNBC. In a preplanned subset analysis, patients with nonbasal Author affiliations phenotype seemed to obtain benefit with capecitabine, although this will require additional validation. and support information (if J Clin Oncol 38:203-213. © 2019 by American Society of Clinical Oncology applicable) appear Creative Commons Attribution Non-Commercial No Derivatives 4.0 License at the end of this article. INTRODUCTION National Cancer Institute SEER reported a 3-year re- Accepted on lapse rate of approximately 8%, 15%, and 40% for November 12, 2019 Early triple-negative breast cancer (TNBC) can be and published at cured with local–regional therapy plus adjuvant patients with stages I, II, and III TNBC,1 respectively; ascopubs.org/journal/ chemotherapy, usually anthracycline- and/or taxane- therefore, new adjuvant options are necessary to im- jco on December 5, based combinations. However, despite these thera- prove the prognosis of this breast cancer subtype. 2019: DOI https://doi. org/10.1200/JCO.19. pies, a proportion of patients eventually experience Capecitabine is an oral prodrug of fluorouracil ap- 00904 relapse and die. A recent analysis of data from the proved for the treatment of metastatic breast cancer in Volume 38, Issue 3 203 Lluch et al patients with prior progression after anthracyclines and consent was obtained from all patients before any study- taxanes and is therefore partially non–cross resistant with related procedures were performed. these two classes of agents.2 On the basis of this concept, we carried out a trial in which capecitabine was sequentially Patient Eligibility added to standard (neo)adjuvant chemotherapy in oper- Eligible patients included women with hormone recep- able TNBC to explore the ability of the drug to reduce the tor–negative (immunohistochemistry staining of estrogen rate of relapse and increase the survival of this disease. and progesterone receptors , 1%) and human epidermal growth factor 2–negative operable breast cancer, with in- vasive adenocarcinoma histologically confirmed. Patients PATIENTS AND METHODS had received 6 to 8 cycles of standard anthracycline- and/ The GEICAM/2003-11_CIBOMA/2004-01 trial is an open- or taxane-containing chemotherapy in the (neo)adjuvant label, randomized phase III study that was conducted in setting, followed by radiation therapy according to in- compliance with the International Council for Harmoniza- stitutional guidelines. In the case of node-negative dis- tion Good Clinical Practice guidelines and the Declaration ease, 4 cycles of doxorubicin and cyclophosphamide of Helsinki. The study was reviewed and approved by the were allowed. Eligible patients were those with ipsilateral independent ethics committees or institutional review axillary node involvement classified as pN1a, pN2a, boards of all participating institutions. Written informed or pN3a—excluding metastatic infraclavicular lymph Assessed for eligibility (n = 1,516) Excluded (n = 640) Not meeting inclusion criteria (n = 341) Refused participation (n = 163) Other reasons (n = 136) Patients randomly assigned (n = 876) Capecitabine arm Observation arm Allocated to intervention (n = 448) Allocated to intervention (n = 428) (ITT population) (ITT population) Capecitabine arm Observation arm Received allocated intervention (n = 436) Received allocated intervention (n = 425) (Safety population) (Safety population) Early discontinuation of protocol therapy (n = 111) Discontinuation in observation arm (n = 30)† Patient refusal (n = 33) Patient refusal (n = 6) Unacceptable toxicity (n = 34) Unacceptable residual toxicity (n = 1) Disease recurrence (n = 9) Disease recurrence (n = 13) Interruption of capecitabine >3 weeks (n = 11) Death (n = 2)‡ Death (n = 4)* Protocol deviation (n = 1) Protocol deviation (n = 5) Lost to follow-up (n = 1) Lost to follow-up (n = 1) Second primary malignancy (n = 1) Other reason (n = 14) Other reason (n = 5) FIG 1. All patients enrolled (N = 876) were included in the efficacy analyses. All patients who had received at least 1 cycle of study treatment (n = 861) were evaluated for safety. Safety population: In the capecitabine arm, all patients who have completed at least one cycle of study treatment and in the observation arm, all patients with a follow-up period $ 14 days. *Reasons of death on these patients: psychiatric disorder, cerebral hemorrhage, septic shock secondary to respiratory infection and stroke (not related with capecitabine). †Discontinuation of initial follow-up period (equivalent to treatment period in capecitabine arm). ‡Reasons of death on these patients: acute myocardial infarction and pulmonary sepsis. 204 © 2019 by American Society of Clinical Oncology Volume 38, Issue 3 Extended Capecitabine in Early Triple-Negative Breast Cancer TABLE 1. Patients’ Demographics and Baseline Disease Characteristics According nodes—according to the American Joint Committee on to Study Arm (intention-to-treat population) Cancer 2002 staging system. Patients without axillary node Capecitabine Arm Observation Arm involvement (N0) were also eligible provided the primary Demographic or Characteristic (n = 448), No. (%) (n = 428), No. (%) tumor measured 1 cm or greater in diameter. Patients were Median age, years (range) 50.0 (20.0-79.0) 49.0 (23.0-82.0) ineligible in the case of bilateral invasive breast cancer, Region absence of surgical treatment with curative intent, resection Spain 272.0 (60.7) 260.0 (60.7) of fewer than 6 lymph nodes when axillary lymph node dissection was performed, or pregnancy or breastfeeding. Latin America 176.0 (39.3) 168.0 (39.3) Triple-negative and basal versus nonbasal status were Race determined centrally by a GEICAM Spanish Breast Cancer White 313.0 (69.9) 309.0 (72.2) Group pathologist (F.R.). Tumors with any staining for Hispanic 107.0 (23.9) 97.0 (22.7) epidermal growth factor receptor and/or cytokeratins 5/6 African American 16.0 (3.6) 11.0 (2.6) were considered basal. Patients with no staining for both Other 12.0 (2.7) 11.0 (2.6) biomarkers were considered nonbasal.3 Karnofsky performance status Study Procedures 100 383.0 (85.5) 344.0 (80.4) Baseline assessments performed before patient randomi- 90 57.0 (12.7) 67.0 (15.7) zation in centrally confirmed eligible patients included 80 8.0 (1.8) 17.0 (4.0) mammography, chest radiography, abdominal ultraso- nography and/or computed tomography (CT), bone scan (if Menopausal status at diagnosis bone pain or increased alkaline phosphatase), and bone Premenopausal 136.0 (30.4) 140.0 (32.7) X-ray (if suspicious lesions on the bone scan). Hematology, Postmenopausal 312.0 (69.6) 288.0 (67.3) biochemistry, and pregnancy test—potentially fertile Histologic type women only—were also completed before randomization. Invasive ductal carcinoma 395.0 (88.2) 369.0 (86.2) Eligible patients were stratified according to basal status Invasive lobular carcinoma 9.0 (2.0) 10.0 (2.3) (yes v no), institution, number of axillary lymph nodes Other 44.0 (9.8) 49.0 (11.4) (0 v 1-3 v 4 or more), and type of adjuvant chemotherapy Histologic grade (anthracyclines plus taxanes v anthracyclines alone). Pa- tients were randomly assigned on a one-to-one basis to G1 15.0 (3.3) 12.0 (2.8) eight cycles of capecitabine 2,000 mg/m2 (1,000 mg/m2 G2 82.0 (18.3) 81.0 (18.9) administered orally two times per day) on days 1 to 14 every G3 323.0 (72.1) 299.0 (69.9) 3 weeks, or observation. Two dose reductions were GX 28.0 (6.3) 36.0 (8.4) permitted—75% and 50% of initial dose—on the basis of Phenotype by IHC hematologic or nonhematologic adverse events (AEs) observed. Randomization was centralized at GEICAM Basala 329.0 (7,373.4) 318.0 (7,474.3) headquarters. Nonbasal 119.0 (2,626.6) 110.0 (2,525.7) AEs were assessed during the study period and graded Stage at diagnosis (AJCC 2002) according to National Cancer Institute Common Termi- I 62.0 (13.8) 74.0 (17.3) nology Criteria for Adverse Events version 3.0. Serious AEs II 270.0 (60.3) 271.0 (63.3) (SAEs) were reported during the study treatment and within III 106.0 (23.7) 80.0 (18.7) 30 days of the end of this time period. Not available 10.0 (2.2) 3.0 (0.7) Physical examination, menopausal status, and presence of Nodal status amenorrhea were assessed at baseline, at every cycle Negative 244.0 (54.5) 242.0 (56.5) during the treatment period, every 3 months during years 1 to 2, every 6 months during years 3 to 5, and yearly af- 1-3 positive nodes 121.0 (27.0) 124.0 (29.0) terward. Mammograms were performed yearly. Chest $ 4 positive nodes 77.0 (17.2) 61.0 (14.3) X-ray, abdominal ultrasounds, CT scan, or bone scans were Missing data 6.0 (1.3) 1.0 (0.2) performed if clinically indicated in the case of suspicion of Type of prior chemotherapy disease recurrence. A complete follow-up on vital status Adjuvant (only) 353.0 (78.8) 352.0 (82.2) was obtained until April 11, 2018, for all patients. Neoadjuvant (6 adjuvant) 89.0 (19.9) 75.0 (17.5) Statistical Analysis Missing data 6.0 (1.3) 1.0 (0.2) Primary end point was disease-free survival (DFS), which (continued on following page) was measured from the date of random assignment in the intent-to-treat (ITT) population to locoregional or distant Journal of Clinical Oncology 205 Lluch et al TABLE 1. Patients’ Demographics and Baseline Disease Characteristics According We used the Kaplan-Meier limit-product method to esti- to Study Arm (intention-to-treat population) (continued) mate DFS and OS and comparison between the two study Capecitabine Arm Observation Arm arms was performed using the stratified log-rank test using Demographic or Characteristic (n = 448), No. (%) (n = 428), No. (%) the stratification factors [basal status, number of axillary pCR in patients with neoadjuvant 22.0 (24.7) 19.0 (25.3) lymph nodes, and type of (neo)adjuvant chemotherapy]. All chemotherapyb tests of hypotheses were two sided. In addition, we per- Chemotherapy regimen formed a multivariable Cox proportional hazard model Anthracyclines based 147.0 (32.8) 138.0 (32.2) analysis for DFS and OS to adjust for major prognostic Anthracyclines and taxanes based 301.0 (67.2) 290.0 (67.8) factors: age, menopausal status, histopathologic findings, tumor size, disease stage, type of surgery, region, and the Breast surgery stratification factors for randomization. Conservative 237.0 (52.9) 242.0 (56.5) The safety analysis was performed in all patients who had Mastectomy 205.0 (45.8) 185.0 (43.2) received at least 1 cycle of study treatment. The worst AE Missing data 6.0 (1.3) 1.0 (0.2) grade per category for each patient was reported. Axillary surgery ALND 6 SLNB 349.0 (78.0) 306.0 (71.5) RESULTS SLNB 99.0 (22.1) 122.0 (28.5) Study Patients Radiation therapy Between October 2006 and September 2011, 876 patients Yes 352.0 (78.6) 346.0 (80.8) were recruited across 80 institutions in 8 countries (Spain, No 91.0 (20.3) 81.0 (18.9) Brazil, Chile, Colombia, Ecuador, Mexico, Peru, and Ven- Unknown 5.0 (1.1) 1.0 (0.2) ezuela; Fig 1). NOTE. Data are presented as No. (%) except where otherwise noted. Demographics and baseline disease characteristics were Abbreviations: AJCC, American Joint Committee on Cancer; ALND, axillary balanced, with no statistical differences between the two lymph node dissection; IHC, immunohistochemistry; pCR, pathologic complete arms but with a slightly numerically higher proportion of response; SLNB, sentinel lymph node biopsy. poor prognosis features in the capecitabine arm (Table 1). a Basal phenotype: cytokeratins 5/6-positive and/or epidermal growth factor The majority of patients were white and postmenopausal, receptor positive. and median age was 49 years. Most frequently, tumors b pCR in the breast and ipsilateral axilla. were of grade 3 (71%), basal phenotype (73.9%), stage II at diagnosis (61.8%), and node negative (55.9%). Small differences were found in relation to disease stage at recurrence, second primary malignancy, or death date, diagnosis—based on American Joint Committee on Cancer whichever occurred first. Secondary end points included 2002—and the number of involved lymph nodes. 5-year DFS, overall survival (OS), safety, and analyses by subgroups and of biomarkers. Most patients in both arms had received adjuvant che- motherapy with anthracyclines and taxanes (67.5%), had According to the GEICAM El Álamo registry,4 estimated breast-conservative surgery (54.7%) and axillary lymph 5-year DFS for a similar population of patients with TNBC node dissection with or without sentinel lymph node biopsy was 64.7%. The aim was to detect an increase in DFS (74.8%), and received radiation therapy (79.7%). to 73.7% with capecitabine, corresponding to a hazard ratio (HR) of 0.701 with a power of 80% using a two-tailed log- Drug Exposure and Discontinuations rank test at 0.05 and considering 4 years of recruitment and Of patients who were assigned to capecitabine, 75.2% 3 years of follow-up. Two hundred fifty-five events were (n = 337) completed 8 cycles of treatment. Median projected and 834 eligible patients were needed. Assuming number of cycles was 8 (range, 1 to 8 cycles). A few pa- a drop-out rate of 5%, 876 patients were to be enrolled—438 tients (n = 12; 2.7%) did not complete at least 1 cycle of patients in each arm. The sample size calculation was treatment and were excluded from the safety analysis as performed using EAST version 5.2. per protocol requirement. Four percent (n = 18) of patients The initial protocol established the main DFS analysis to completed 1 cycle of capecitabine, 10.3% (n = 46) of be performed after 255 events; however, the number of patients completed 2 to 4 cycles, and 7.8% (n = 35) of DFS events was much lower than expected and the patients completed 5 to 7 cycles. Median dose intensity was steering committee of the study—with the advice of the 86.3% (range, 0.86% to 136.2%). Dose intensity rate was independent data monitoring committee—therefore de- between 110% and 80% in 55.8% (n = 250) of patients cided to perform the analysis after a median follow-up of and less than 75% in 33.5% (n = 150) of patients. Five more than 7 years after a total of 225 events and when the patients were reported to have a dose intensity rate between rate of annual recurrences was low in both arms of 110% and 136.2%. In four of these patients, it was because the study. of a mistake or rounding the capecitabine dose and in the 206 © 2019 by American Society of Clinical Oncology Volume 38, Issue 3 Extended Capecitabine in Early Triple-Negative Breast Cancer A B 100 100 90 90 DFS Probability (%) OS Probability (%) 80 80 70 70 Log-rank P = .623 60 Log-rank P = .135 60 Stratified log-rank P = .399 50 Stratified log-rank P = .097 50 40 40 30 30 20 Capecitabine 20 Capecitabine 10 Observation 10 Observation 0 1 2 3 4 5 6 7 8 9 10 11 0 1 2 3 4 5 6 7 8 9 10 11 Time (years) Time (years) No. at risk: No. at risk: Observation 428 379 347 329 313 290 262 204 123 58 25 2 Observation 428 407 375 350 339 318 296 232 145 73 28 2 Capecitabine 448 396 365 344 334 323 304 248 154 60 17 1 Capecitabine 448 417 393 367 354 347 324 267 170 71 24 1 C D 100 100 90 90 DFS Probability (%) DFS Probability (%) 80 80 70 70 60 Log-rank P = .696 60 Log-rank P = .020 50 50 40 40 30 30 Arm Arm 20 20 Capecitabine Capecitabine 10 Observation 10 Observation 0 1 2 3 4 5 6 7 8 9 10 0 1 2 3 4 5 6 7 8 9 10 Time (years) Time (years) No. at risk: No. at risk: Observation 318 287 263 252 237 219 195 154 102 49 22 Observation 110 92 84 77 76 71 67 50 21 9 3 Capecitabine 329 290 266 247 241 232 223 186 126 52 14 Capecitabine 119 106 99 97 93 91 81 62 28 8 3 E F 100 100 90 90 OS Probability (%) OS Probability (%) 80 80 70 Log-rank P = .286 70 60 60 Log-rank P = .007 50 50 40 40 30 30 Arm Arm 20 Capecitabine 20 Capecitabine 10 Observation 10 Observation 0 1 2 3 4 5 6 7 8 9 10 11 0 1 2 3 4 5 6 7 8 9 10 11 Time (years) Time (years) No. at risk: No. at risk: Observation 318 301 284 268 259 242 223 179 123 64 25 2 Observation 110 106 91 82 80 76 73 53 22 9 3 Capecitabine 329 307 286 263 256 249 238 200 139 63 21 1 Capecitabine 119 110 107 104 98 98 86 67 31 8 3 FIG 2. (A, C, D) Disease-free survival (DFS) and (B, E, F) overall survival (OS) Kaplan-Meier curves on the intention-to-treat population and subpopulations based on the immunohistochemistry phenotype. Journal of Clinical Oncology 207 Lluch et al fifth patient the reason is unknown. Dose reductions of OS between study arms (unadjusted HR, 0.92; 95% CI, capecitabine were reported in 161 patients (36.9%). 0.66 to 1.28; P = .623; adjusted HR according to strati- fication factors, 0.88; 95% CI, 0.64 to 1.23; P = .4562; and Main reasons for discontinuation of capecitabine (n = 97) fully adjusted HR, 0.86; 95% CI, 0.6262 to 1.20; P = .371). were patient refusal, unacceptable toxicity, disease re- Five-year OS rates were 86.2% (95% CI, 82.9% to 89.4%) currence, or interruption of capecitabine for more than in the capecitabine arm and 85.9% (95% CI, 82.4% to 3 weeks because of AEs (Fig 1). 89.3%) in the observation arm. Figure 2B shows the Kaplan-Meier curves for OS. Efficacy At the time of data cutoff, median follow-up was 7.4 years An exploratory subgroup analysis for DFS in the ITT pop- and 7.2 years in the capecitabine and observation arms, ulation (Fig 3) showed similar treatment effects by men- respectively. A total of 225 events were observed, 105 opausal status (pre- v postmenopausal), phenotype (basal (23.4%) in the capecitabine arm and 120 (28%) in the v nonbasal), nodal status (negative v 1 to 3 positive nodes, 4 observation arm. In the ITT analysis (n = 876), results of the or more positive nodes), type of previous CT scan (neo- Cox proportional hazards regression model did not dem- adjuvant v adjuvant), prior administration of taxanes (yes v onstrate a statistically significant difference in DFS between no) and region (Spain v Latin America). Patients with the capecitabine and observation arms (unadjusted HR, a nonbasal phenotype had a statistically significant in- 0.82; 95% CI, 0.63 to 1.06; P = .136; adjusted HR crease in DFS (HR, 0.53; 95% CI, 0.31 to 0.91; P = .022) according to stratification factors, 0.79; 95% CI, 0.61 to and OS (HR, 0.42; 95% CI, 0.21 to 0.81; P = .0095) with 1.03; P = .082; and fully adjusted HR, 0.77; 95% CI, 0.59 capecitabine. Five-year DFS rates were 82.6% (95% CI, to 1.00; P = .051). Five-year DFS rates were 79.6% (95% 75.7% to 89.5%) with capecitabine and 72.9% (95% CI, CI, 75.8% to 83.4%) in the capecitabine arm and 76.8% 64.4% to 81.3%) in the observation arm. Five-year OS rates (95% CI, 72.7% to 80.9%) in the observation arm. were 89.5% (95% CI, 83.9% to 95.1%) with capecitabine Figure 2A shows the Kaplan-Meier curves for DFS. In and 79.6% (95% CI, 71.7% to 87.4%) in the observation addition, there was no statistically significant difference in arm. The interaction tests treatment/nonbasal status had Subgroup Analysis of DFS Subgroup No. of Patients (%) HR No. of Events HR (95% CI) Capecitabine Observation Overall 876 (100) 105 120 0.819 (0.630 to 1.065) Menopausal status Premenopausal 276 (32) 24 35 0.686 (0.408 to 1.153) Postmenopausal 600 (68) 81 85 0.867 (0.639 to 1.176) Phenotype Basal 647 (74) 84 86 0.942 (0.697 to 1.272) Nonbasal 229 (26) 21 34 0.530 (0.307 to 0.913) Neoadjuvant v adjuvant treatment Neoadjuvant 164 (19) 29 24 1.006 (0.586 to 1.727) Adjuvant 705 (81) 74 96 0.747 (0.552 to 1.012) Chemotherapy regimen Anthracyclines without taxanes 285 (33) 33 36 0.884 (0.551 to 1.418) Anthracyclines and taxanes 591 (67) 72 84 0.798 (0.583 to 1.093) Nodal status Negative nodes 486 (56) 39 55 0.687 (0.456 to 1.037) 1-3 positive nodes 245 (28) 31 37 0.800 (0.496 to 1.289) 4 or more positive nodes 138 (16) 33 28 0.937 (0.566 to 1.550) Region Spain 532 (61) 60 75 0.750 (0.534 to 1.053) Latin America 344 (39) 45 45 0.934 (0.618 to 1.413) 0.4 0.6 0.8 1.2 1.6 2 Capecitabine Observation FIG 3. Subgroup analysis for disease-free survival (DFS) on the intention-to-treat (ITT) population. HR, hazard ratio. 208 © 2019 by American Society of Clinical Oncology Volume 38, Issue 3 Extended Capecitabine in Early Triple-Negative Breast Cancer TABLE 2. Disease-Free Survival Events in Overall Population (intention to treat) and Nonbasal Phenotype Subpopulation Overall Population, No. (%) Nonbasal Population, No. (%) Variable Capecitabine (n = 448) Observation (n = 428) Capecitabine (n = 119) Observation (n = 110) Event No event 343.0 (76.6) 308.0 (72.0) 98.0 (82.4) 76.0 (69.1) Disease recurrence 78.0 (17.4) 94.0 (22.0) 18.0 (15.1) 24.0 (21.8) Death 14.0 (3.1) 10.0 (2.3) 2.0 (1.7) 3.0 (2.7) Second primary malignancy 13.0 (2.9) 16.0 (3.7) 1.0 (0.8) 7.0 (6.4) Type of event Any DFS event 105.0 (23.4) 120.0 (28.0) 21.0 (17.6) 34.0 (30.9) Distant recurrence (any) 64.0 (14.3) 66.0 (15.4) 13.0 (10.9) 18.0 (16.4) Contralateral invasive breast cancer 12.0 (2.7) 14.0 (3.3) 3.0 (2.5) 2.0 (1.8) Ipsilateral breast cancer recurrence 5.0 (1.1) 12.0 (2.8) 2.0 (1.7) 3.0 (2.7) Locoregional invasive recurrence (after 0.0 4.0 (0.9) 0.0 2.0 (1.8) mastectomy) Regional invasive recurrence (after BCS) 3.0 (0.7) 1.0 (0.2) 0.0 0.0 Disease recurrence (unknown location) 1.0 (0.2) 0.0 0.0 0.0 Second primary malignancy (nonbreast) 6.0 (1.3) 13.0 (3.0) 1.0 (0.8) 6.0 (5.5) Death 14.0 (3.1) 10.0 (2.3) 2.0 (1.7) 3.0 (2.7) Location of distant recurrence Lung 31.0 (6.9) 29.0 (6.8) 7.0 (5.9) 6.0 (5.5) Bone 19.0 (4.2) 19.0 (4.4) 4.0 (3.4) 5.0 (4.5) Lymph nodes 16.0 (3.6) 18.0 (4.2) 1.0 (0.8) 4.0 (3.6) Liver 13.0 (2.9) 20.0 (4.7) 2.0 (1.7) 6.0 (5.5) CNS 13.0 (2.9) 15.0 (3.5) 3.0 (2.5) 6.0 (5.5) Skin 2.0 (0.4) 0.0 0.0 0.0 Brain 2.0 (0.4) 1.0 (0.2) 0.0 0.0 Other 9.0 (2.0) 12.0 (2.8) 2.0 (1.7) 3.0 (2.7) NOTE. The location of distant recurrence is not exclusive. Patients may have several organs involved as part of their distant recurrence. Abbreviations: BCS, breast-conserving surgery; DFS, disease-free survival. adjusted P values of .0694 for DFS and .0052 for OS. 425 patients (99.3%) in the observation arm. AEs were Figures 2C and 2D show the Kaplan-Meier curves for DFS reported in 95.4% (n = 416) of patients in the capecitabine and OS, respectively, in the basal and nonbasal phenotype arm and 63.8% (n = 271) in the observation arm (Table 4). subpopulations. In addition, 40.6% (n = 177) and 15.5% (n = 66) of The number and type of DFS events in the overall and patients had AEs of grade 3 or greater in the capeci- nonbasal populations are shown in Table 2. Of note, in the tabine and observation arms, respectively. With cape- nonbasal subpopulation, and in agreement with DFS and citabine, 92.4% (n = 403) of patients had AEs related to OS data, DFS events were more frequent in the observation study treatment, and in 30% (n = 131) of patients these arm [30.9% (n = 34)] compared with the capecitabine arm AEs were of grade 3 or greater. Patients who experi- [17.6% (n = 21)]. Remarkably, in this subtype the re- enced at least one SAE were 5.3% (n = 23) in the duction of DFS events with capecitabine was mainly a result capecitabine arm and 1.4% (n = 6) in the observation of distant relapses, particularly in liver, CNS, and lymph arm. In addition, there were a few patients with SAEs that nodes. Demographics and baseline disease characteristics caused death: 1.1% (n = 5) in the capecitabine arm and according to basal versus nonbasal phenotype are included 0.5% (n = 2) in the observation arm. Two deaths in the in Table 3. capecitabine arm were probably related to study treat- ment according to investigator’s criteria. These SAEs Safety included one case of septic shock in the absence of Safety was assessed in 861 patients of the study pop- neutropenia and one case of grade 4 hyperbilirubinemia ulation: 436 patients (97.3%) in the capecitabine arm and and systemic organ failure. Journal of Clinical Oncology 209 Lluch et al TABLE 3. Patients’ Demographics and Baseline Disease Characteristics According to Basal Versus Nonbasal Phenotype (intention-to-treat population) Capecitabine, No. (%) Observation, No. (%) a a a Basal Phenotype Nonbasal Phenotype Basal Phenotype Nonbasala Phenotype Demographic or Characteristic (n = 329) (n = 119) (n = 318) (n = 110) Median age, years (range) 50.0 (24.0-79.0) 50.0 (20.0-75.0) 49.0 (26.0-82.0) 48.0 (23.0-74.0) Region Spain 202.0 (61.4) 70.0 (58.8) 189.0 (59.4) 71.0 (64.5) Latin America 127.0 (38.6) 49.0 (41.2) 129.0 (40.6) 39.0 (35.5) Menopausal status at diagnosis Premenopausal 105.0 (31.9) 31.0 (26.1) 107.0 (33.6) 33.0 (30.0) Postmenopausal 224.0 (68.1) 88.0 (73.9) 211.0 (66.4) 77.0 (70.0) Histologic grade G1 10.0 (3.0) 5.0 (4.2) 9.0 (2.8) 3.0 (2.7) G2 62.0 (18.8) 20.0 (16.8) 55.0 (17.3) 26.0 (23.6) G3 238.0 (72.3) 85.0 (71.4) 235.0 (73.9) 64.0 (58.2) GX 19.0 (5.8) 9.0 (7.6) 19.0 (6.0) 17.0 (15.5) Stage at diagnosis (AJCC 2002) I 50.0 (15.2) 12.0 (10.1) 59.0 (18.6) 15.0 (13.6) II 201.0 (61.1) 69.0 (58.0) 200.0 (62.9) 71.0 (64.5) III 73.0 (22.2) 33.0 (27.7) 56.0 (17.6) 24.0 (21.8) Not available 5.0 (1.5) 5.0 (4.2) 3.0 (0.9) 0.0 Nodal status Negative 179.0 (54.4) 65.0 (54.6) 187.0 (58.8) 55.0 (50.0) 1-3 positive nodes 90.0 (27.4) 31.0 (26.1) 88.0 (27.7) 36.0 (32.7) $ 4 positive nodes 57.0 (17.3) 20.0 (16.8) 42.0 (13.2) 19.0 (17.3) Missing data 3.0 (0.9) 3.0 (2.5) 1.0 (0.3) 0.0 Type of prior chemotherapy Adjuvant (only) 273.0 (83.0) 80.0 (67.2) 269.0 (84.6) 83.0 (75.5) Neoadjuvant (6 adjuvant) 53.0 (16.1) 36.0 (30.3) 48.0 (15.1) 27.0 (24.5) Missing data 3.0 (0.9) 3.0 (2.5) 1.0 (0.3) 0.0 b pCR in patients with neoadjuvant chemotherapy 12.0 (22.6) 10.0 (27.8) 12.0 (25.0) 7.0 (25.9) Chemotherapy regimen Anthracyclines based 118.0 (35.9) 29.0 (24.4) 109.0 (34.3) 29.0 (26.4) Anthracyclines and taxanes based 211.0 (64.1) 90.0 (75.6) 209.0 (65.7) 81.0 (73.6) NOTE. Data are presented as No. (%) except where otherwise noted. Abbreviations: AJCC, American Joint Committee on Cancer; pCR, pathologic complete response. a Basal phenotype: cytokeratins 5/6 positive and/or epidermal growth factor receptor positive; and nonbasal phenotype: cytokeratins 5/6 and epidermal growth factor receptor negative. b pCR in the breast and ipsilateral axilla. DISCUSSION in combination with other drugs as adjuvant therapy of Our study failed to show a statistically significant im- operable breast cancer is still unclear.5-7 As a single agent, provement in DFS by adding 8 cycles of extended cape- adjuvant capecitabine was inferior to standard adjuvant citabine to standard (neo)adjuvant chemotherapy for therapy—either cyclophosphamide, methotrexate, fluoro- operable TNBC after a median follow-up of more than uracil; or doxorubicin plus cyclophosphamide—in patients 7 years. Adjusted HR, considering the stratification factors, with breast cancer age 65 years or older.8 A recent meta- was 0.79 (P = .082); therefore, the study was formally analysis of (neo)adjuvant capecitabine trials, including negative in accordance with the statistical assumption 8 trials and 9,302 patients, found that globally, capecitabine made when the trial was designed. The role of capecitabine did not improve DFS9; however, in trials in which capecitabine 210 © 2019 by American Society of Clinical Oncology Volume 38, Issue 3 Extended Capecitabine in Early Triple-Negative Breast Cancer TABLE 4. Safety Profile According to Study Arm (safety population) Capecitabine Arm (n = 436), No. (%) Observation Arm (n = 425), No. (%) AEs Based on NCI-CTCAE v3.0 (AEs reported in ‡ 5% globally) Grade 1-4 Grade 3 Grade 4 Grade 1-4 Grade 3 Grade 4 Hand and foot syndrome 306.0 (70.2) 82.0 (18.8) — 3.0 (0.7) — — Diarrhea 154.0 (35.3) 14.0 (3.2) 1.0 (0.2) 6.0 (1.4) — — Nausea 103.0 (23.6) 4.0 (0.9) — 6.0 (1.4) — — Vomiting 45.0 (10.3) 3.0 (0.7) — 2.0 (0.5) — — Abdominal pain, general 27.0 (6.2) 1.0 (0.2) — 1.0 (0.2) — — Any cardiac event, general 5.0 (1.1) 2.0 (0.5) — 4.0 (0.9) 1.0 (0.2) — Fatigue 172.0 (39.44) 13.0 (3.0) — 48.0 (11.3) — — Irregular menses 69.0 (15.8) 57.0 (13.1) — 67.0 (15.8) 55.0 (12.9) — Hemoglobin decrease 107.0 (24.5) 1.0 (0.2) — 27.0 (6.4) — — Leukocytes (total WBC) decrease 136.0 (31.2) 1.0 (0.2) — 58.0 (13.6) — — Lymphopenia 63.0 (14.4) 3.0 (0.7) 1.0 (0.2) 33.0 (7.8) 1.0 (0.2) — Neutrophils/granulocytes decrease 125.0 (28.7) 8.0 (1.8) — 46.0 (10.8) — — Thrombocytopenia 22.0 (5.0) 1.0 (0.2) — 8.0 (1.9) — — ALT, SGPT increase 85.0 (19.5) 1.0 (0.2) — 28.0 (6.6) — — AST, SGOT increase 83.0 (19.0) — 1.0 (0.2) 23.0 (5.4) — — Hyperbilirubinemia 52.0 (11.9) 2.0 (0.5) 1.0 (0.2) 2.0 (0.5) — — Alkaline phosphatase increase 63.0 (14.4) — — 30.0 (7.1) — — Hypercholesterolemia 34.0 (7.8) — — 35.0 (8.2) — — Heartburn/dyspepsia 53.0 (12.2) — — 5.0 (1.2) — — Nail changes 42.0 (9.6) 2.0 (0.5) — 3.0 (0.7) — — Sensory neuropathy 66.0 (15.1) 3.0 (0.7) — 25.0 (5.9) 1.0 (0.2) — Musculoskeletal pain (joint) 54.0 (12.4) 1.0 (0.2) — 29.0 (6.8) 1.0 (0.2) — Musculoskeletal pain (muscle) 39.0 (8.9) 1.0 (0.2) — 9.0 (2.1) — — Headache 43.0 (9.9) — — 7.0 (1.6) — — Abbreviations: AE, adverse event; NCI-CTCAE v3.0, National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0; SGOT, serum glutamic oxaloacetic transaminase; SGPT, serum glutamic pyruvic transaminase. was added to standard adjuvant chemotherapy (in contrast DFS and OS with capecitabine. The effect was particularly to those trials in which capecitabine replaced standard remarkable in TNBC. Compared with our trial, the pop- agents), a significant DFS advantage was found. Of note, in ulations in both studies were significantly different, as this meta-analysis the benefit of adding capecitabine to Asian patients had a significantly higher risk of relapse, as standard chemotherapy was mainly observed in patients shown by the 56.1% 5-year DFS for patients with TNBC in with TNBC. The GEICAM-CIBOMA study added sequential the control arm of the CREATE-X trial. In contrast, DFS in capecitabine to standard (neo)adjuvant chemotherapy in the control arm in our trial was better than expected: DFS patients with operable TNBC but was unable to show at 5 years was 76.8%, while our statistical hypothesis a statistically significant improvement in DFS in the overall assumed a 5-year DFS of 64.7% on the basis of historical population. The results of our study were therefore ap- controls. parently different from those of the meta-analysis and, in Moreover, the selection criteria in the CREATE-X trial particular, from those of the the Capecitabine for Residual limited to patients with residual disease after neoadjuvant Cancer as Adjuvant Therapy (CREATE-X) trial,10 which treatment suggest that capecitabine could have a more addressed a similar question but in a population at higher relevant role in patients with tumors that are less sensitive risk of relapse. The CREATE-X trial randomly assigned or partially resistant to regimens containing anthracyclines patients with breast cancer with residual disease at surgery and taxanes. after standard neoadjuvant chemotherapy to 6 to 8 cycles of capecitabine versus observation—plus hormone therapy The DFS events in our trial were numerically higher in the in both arms for patients with hormone receptor–positive control group (n = 120) than in the capecitabine group tumors—and found a statistically significant increase in (n = 105), arguably because of the apparent efficacy of Journal of Clinical Oncology 211 Lluch et al capecitabine in a predefined subgroup of patients—being The tolerability of capecitabine was as expected, with a stratification factor as well—with nonbasal phenotype, a median dose intensity of 86.3% and 75.2% of patients as defined by central immunohistochemistry (lack of receiving the planned 8 cycles of therapy. staining for epidermal growth factor receptor and cyto- Among the limitations of this trial, we can include the fact that keratins 5/6). In these patients, both DFS and OS were it was an open-label study. In addition, the population enrolled statistically superior with capecitabine. TNBC is a het- demonstrated a much lower recurrence rate than expected. erogeneous disease that encompasses a wide spectrum of clinical and molecular subtypes with different sensitivity to The latter finding has been observed in other recent adjuvant standard therapies,11 The results in the nonbasal sub- trials and compromises the ability to show a difference be- group suggest that the activity of capecitabine might be tween treatment strategies. In contrast, designed in 2002 to selective for this particular subset of patients, although 2003, this was one of the first trials, to our knowledge, devoted a validation of this hypothesis in other TNBC adjuvant to this specific subtype of breast cancer. trials exploring capecitabine is necessary to confirm the In conclusion, the GEICAM-CIBOMA study failed to show finding. Perhaps capecitabine is less effective in basal-like a statistically significant improvement in DFS by adding tumors as these are highly proliferative tumors and more capecitabine to standard (neo)adjuvant chemotherapy for sensitive to taxanes carboplatin and eribulin, as seen in the TNT trial comparing docetaxel with carboplatin12 and operable TNBC. An apparent improvement in DFS and OS the 301 study comparing eribulin with capecitabine,13 was observed in the nonbasal subset of patients, although whereas nonbasal tumors could be more sensitive to an the real implication of this finding should be further con- antimetabolite drug, such as capecitabine, as they have firmed with the analysis of other (neo)adjuvant capecita- a lower proliferation index. bine trials. 31 AFFILIATIONS Instituto de Investigación Sanitaria Aragon, Hospital Universitario 1 Hospital Clı́nico Universitario de Valencia and Biomedical Research Miguel Servet, Zaragoza, Spain 32 Institute INCLIVA, University of Valencia, Valencia, Spain Hospital Nuestra Señora de la Candelaria, Santa Cruz de Tenerife, Spain 33 2 Centro de Investigación Biomédica en Red de Oncologı́a ISCIII, Madrid, Social S Hospital Teodoro Maldonado Carbo, Guayaquil, Ecuador 34 Spain Oncologistas Associados–Oncologia D’Or, Rio de Janeiro, Brazil 35 3 GEICAM, Spanish Breast Cancer Group, Madrid, Spain Hospital Regional Universitario Carlos Haya, Málaga, Spain 4 Centro de Pesquisa Clı́nica Hospital São Lucas da PUCRS, Porto Alegre, 36 Hospital Beneficiencia Española, San Luis de Potosı́, México Brazil 37 Clı́nica Amo Itaigara, Salvador, Brazil 38 5 LACOG, Latin American Cooperative Oncology Group, Porto Alegre, Hospital Base de Valdivia, Valdivia, Chile 39 Brazil Instituto de Investigación Sanitaria Gregorio Marañón, Universidad 6 Centro Médico Nacional 20 de Noviembre, Instituto de Seguridad y Complutense, Madrid, Spain Servicios Sociales de los Trabajadores del Estado, Ciudad de México, México 7 Hospital Universitario Virgen del Rocı́o, Sevilla, Spain CORRESPONDING AUTHOR 8 Instituto Nacional de Câncer, Rio de Janeiro, Brazil Miguel Martı́n, MD, PhD, Medical Oncology, Instituto de Investigación 9 Hospital Amaral Carvalho, Sao Paolo, Brazil Sanitaria Gregorio Marañon, Calle del Dr Esquerdo, 46, 28007 Madrid, 10 Instituto Valenciano de Oncologı́a, Valencia, Spain Spain; Twitter: @GEICAM; e-mail: mmartin@geicam.org. 11 Hospital Clı́nico San Carlos, Madrid, Spain 12 Instituto Nacional del Cáncer, Santiago, Chile 13 Hospital Universitario Reina Sofı́a, Córdoba, Spain PRIOR PRESENTATION 14 Hospital General Universitario Morales Meseguer, Murcia, Spain Presented in part at the 15th European Cancer Organization and 34th 15 Instituto Nacional de Enfermedades Neoplásicas, Lima, Perú European Society for Medical Oncology Multidisciplinary Congress, 16 GECOPERU, Peruvian Oncological Clinical Studies Group, Lima, Peru Berlin, Germany, September 20-24, 2009; the 33rd Annual San Antonio 17 Hospital Arnau de Vilanova, Lleida, Spain Breast Cancer Symposium, San Antonio, TX, December 8-12, 2010; the 18 Hospital Universitario Na Sa de Valme, Sevilla, Spain 47th American Society of Clinical Oncology Annual Meeting, Chicago, IL, 19 Hospital Universitario Puerta del Mar and Instituto de Investigación e June 3-7, 2011; the 8th European Breast Cancer Conference, Vienna, Innovación Biomédica de Cádiz, Cádiz, Spain Austria, March 21-24, 2012; the 36th Annual San Antonio Breast 20 Hospital de la Santa Creu i Sant Pau, Medicine Department Universitat Cancer Symposium, San Antonio, TX, December 10-14, 2013; and 2018 Autonoma, Institut Recerca Biomedica Sant Pau, Barcelona, Spain San Antonio Breast Cancer Symposium, San Antonio, TX, December 4- 21 Complexo Hospitalario Universitario A Coruña, A Coruña, Spain 8, 2018. 22 Hospital de San José, Ciudad Obregón, Sonora, México 23 Centro Oncológico de Galicia, A Coruña, Spain SUPPORT 24 Complexo Hospitalario Universitario de Vigo, Vigo, Spain Written on behalf of GEICAM Spanish Breast Cancer Group, CIBOMA 25 Hospital General Universitario de Elche, Alicante, Spain (Iberoamerican Coalition for Research in Breast Oncology), and LACOG 26 Centro Médico Colima, Colima, México (Latin American Cooperative Oncology Group). Funded by F Hoffmann-La 27 Unidade de Novos Tratamentos CliniOnco, Porto Alegre, Brazil Roche. The company also contributed with the study drug (capecitabine; 28 Consorcio Hospitalario Provincial de Castellón, Castellón, Spain Xeloda), but were not involved in study design, data collection, data 29 Hospital General Universitario de Valencia, Valencia, Spain analyses or interpretation, or writing of this report. 30 Corporació Sanitaria Parc Taulı́ de Sabadell, Barcelona, Spain 212 © 2019 by American Society of Clinical Oncology Volume 38, Issue 3 Extended Capecitabine in Early Triple-Negative Breast Cancer AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF Lescure, Jesús Cárdenas, Jeferson Vinholes, Eduardo Martı́nez de INTEREST AND DATA AVAILABILITY STATEMENT Dueñas, Marı́a J. Godes, Miguel A. Seguı́, Antonio Antón, Pilar López- Álvarez, Jorge Moncayo, Gilberto Amorim, Esther Villar, Salvador Reyes, Disclosures provided by the authors and data availability statement (if Carlos Sampaio, Bernardita Cardemil, Miguel Martı́n applicable) are available with this article at DOI https://doi.org/10.1200/ Data analysis and interpretation: Ana Lluch, Carlos H. Barrios, Laura JCO.19.00904. Torrecillas, Maria J. Escudero, Susana Bezares, Eva Carrasco, Miguel Martı́n AUTHOR CONTRIBUTIONS Manuscript writing: All authors Conception and design: Ana Lluch, Carlos H. Barrios, Laura Torrecillas Final approval of manuscript: All authors Miguel Martı́n Accountable for all aspects of the work: All authors Provision of study materials or patients: Ana Lluch, Carlos H. Barrios, Laura Torrecillas, Manuel Ruiz-Borrego, Jose Bines, Jose Segalla, Ángel ACKNOWLEDGMENT Guerrero-Zotano, Jose A. Garcı́a-Sáenz, Roberto Torres, Juan de la Haba, The authors thank the investigators involved in the GEICAM/2003- Elena Garcı́a-Martı́nez, Henry L. Gómez, Antonio Llombart, Javier 11_CIBOMA/2004-01 study: J. Corona, C. Jara, B. Cardemil, R. Toro, C. Salvador Bofill, José M. Baena-Cañada, Agustı́ Barnadas, Lourdes Calvo, Pimentel, B. Hernando, E. Vicente, L. Zagame, M. Gil, L. Garcı́a Estévez, Laura Pérez-Michel, Manuel Ramos, Isaura Fernández, Álvaro Rodrı́guez- C. Rodrı́guez, M.A. de la Cruz, J.M. Tello, S. Campos, M. Lomas, D. Lescure, Jesús Cárdenas, Jeferson Vinholes, Eduardo Martı́nez de Capdevile, M. Campos, M. Margelı́, R. Andrés, I. Tusquets, A. Dueñas, Maria J. Godes, Miguel A. Seguı́, Antonio Antón, Pilar López- Ballesteros, A. Guerrero, M. Arguello, J.L. Rodrı́guez, M. Muñoz, Álvarez, Jorge Moncayo, Gilberto Amorim, Esther Villar, Salvador Reyes, J. Florian, S. Azevedo, R. Mondragón, J. Peralta, A.E. Palomo, Carlos Sampaio, Bernardita Cardemil, Miguel Martı́n L.J. Barajas, A. Arcusa, H. Carranza, C. Garcı́a, C. Umbrı́a, José E. Alés, Collection and assembly of data: Ana Lluch, Carlos H. Barrios, Laura J.M. López Vega, M. Romeo, J. Valero, J.L. Alonso, C. Mathias, F. Torrecillas, Manuel Ruiz-Borrego, Jose Bines, Jose Segalla, Ángel Gutierrez, E. Adrover, P. Nuñez, C. Mendiola, and J. Cassinello, A. de la Guerrero-Zotano, Jose A. Garcı́a-Sáenz, Roberto Torres, Juan de la Haba, Huerta. We acknowledge Dr Javier Castellanos and his contribution to this Elena Garcı́a-Martı́nez, Henry L. Gómez, Antonio Llombart, Javier study in life. Salvador Bofill, José M. Baena-Cañada, Agustı́ Barnadas, Lourdes Calvo, Laura Pérez-Michel, Manuel Ramos, Isaura Fernández, Álvaro Rodrı́guez- REFERENCES 1. Li X, Yang J, Peng L, et al: Triple-negative breast cancer has worse overall survival and cause-specific survival than non-triple-negative breast cancer. Breast Cancer Res Treat 161:279-287, 2017 2. Walko CM, Lindley C: Capecitabine: A review. 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Kaufman PA, Awada A, Twelves C, et al: Phase III open-label randomized study of eribulin mesylate versus capecitabine in patients with locally advanced or metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol 33:594-601, 2015 n n n Journal of Clinical Oncology 213 Lluch et al AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Phase III Trial of Adjuvant Capecitabine After Standard Neo-/Adjuvant Chemotherapy in Patients With Early Triple-Negative Breast Cancer (GEICAM/2003-11_CIBOMA/2004-01) 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 = Immediate Family Member, Inst = 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/journal/jco/site/ifc. Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments). Ana Lluch Agustı́ Barnadas Consulting or Advisory Role: Novartis, Pfizer, Genentech, Eisai, Celgene Honoraria: Pfizer Research Funding: Roche (Inst), AstraZeneca (Inst), Merck (Inst), PharmaMar Consulting or Advisory Role: Pfizer, Novartis, Eli Lilly (Inst), Boehringer Ingelheim (Inst), Amgen (Inst), GlaxoSmithKline (Inst), Speakers’ Bureau: Roche, Pfizer, Novartis, Genomic Health International Novartis (Inst), Pfizer (Inst), Eisai (Inst), Celgene (Inst), Pierre Fabre (Inst) Travel, Accommodations, Expenses: Roche, Pfizer Travel, Accommodations, Expenses: Genentech, Novartis Manuel Ramos Carlos H. Barrios Consulting or Advisory Role: Novartis Stock and Other Ownership Interests: Biomarker, MedSIR, Tummi Speakers’ Bureau: AstraZeneca, Roche, Novartis, Pfizer Honoraria: Novartis, Genentech, Pfizer, GlaxoSmithKline, Sanofi, Boehringer Travel, Accommodations, Expenses: Pfizer Ingelheim, Eisai Álvaro Rodrı́guez-Lescure Consulting or Advisory Role: Boehringer Ingelheim, Genentech, Novartis, Honoraria: Roche, Pfizer, Novartis, Mylan GlaxoSmithKline, Eisai, Pfizer, AstraZeneca, Libbs, MSD Oncology, United Consulting or Advisory Role: Roche, Pfizer, Novartis, AstraZeneca, Mylan Medical Speakers’ Bureau: Pfizer, Novartis, Roche, Kern Pharma Research Funding: Pfizer, Novartis, Amgen, AstraZeneca, Boehringer Research Funding: Roche (Inst), Novartis (Inst), Pfizer (Inst), Eli Lilly (Inst) Ingelheim, GlaxoSmithKline, Genentech, Eli Lilly, Sanofi, GlaxoSmithKline, Taiho Expert Testimony: Pfizer, Novartis, Roche, Kern Pharma Pharmaceutical, Mylan, Merrimack Pharmaceuticals, Merck, AbbVie, Astellas Travel, Accommodations, Expenses: Roche, Pfizer Pharma, Biomarin, Bristol-Myers Squibb, Daiichi Sankyo, Abraxis BioScience, AB Science, Asana Biosciences, Medivation, Daiichi Sankyo, Exelixis, ImClone Jeferson Vinholes Systems, LEO Pharma, Millennium Pharmaceuticals, Janssen Pharmaceuticals, Research Funding: Roche Atlantis Clinica, INC Research, Halozyme, Covance, Celgene, Celgene, inVentiv Travel, Accommodations, Expenses: Roche Health Eduardo Martı́nez de Dueñas Travel, Accommodations, Expenses: Genentech, Novartis, Pfizer, Bristol-Myers Consulting or Advisory Role: Novartis, Roche Squibb, AstraZeneca, MSD Oncology Travel, Accommodations, Expenses: Roche Laura Torrecillas Miguel A. Seguı́ Consulting or Advisory Role: Pfizer, Roche, Merck, Bristol-Myers Squibb, Bayer Consulting or Advisory Role: Roche, Pfizer, Novartis, Amgen, Eisai, Eli Lilly Speakers’ Bureau: Pfizer, Roche, Eli Lilly, Amgen, Bayer Speakers’ Bureau: Roche, Pfizer, Amgen Travel, Accommodations, Expenses: Pfizer, Roche, Merck, Ipsen Research Funding: Roche (Inst), Novartis (Inst) Manuel Ruiz-Borrego Travel, Accommodations, Expenses: Roche, Pfizer, Novartis, Amgen Honoraria: Genentech Antonio Antón Consulting or Advisory Role: Roche Consulting or Advisory Role: Bayer Jose Bines Gilberto Amorim Honoraria: Roche Honoraria: Roche, Novartis, Eli Lilly, Sanofi Consulting or Advisory Role: Roche Consulting or Advisory Role: Novartis, Roche Travel, Accommodations, Expenses: Roche Travel, Accommodations, Expenses: Roche Ángel Guerrero-Zotano Carlos Sampaio Consulting or Advisory Role: AstraZeneca, Novartis Employment: Clinica AMO Speakers’ Bureau: Novartis, Roche, Pfizer, AstraZeneca Leadership: Clinica AMO Research Funding: Pfizer (Inst) Stock and Other Ownership Interests: Clinica AMO Travel, Accommodations, Expenses: Roche, Pfizer, Novartis Consulting or Advisory Role: Pneuma Respiratory Jose A. Garcı́a-Sáenz Susana Bezares Consulting or Advisory Role: Novartis, Celgene, AstraZeneca, Eli Lilly Employment: Eli Lilly (I) Research Funding: AstraZeneca (Inst) Stock and Other Ownership Interests: Eli Lilly (I) Travel, Accommodations, Expenses: Roche, Novartis Eva Carrasco Juan de la Haba Stock and Other Ownership Interests: Eli Lilly Speakers’ Bureau: Roche, Novartis, Pfizer Consulting or Advisory Role: Bristol-Myers Squibb (I), Novartis (I), Celgene (I), Travel, Accommodations, Expenses: Roche, Novartis Roche (I), Janssen Pharmaceuticals (I), Amgen (I), Pfizer (I), Incyte (I), Elena Garcı́a-Martı́nez AbbVie (I) Consulting or Advisory Role: AstraZeneca, Roche Research Funding: Genentech (Inst), Novartis (Inst), Pfizer (Inst), Bristol-Myers Travel, Accommodations, Expenses: Roche, PharmaMar, AstraZeneca, Pfizer, Squibb (Inst), Celgene (Inst), AstraZeneca (Inst), Merck Sharp & Dohme (Inst), Bristol-Myers Squibb AstraZeneca (Inst), Pierre Fabre (Inst), Takeda (Inst), Celgene (I), Janssen Pharmaceuticals (I), Genentech (I), Novartis (I), Bristol-Myers Squibb (I), Amgen Henry L. Gómez (I), Pfizer (I), AbbVie (I) Speakers’ Bureau: Roche, Novartis, AstraZeneca, Bristol-Myers Squibb Patents, Royalties, Other Intellectual Property: PAM 50 taxane predictor Antonio Llombart Travel, Accommodations, Expenses: Roche, Novartis (I), Bristol-Myers Squibb Honoraria: Roche, Eli Lilly, AstraZeneca, Amgen, Novartis, Pfizer (I), Celgene (I) Consulting or Advisory Role: Novartis, Pfizer, Roche, Eli Lilly, AstraZeneca, Eisai Miguel Martı́n Research Funding: Pfizer, Genentech, Tesaro, Novartis, Eisai Consulting or Advisory Role: Genentech, Novartis, Pfizer, Eli Lilly, AstraZeneca, Travel, Accommodations, Expenses: Roche, Pfizer, Celgene, Eli Lilly Taiho Pharmaceutical, PharmaMar Other Relationship: MedSIR Research Funding: Novartis (Inst), Roche (Inst) José M. Baena-Cañada No other potential conflicts of interest were reported. Consulting or Advisory Role: Roche, Pfizer, Novartis, Grünenthal Group, Eisai Travel, Accommodations, Expenses: Roche, Pfizer, MSD Oncology © 2019 by American Society of Clinical Oncology Volume 38, Issue 3