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)

original reports 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) Ana Lluch, PhD 1,2,3 ; Carlos H. Barrios, MD 4,5 ; Laura Torrecillas, MD 6 ; Manuel Ruiz-Borrego, MD 3,7 ; Jose Bines, MD, PhD 5,8 ; Jose Segalla, MSc, MD 5,9 ;´ Angel Guerrero-Zotano, MD 3,10 ; Jose A. Garc´ ıa-S´ aenz, MD, PhD 3,11 ; Roberto Torres, MD 12 ; Juan de la Haba, MD, PhD 2,3,13 ; Elena Garc´ ıa-Mart´ ınez, MD, PhD 3,14 ; Henry L. G´ omez, MD 15,16 ; Antonio Llombart, MD, PhD 3,17 ; Javier Salvador Bofill, MD 3,18 ; Jos´ e M. Baena-Cañada, PhD 3,19 ; Agust´ ıBarnadas, MD, PhD 2,3,20 ; Lourdes Calvo, MD 3,21 ; Laura P´ erez-Michel, MD 22 ; Manuel Ramos, MD 3,23 ; Isaura Fern´ andez, MD 3,24 ;´ Alvaro Rodr´ ıguez-Lescure, MD, PhD 3,25 ; Jes ´ us C´ ardenas, MD 26 ; Jeferson Vinholes, MD, PhD 5,27 ; Eduardo Mart´ ınez de Dueñas, MD, PhD 3,28 ; Maria J. Godes, MD 3,29 ; Miguel A. Segu´ ı,PhD 3,30 ; Antonio Ant´ on, MD 3,31 ; Pilar L´ opez- ´ Alvarez, MD 3,32 ; Jorge Moncayo, MD 33 ; Gilberto Amorim, MD 5,34 ; Esther Villar, MD 3,35 ; Salvador Reyes, MD 36 ; Carlos Sampaio, MD 5,37 ; Bernardita Cardemil, MD 38 ; Maria J. Escudero, MD 3 ; Susana Bezares, MD 3 ; Eva Carrasco, MD 3 ; and Miguel Mart´ ın, MD, PhD 2,3,39 ; 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 vnonbasal, 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 observation (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 (interaction test P= .0694) and an HR for overall survival of 0.42 versus 1.23 in basal phenotype (interaction test P= .0052). Tolerance of capecitabine was as expected, with 75.2% of patients completing the planned 8 cycles. CONCLUSION This study failed to show a statistically significant increase in DFS by adding extended capecitabine to standard chemotherapy in patients with early TNBC. In a preplanned subset analysis, patients with nonbasal phenotype seemed to obtain benefit with capecitabine, although this will require additional validation. J Clin Oncol 38:203-213. © 2019 by American Society of Clinical Oncology Creative Commons Attribution Non-Commercial No Derivatives 4.0 License INTRODUCTION Early triple-negative breast cancer (TNBC) can be cured with local–regional therapy plus adjuvant chemotherapy, usually anthracycline- and/or taxanebased combinations. However, despite these therapies, a proportion of patients eventually experience relapse and die. A recent analysis of data from the National Cancer Institute SEER reported a 3-year relapse rate of approximately 8%, 15%, and 40% for patients with stages I, II, and III TNBC, 1 respectively; therefore, new adjuvant options are necessary to improve the prognosis of this breast cancer subtype. Capecitabine is an oral prodrug of fluorouracil approved for the treatment of metastatic breast cancer in ASSOCIATED CONTENT See accompanying Editorial on page 179 Data Supplement Protocol Author affiliations and support information (if applicable) appear at the end of this article. Accepted on November 12, 2019 and published at ascopubs.org/journal/ jco on December 5, 2019: DOI https://doi. org/10.1200/JCO.19. 00904 Volume 38, Issue 3 203 Downloaded from ascopubs.org by 150.214.182.238 on April 18, 2023 from 150.214.182.238 Copyright © 2023 American Society of Clinical Oncology. All rights reserved. patients with prior progression after anthracyclines and taxanes and is therefore partially non–cross resistant with these two classes of agents. 2 On the basis of this concept, we carried out a trial in which capecitabine was sequentially added to standard (neo)adjuvant chemotherapy in operable TNBC to explore the ability of the drug to reduce the rate of relapse and increase the survival of this disease. PATIENTS AND METHODS The GEICAM/2003-11_CIBOMA/2004-01 trial is an openlabel, randomized phase III study that was conducted in compliance with the International Council for Harmonization Good Clinical Practice guidelines and the Declaration of Helsinki. The study was reviewed and approved by the independent ethics committees or institutional review boards of all participating institutions. Written informed consent was obtained from all patients before any studyrelated procedures were performed. Patient Eligibility Eligible patients included women with hormone receptor–negative (immunohistochemistry staining of estrogen and progesterone receptors ,1%) and human epidermal growth factor 2–negative operable breast cancer, with invasive adenocarcinoma histologically confirmed. Patients had received 6 to 8 cycles of standard anthracycline- and/ or taxane-containing chemotherapy in the (neo)adjuvant setting, followed by radiation therapy according to institutional guidelines. In the case of node-negative disease, 4 cycles of doxorubicin and cyclophosphamide were allowed. Eligible patients were those with ipsilateral axillary node involvement classified as pN1a, pN2a, or pN3a—excluding metastatic infraclavicular lymph Patients randomly assigned (n = 876) Capecitabine arm Allocated to intervention (ITT population) (n = 448) Assessed for eligibility (n = 1,516) Excluded Not meeting inclusion criteria Refused participation Other reasons (n = 640) (n = 341) (n = 163) (n = 136) Observation arm Allocated to intervention (ITT population) (n = 428) Early discontinuation of protocol therapy Patient refusal Unacceptable toxicity Disease recurrence Interruption of capecitabine >3 weeks Death Protocol deviation Lost to follow-up Other reason (n = 111) (n = 33) (n = 34) (n = 9) (n = 11) (n = 4)* (n = 5) (n = 1) (n = 14) Discontinuation in observation arm Patient refusal Unacceptable residual toxicity Disease recurrence Death Protocol deviation Lost to follow-up Second primary malignancy Other reason (n = 6) (n = 1) (n = 13) (n = 1) (n = 1) (n = 1) (n = 5) Observation arm Received allocated intervention (Safety population) (n = 425) Capecitabine arm Received allocated intervention (Safety population) (n = 436) (n = 30)† (n = 2)‡ 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 Lluch et al Downloaded from ascopubs.org by 150.214.182.238 on April 18, 2023 from 150.214.182.238 Copyright © 2023 American Society of Clinical Oncology. All rights reserved. nodes—according to the American Joint Committee on Cancer 2002 staging system. Patients without axillary node involvement (N0) were also eligible provided the primary tumor measured 1 cm or greater in diameter. Patients were ineligible in the case of bilateral invasive breast cancer, absence of surgical treatment with curative intent, resection of fewer than 6 lymph nodes when axillary lymph node dissection was performed, or pregnancy or breastfeeding. Triple-negative and basal versus nonbasal status were determined centrally by a GEICAM Spanish Breast Cancer Group pathologist (F.R.). Tumors with any staining for epidermal growth factor receptor and/or cytokeratins 5/6 were considered basal. Patients with no staining for both biomarkers were considered nonbasal. 3 Study Procedures Baseline assessments performed before patient randomization in centrally confirmed eligible patients included mammography, chest radiography, abdominal ultrasonography and/or computed tomography (CT), bone scan (if bone pain or increased alkaline phosphatase), and bone X-ray (if suspicious lesions on the bone scan). Hematology, biochemistry, and pregnancy test—potentially fertile women only—were also completed before randomization. Eligible patients were stratified according to basal status (yes vno), institution, number of axillary lymph nodes (0 v1-3 v4 or more), and type of adjuvant chemotherapy (anthracyclines plus taxanes vanthracyclines alone). Patients were randomly assigned on a one-to-one basis to eight cycles of capecitabine 2,000 mg/m 2 (1,000 mg/m 2 administered orally two times per day) on days 1 to 14 every 3 weeks, or observation. Two dose reductions were permitted—75% and 50% of initial dose—on the basis of hematologic or nonhematologic adverse events (AEs) observed. Randomization was centralized at GEICAM headquarters. AEs were assessed during the study period and graded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0. Serious AEs (SAEs) were reported during the study treatment and within 30 days of the end of this time period. Physical examination, menopausal status, and presence of amenorrhea were assessed at baseline, at every cycle during the treatment period, every 3 months during years 1 to 2, every 6 months during years 3 to 5, and yearly afterward. Mammograms were performed yearly. Chest X-ray, abdominal ultrasounds, CT scan, or bone scans were performed if clinically indicated in the case of suspicion of disease recurrence. A complete follow-up on vital status was obtained until April 11, 2018, for all patients. Statistical Analysis Primary end point was disease-free survival (DFS), which was measured from the date of random assignment in the intent-to-treat (ITT) population to locoregional or distant TABLE 1. Patients’Demographics and Baseline Disease Characteristics According to Study Arm (intention-to-treat population) Demographic or Characteristic Capecitabine Arm (n = 448), No. (%) Observation Arm (n = 428), No. (%) Median age, years (range) 50.0 (20.0-79.0) 49.0 (23.0-82.0) Region Spain 272.0 (60.7) 260.0 (60.7) Latin America 176.0 (39.3) 168.0 (39.3) Race White 313.0 (69.9) 309.0 (72.2) Hispanic 107.0 (23.9) 97.0 (22.7) African American 16.0 (3.6) 11.0 (2.6) Other 12.0 (2.7) 11.0 (2.6) Karnofsky performance status 100 383.0 (85.5) 344.0 (80.4) 90 57.0 (12.7) 67.0 (15.7) 80 8.0 (1.8) 17.0 (4.0) Menopausal status at diagnosis Premenopausal 136.0 (30.4) 140.0 (32.7) Postmenopausal 312.0 (69.6) 288.0 (67.3) Histologic type Invasive ductal carcinoma 395.0 (88.2) 369.0 (86.2) Invasive lobular carcinoma 9.0 (2.0) 10.0 (2.3) Other 44.0 (9.8) 49.0 (11.4) Histologic grade G1 15.0 (3.3) 12.0 (2.8) G2 82.0 (18.3) 81.0 (18.9) G3 323.0 (72.1) 299.0 (69.9) GX 28.0 (6.3) 36.0 (8.4) Phenotype by IHC Basal a 329.0 (7,373.4) 318.0 (7,474.3) Nonbasal 119.0 (2,626.6) 110.0 (2,525.7) Stage at diagnosis (AJCC 2002) I 62.0 (13.8) 74.0 (17.3) II 270.0 (60.3) 271.0 (63.3) III 106.0 (23.7) 80.0 (18.7) Not available 10.0 (2.2) 3.0 (0.7) Nodal status Negative 244.0 (54.5) 242.0 (56.5) 1-3 positive nodes 121.0 (27.0) 124.0 (29.0) $4 positive nodes 77.0 (17.2) 61.0 (14.3) Missing data 6.0 (1.3) 1.0 (0.2) Type of prior chemotherapy Adjuvant (only) 353.0 (78.8) 352.0 (82.2) Neoadjuvant (6adjuvant) 89.0 (19.9) 75.0 (17.5) Missing data 6.0 (1.3) 1.0 (0.2) (continued on following page) Journal of Clinical Oncology 205 Extended Capecitabine in Early Triple-Negative Breast Cancer Downloaded from ascopubs.org by 150.214.182.238 on April 18, 2023 from 150.214.182.238 Copyright © 2023 American Society of Clinical Oncology. All rights reserved. recurrence, second primary malignancy, or death date, whichever occurred first. Secondary end points included 5-year DFS, overall survival (OS), safety, and analyses by subgroups and of biomarkers. According to the GEICAM El ´ Alamo registry, 4 estimated 5-year DFS for a similar population of patients with TNBC was 64.7%. The aim was to detect an increase in DFS to 73.7% with capecitabine, corresponding to a hazard ratio (HR) of 0.701 with a power of 80% using a two-tailed logrank test at 0.05 and considering 4 years of recruitment and 3 years of follow-up. Two hundred fifty-five events were projected and 834 eligible patients were needed. Assuming a drop-out rate of 5%, 876 patients were to be enrolled—438 patients in each arm. The sample size calculation was performed using EAST version 5.2. The initial protocol established the main DFS analysis to be performed after 255 events; however, the number of DFS events was much lower than expected and the steering committee of the study—with the advice of the independent data monitoring committee—therefore decided to perform the analysis after a median follow-up of more than 7 years after a total of 225 events and when the rate of annual recurrences was low in both arms of the study. We used the Kaplan-Meier limit-product method to estimate DFS and OS and comparison between the two study arms was performed using the stratified log-rank test using the stratification factors [basal status, number of axillary lymph nodes, and type of (neo)adjuvant chemotherapy]. All tests of hypotheses were two sided. In addition, we performed a multivariable Cox proportional hazard model analysis for DFS and OS to adjust for major prognostic factors: age, menopausal status, histopathologic findings, tumor size, disease stage, type of surgery, region, and the stratification factors for randomization. The safety analysis was performed in all patients who had received at least 1 cycle of study treatment. The worst AE grade per category for each patient was reported. RESULTS Study Patients Between October 2006 and September 2011, 876 patients were recruited across 80 institutions in 8 countries (Spain, Brazil, Chile, Colombia, Ecuador, Mexico, Peru, and Venezuela; Fig 1). Demographics and baseline disease characteristics were balanced, with no statistical differences between the two arms but with a slightly numerically higher proportion of poor prognosis features in the capecitabine arm (Table 1). The majority of patients were white and postmenopausal, and median age was 49 years. Most frequently, tumors 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 diagnosis—based on American Joint Committee on Cancer 2002—and the number of involved lymph nodes. Most patients in both arms had received adjuvant chemotherapy with anthracyclines and taxanes (67.5%), had breast-conservative surgery (54.7%) and axillary lymph node dissection with or without sentinel lymph node biopsy (74.8%), and received radiation therapy (79.7%). Drug Exposure and Discontinuations Of patients who were assigned to capecitabine, 75.2% (n = 337) completed 8 cycles of treatment. Median number of cycles was 8 (range, 1 to 8 cycles). A few patients (n = 12; 2.7%) did not complete at least 1 cycle of treatment and were excluded from the safety analysis as per protocol requirement. Four percent (n = 18) of patients completed 1 cycle of capecitabine, 10.3% (n = 46) of patients completed 2 to 4 cycles, and 7.8% (n = 35) of patients completed 5 to 7 cycles. Median dose intensity was 86.3% (range, 0.86% to 136.2%). Dose intensity rate was between 110% and 80% in 55.8% (n = 250) of patients and less than 75% in 33.5% (n = 150) of patients. Five patients were reported to have a dose intensity rate between 110% and 136.2%. In four of these patients, it was because of a mistake or rounding the capecitabine dose and in the TABLE 1. Patients’Demographics and Baseline Disease Characteristics According to Study Arm (intention-to-treat population) (continued) Demographic or Characteristic Capecitabine Arm (n = 448), No. (%) Observation Arm (n = 428), No. (%) pCR in patients with neoadjuvant chemotherapy b 22.0 (24.7) 19.0 (25.3) Chemotherapy regimen Anthracyclines based 147.0 (32.8) 138.0 (32.2) Anthracyclines and taxanes based 301.0 (67.2) 290.0 (67.8) Breast surgery Conservative 237.0 (52.9) 242.0 (56.5) Mastectomy 205.0 (45.8) 185.0 (43.2) Missing data 6.0 (1.3) 1.0 (0.2) Axillary surgery ALND 6SLNB 349.0 (78.0) 306.0 (71.5) SLNB 99.0 (22.1) 122.0 (28.5) Radiation therapy Yes 352.0 (78.6) 346.0 (80.8) No 91.0 (20.3) 81.0 (18.9) Unknown 5.0 (1.1) 1.0 (0.2) NOTE. Data are presented as No. (%) except where otherwise noted. Abbreviations: AJCC, American Joint Committee on Cancer; ALND, axillary lymph node dissection; IHC, immunohistochemistry; pCR, pathologic complete response; SLNB, sentinel lymph node biopsy. a Basal phenotype: cytokeratins 5/6-positive and/or epidermal growth factor receptor positive. b pCR in the breast and ipsilateral axilla. 206 © 2019 by American Society of Clinical Oncology Volume 38, Issue 3 Lluch et al Downloaded from ascopubs.org by 150.214.182.238 on April 18, 2023 from 150.214.182.238 Copyright © 2023 American Society of Clinical Oncology. All rights reserved. fifth patient the reason is unknown. Dose reductions of capecitabine were reported in 161 patients (36.9%). Main reasons for discontinuation of capecitabine (n = 97) were patient refusal, unacceptable toxicity, disease recurrence, or interruption of capecitabine for more than 3 weeks because of AEs (Fig 1). Efficacy At the time of data cutoff, median follow-up was 7.4 years and 7.2 years in the capecitabine and observation arms, respectively. A total of 225 events were observed, 105 (23.4%) in the capecitabine arm and 120 (28%) in the observation arm. In the ITT analysis (n = 876), results of the ObservationCapecitabine 012345678910 11 Time (years) DFS Probability (%) 448 396 365 344 334 323 304 248 154 60 17 1 428 379 347 329 313 290 262 204 123 58 25 2 Capecitabine Observation No. at risk: 10 20 30 40 50 60 70 80 90 100 Log-rank P = .135 Stratified log-rank P = .097 A ObservationCapecitabine 012345678910 Time (years) DFS Probability (%) 329 290 266 247 241 232 223 186 126 52 14 318 287 263 252 237 219 195 154 102 49 22 Capecitabine Observation No. at risk: 10 20 30 40 50 60 70 80 90 100 Log-rank P = .696 C ObservationCapecitabine 012345678910 Time (years) 10 20 30 40 50 60 70 80 90 100 DFS Probability (%) 119 106 99 97 93 91 81 62 28 8 3 110 92 84 77 76 71 67 50 21 9 3 Capecitabine Observation No. at risk: Log-rank P = .020 E 01234567891011 Time (years) ObservationCapecitabine 448 417 393 367 354 347 324 267 170 71 24 1 428 407 375 350 339 318 296 232 145 73 28 2 Capecitabine Observation No. at risk: 10 20 30 40 50 60 70 80 90 100 OS Probability (%) Log-rank P = .623 B ObservationCapecitabine 01234567891011 Time (years) 329 307 286 263 256 249 238 200 139 63 21 1 318 301 284 268 259 242 223 179 123 64 25 2 Capecitabine Observation No. at risk: 10 20 30 40 50 60 70 80 90 100 OS Probability (%) Log-rank P = .286 D ObservationCapecitabine 01234567891011 Time (years) 10 20 30 40 50 60 70 80 90 100 OS Probability (%) 119 110 107 104 98 98 86 67 31 8 3 110 106 91 82 80 76 73 53 22 9 3 Capecitabine Observation No at risk: Log-rank P = .007 F FIG 2. Disease-free survival (DFS) and overall survival (OS) Kaplan-Meier curves on the intention-to-treat population and subpopulations based on the immunohistochemistry phenotype. (A) DFS on the ITT population. (B) OS on the ITT population. (C) DFS on the basal phenotype. (D) OS on the basal phenotype. (E) DFS on the nonbasal phenotype. (F) OS on the nonbasal phenotype. Journal of Clinical Oncology 207 Extended Capecitabine in Early Triple-Negative Breast Cancer Downloaded from ascopubs.org by 150.214.182.238 on April 18, 2023 from 150.214.182.238 Copyright © 2023 American Society of Clinical Oncology. All rights reserved. Cox proportional hazards regression model did not demonstrate a statistically significant difference in DFS between the capecitabine and observation arms (unadjusted HR, 0.82; 95% CI, 0.63 to 1.06; P= .136; adjusted HR according to stratification factors, 0.79; 95% CI, 0.61 to 1.03; P= .082; and fully adjusted HR, 0.77; 95% CI, 0.59 to 1.00; P= .051). Five-year DFS rates were 79.6% (95% CI, 75.8% to 83.4%) in the capecitabine arm and 76.8% (95% CI, 72.7% to 80.9%) in the observation arm. Figure 2A shows the Kaplan-Meier curves for DFS. In addition, there was no statistically significant difference in OS between study arms (unadjusted HR, 0.92; 95% CI, 0.66 to 1.28; P= .623; adjusted HR according to stratification factors, 0.88; 95% CI, 0.64 to 1.23; P= .4562; and fully adjusted HR, 0.86; 95% CI, 0.6262 to 1.20; P= .371). Five-year OS rates were 86.2% (95% CI, 82.9% to 89.4%) in the capecitabine arm and 85.9% (95% CI, 82.4% to 89.3%) in the observation arm. Figure 2B shows the Kaplan-Meier curves for OS. An exploratory subgroup analysis for DFS in the ITT population (Fig 3) showed similar treatment effects by menopausal status (prevpostmenopausal), phenotype (basal vnonbasal), nodal status (negative v1 to 3 positive nodes, 4 or more positive nodes), type of previous CT scan (neoadjuvant vadjuvant), prior administration of taxanes (yes vno) and region (Spain vLatin America). Patients with a nonbasal phenotype had a statistically significant increase in DFS (HR, 0.53; 95% CI, 0.31 to 0.91; P= .022) and OS (HR, 0.42; 95% CI, 0.21 to 0.81; P= .0095) with capecitabine. Five-year DFS rates were 82.6% (95% CI, 75.7% to 89.5%) with capecitabine and 72.9% (95% CI, 64.4% to 81.3%) in the observation arm. Five-year OS rates were 89.5% (95% CI, 83.9% to 95.1%) with capecitabine and 79.6% (95% CI, 71.7% to 87.4%) in the observation arm. The interaction tests treatment/nonbasal status had adjusted Pvalues of .0694 for DFS and .0052 for OS. Figures 2C and 2D show the Kaplan-Meier curves for DFS and OS, respectively, in the basal phenotype subpopulation. Figures 2E and 2F show the Kaplan-Meier curves for DFS and OS, respectively, in the nonbasal phenotype subpopulation. The number and type of DFS events in the overall and nonbasal populations are shown in Table 2. Of note, in the nonbasal subpopulation, and in agreement with DFS and OS data, DFS events were more frequent in the observation arm [30.9% (n = 34)] compared with the capecitabine arm [17.6% (n = 21)]. Remarkably, in this subtype the reduction of DFS events with capecitabine was mainly a result of distant relapses, particularly in liver, CNS, and lymph Subgroup Analysis of DFS HR (95% CI)No. of EventsHRNo. of Patients (%)Subgroup 0.819 (0.630 to 1.065) 0.686 (0.408 to 1.153) 0.867 (0.639 to 1.176) 0.942 (0.697 to 1.272) 0.530 (0.307 to 0.913) 1.006 (0.586 to 1.727) 0.747 (0.552 to 1.012) 0.884 (0.551 to 1.418) 0.798 (0.583 to 1.093) 0.687 (0.456 to 1.037) 0.800 (0.496 to 1.289) 0.937 (0.566 to 1.550) 0.750 (0.534 to 1.053) 0.934 (0.618 to 1.413) 105 24 81 84 21 29 74 33 72 39 31 33 60 45 120 35 85 86 34 24 96 36 84 55 37 28 75 45 Capecitabine Observation 0.4 0.6 0.8 1.2 1.6 2 Capecitabine Observation 876 (100) 276 (32) 600 (68) 647 (74) 229 (26) 164 (19) 705 (81) 285 (33) 591 (67) 486 (56) 245 (28) 138 (16) 532 (61) 344 (39) Overall Menopausal status Phenotype Neoadjuvant v adjuvant treatment Chemotherapy regimen Nodal status Region Premenopausal Postmenopausal Basal Nonbasal Neoadjuvant Adjuvant Anthracyclines without taxanes Anthracyclines and taxanes Negative nodes 1-3 positive nodes 4 or more positive nodes Spain Latin America 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 Lluch et al Downloaded from ascopubs.org by 150.214.182.238 on April 18, 2023 from 150.214.182.238 Copyright © 2023 American Society of Clinical Oncology. All rights reserved. nodes. Demographics and baseline disease characteristics according to basal versus nonbasal phenotype are included in Table 3. Safety Safety was assessed in 861 patients of the study population: 436 patients (97.3%) in the capecitabine arm and 425 patients (99.3%) in the observation arm. AEs were reported in 95.4% (n = 416) of patients in the capecitabine arm and 63.8% (n = 271) in the observation arm (Table 4). In addition, 40.6% (n = 177) and 15.5% (n = 66) of patients had AEs of grade 3 or greater in the capecitabine and observation arms, respectively. With capecitabine, 92.4% (n = 403) of patients had AEs related to study treatment, and in 30% (n = 131) of patients these AEs were of grade 3 or greater. Patients who experienced at least one SAE were 5.3% (n = 23) in the capecitabine arm and 1.4% (n = 6) in the observation arm. In addition, there were a few patients with SAEs that caused death: 1.1% (n = 5) in the capecitabine arm and 0.5% (n = 2) in the observation arm. Two deaths in the capecitabine arm were probably related to study treatment according to investigator’s criteria. These SAEs included one case of septic shock in the absence of neutropenia and one case of grade 4 hyperbilirubinemia and systemic organ failure. DISCUSSION Our study failed to show a statistically significant improvement in DFS by adding 8 cycles of extended capecitabine to standard (neo)adjuvant chemotherapy for operable TNBC after a median follow-up of more than 7 years. Adjusted HR, considering the stratification factors, was 0.79 (P= .082); therefore, the study was formally negative in accordance with the statistical assumption made when the trial was designed. The role of capecitabine in combination with other drugs as adjuvant therapy of TABLE 2. Disease-Free Survival Events in Overall Population (intention to treat) and Nonbasal Phenotype Subpopulation Variable Overall Population, No. (%) Nonbasal Population, No. (%) 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 mastectomy) 0.0 4.0 (0.9) 0.0 2.0 (1.8) 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. Journal of Clinical Oncology 209 Extended Capecitabine in Early Triple-Negative Breast Cancer Downloaded from ascopubs.org by 150.214.182.238 on April 18, 2023 from 150.214.182.238 Copyright © 2023 American Society of Clinical Oncology. All rights reserved. operable breast cancer is still unclear. 5-7 As a single agent, adjuvant capecitabine was inferior to standard adjuvant therapy—either cyclophosphamide, methotrexate, fluorouracil; or doxorubicin plus cyclophosphamide—in patients with breast cancer age 65 years or older. 8 A recent metaanalysis of (neo)adjuvant capecitabine trials, including 8 trials and 9,302 patients, found that globally, capecitabine did not improve DFS 9 ; however, in trials in which capecitabine was added to standard adjuvant chemotherapy (in contrast to those trials in which capecitabine replaced standard agents), a significant DFS advantage was found. Of note, in this meta-analysis the benefit of adding capecitabine to standard chemotherapy was mainly observed in patients with TNBC. The GEICAM-CIBOMA study added sequential capecitabine to standard (neo)adjuvant chemotherapy in patients with operable TNBC but was unable to show a statistically significant improvement in DFS in the overall population. The results of our study were therefore TABLE 3. Patients’Demographics and Baseline Disease Characteristics According to Basal Versus Nonbasal Phenotype (intention-to-treat population) Demographic or Characteristic Capecitabine, No. (%) Observation, No. (%) Basal a Phenotype (n = 329) Nonbasal a Phenotype (n = 119) Basal a Phenotype (n = 318) Nonbasal a Phenotype (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 (6adjuvant) 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 pCR in patients with neoadjuvant chemotherapy b 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. 210 © 2019 by American Society of Clinical Oncology Volume 38, Issue 3 Lluch et al Downloaded from ascopubs.org by 150.214.182.238 on April 18, 2023 from 150.214.182.238 Copyright © 2023 American Society of Clinical Oncology. All rights reserved. apparently different from those of the meta-analysis and, in particular, from those of the the Capecitabine for Residual Cancer as Adjuvant Therapy (CREATE-X) trial, 10 which addressed a similar question but in a population at higher risk of relapse. The CREATE-X trial randomly assigned patients with breast cancer with residual disease at surgery after standard neoadjuvant chemotherapy to 6 to 8 cycles of capecitabine versus observation—plus hormone therapy in both arms for patients with hormone receptor–positive tumors—and found a statistically significant increase in DFS and OS with capecitabine. The effect was particularly remarkable in TNBC. Compared with our trial, the populations in both studies were significantly different, as Asian patients had a significantly higher risk of relapse, as shown by the 56.1% 5-year DFS for patients with TNBC in the control arm of the CREATE-X trial. In contrast, DFS in the control arm in our trial was better than expected: DFS at 5 years was 76.8%, while our statistical hypothesis assumed a 5-year DFS of 64.7% on the basis of historical controls. Moreover, the selection criteria in the CREATE-X trial limited to patients with residual disease after neoadjuvant treatment suggest that capecitabine could have a more relevant role in patients with tumors that are less sensitive or partially resistant to regimens containing anthracyclines and taxanes. The DFS events in our trial were numerically higher in the control group (n = 120) than in the capecitabine group (n = 105), arguably because of the apparent efficacy of capecitabine in a predefined subgroup of patients—being astratification factor as well—with nonbasal phenotype, as defined by central immunohistochemistry (lack of staining for epidermal growth factor receptor and cytokeratins 5/6). In these patients, both DFS and OS were statistically superior with capecitabine. TNBC is a heterogeneous disease that encompasses a wide spectrum of clinical and molecular subtypes with different sensitivity to standard therapies, 11 The results in the nonbasal subgroup suggest that the activity of TABLE 4. Safety Profile According to Study Arm (safety population) AEs Based on NCI-CTCAE v3.0 (AEs reported in ‡5% globally) Capecitabine Arm (n = 436), No. (%) Observation Arm (n = 425), No. (%) 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. Journal of Clinical Oncology 211 Extended Capecitabine in Early Triple-Negative Breast Cancer Downloaded from ascopubs.org by 150.214.182.238 on April 18, 2023 from 150.214.182.238 Copyright © 2023 American Society of Clinical Oncology. All rights reserved.