News Release

Capecitabine improved outcomes for breast cancer patients with disease after presurgery chemo

Peer-Reviewed Publication

American Association for Cancer Research

SAN ANTONIO -- Treatment with the chemotherapy agent capecitabine increased disease-free survival for women with HER2-negative breast cancer that was not eliminated by presurgery chemotherapy, according to results from the phase III CREATE-X clinical trial presented at the 2015 San Antonio Breast Cancer Symposium, held Dec. 8-12.

Treatment given to shrink or eliminate a tumor before surgery is called neoadjuvant therapy. In some patients with breast cancer treated with neoadjuvant chemotherapy, residual invasive cancer can be detected in breast tissue samples and lymph nodes removed during surgery. These patients tend to have worse long-term outcomes compared with women who respond completely to neoadjuvant therapy.

"It has been suggested that patients with residual invasive disease after neoadjuvant chemotherapy have chemoresistant breast cancer, but there have been no large-scale clinical trials to test whether adjuvant systemic chemotherapy is beneficial for these patients," said Masakazu Toi, MD, PhD, a professor at Kyoto University Hospital in Japan, and founder and senior director of the Japan Breast Cancer Research Group (JBCRG). "CREATE-X was designed to evaluate this clinical question by testing whether capecitabine could improve disease-free survival for patients with residual invasive disease after neoadjuvant chemotherapy.

"These first efficacy results show that after two years of follow-up, disease-free survival is significantly improved by addition of capecitabine to standard therapy," continued Toi. "These data are exciting, because the side effects of the treatment were manageable and the benefit of capecitabine treatment was clear."

Toi and colleagues enrolled 910 patients in the trial all of whom had HER2-negative breast cancer and residual invasive disease after neoadjuvant therapy that included an anthracycline and/or a taxane. All patients received standard treatment and were randomly assigned to capecitabine or no additional therapy. The 455 patients randomly assigned capecitabine received eight cycles, each lasting 21 days, with 1,250 milligrams of the chemotherapeutic per meter squared twice a day for the first 14 days, followed by seven days with no treatment.

The researchers found that, two years after starting the study, patients who were assigned capecitabine had a 30 percent reduced risk of disease recurrence compared with those assigned no capecitabine. Disease-free survival was 87.2 percent for those assigned capecitabine and 80.4 percent for those assigned no capecitabine.

According to Toi, a recent analysis with updates showed that there was a significant difference in median overall survival between the two groups. Two-year median overall survival was 96.4 percent for those assigned capecitabine versus 94.2 percent for those assigned no capecitabine.

Toi also noted that the researchers are conducting subset analyses to determine whether certain groups of patients benefited more than others from capecitabine. For example, they are looking at whether hormone-receptor status affected outcomes, he said.


This study was supported by a grant from Specified Nonprofit Corporation - Advanced Clinical Research Organization (ACRO) and other donations to JBCRG. Toi receives a research grant from Chugai Pharmaceutical Company.

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The mission of the 2015 San Antonio Breast Cancer Symposium is to produce a unique and comprehensive scientific meeting that encompasses the full spectrum of breast cancer research, facilitating the rapid translation of new knowledge into better care for patients with breast cancer. The Cancer Therapy & Research Center (CTRC) at The University of Texas Health Science Center at San Antonio, the American Association for Cancer Research (AACR), and Baylor College of Medicine are joint sponsors of the San Antonio Breast Cancer Symposium. This collaboration utilizes the clinical strengths of the CTRC and Baylor and the AACR's scientific prestige in basic, translational, and clinical cancer research to expedite the delivery of the latest scientific advances to the clinic. For more information about the symposium, please visit

Abstract: S1-07

Title: A phase III trial of adjuvant capecitabine in breast cancer patients with HER2-negative pathologic residual invasive disease after neoadjuvant chemotherapy (CREATE-X, JBCRG-04)

Authors: Soo-Jung Lee1, Masakazu Toi2, Eun Sook Lee3, Shoichiro Ohtani4, Young-Hyuck Im5, Seock-Ah Im6, Byeong-Woo Park7, Sung-Bae Kim8, Yasuhiro Yanagita9, Shintaro Takao10, Shinji Ohno1, Kenjiro Aogi12, Hiroji Iwata13, Aeree Kim14, Hironobu Sasano15, Isao Yokota16, Yasuo Ohashi18 and Norikazu Masuda18. 1Yeungnam University Hospital, Daegu, Korea; 2Kyoto University Hospital, Kyoto, Japan; 3National Cancer Center, Seoul, Korea; 4Hiroshima City Hospital, Hiroshima City, Hiroshima, Japan; 5Samsung Medical Center, Seoul, Korea; 6Seoul National University Hospital, Seoul, Korea; 7Severance Hospital, Yonsei University College of Medicine, Seoul, Korea; 8Asan Medical Center, Seoul, Korea; 9Gunma Prefectural Cancer Center, Ota, Gunma, Japan; 10Hyogo Cancer Center, Akashi, Hyogo, Japan; 11National Kyusyu Cancer Center, Fukuoka, Japan; 12NHO Shikoku Cancer Center, Matsuyama, Ehime, Japan; 13Aichi Cancer Center, Nagoya, Aichi, Japan; 14Korea University Guro Hospital, Seoul, Korea; 15Tohoku University, Sendai, Miyagi, Japan; 16Kyoto Prefectural University of Medicine, Kyoto, Japan; 17Chuo University, Tokyo, Japan and 18NHO Osaka National Hospital, Osaka, Japan.


Background: Patients (pts) with pathologic residual invasive disease after neoadjuvant chemotherapy (NAC) have an intermediate or high-risk for relapse. It is not clear whether further systemic chemotherapy is beneficial for these pts. CREATE-X is a multicenter open-label randomized phase III trial evaluating this major clinical issue using capecitabine (X) in pts without pCR after NAC (UMIN000000843). We have shown previously that the addition of 8 cycles of X to standard adjuvant therapy is feasible and well tolerated (Ohtani S, et al. SABCS2013#P3-12-03). We report the first efficacy results from a pre-planned interim analysis after 2-year follow-up.

Methods: Pts with HER2-negative residual invasive cancer after anthracycline- and/or taxane-containing NAC were randomized to standard treatment (RT, hormone therapy (HT) as appropriate) with or without 8 cycles of X (1250 mg/m2 bid, days1-14,q3w). Pts with hormone receptor (HR)-positive disease received HT either with or after X, according to each center's prespecified standard practice. The primary endpoint was disease-free survival (DFS). Secondary endpoints included overall survival (OS), safety, and cost-effectiveness. It was originally planned to enroll 450 pts in each arm in order to detect a HR 0.74 improvement in the X arm with 80% power and a two-sided 5% significance level. We planned one interim analysis of DFS at 2-years after all pts enrolled using Lan-DeMets alpha spending function method (O'Brein-Fleming type).

Results: Between Feb 2007 and Jul 2012, 910 pts were randomized, with 455 pts to receive X. The full analysis consisted of 902 pts who matched the inclusion criteria. Baseline characteristics were well balanced. The median age was 48 years in both arms; 63.5% were HR-positive. In the investigational arm, HT was given with X concurrently in 200 pts and after X in 24 pts. The relative dose intensity of X was 78.8%. At the time of the interim analysis, DFS events were confirmed in 81 (18.8%) in the investigational arm and 109 (24.7%) in the standard arm, and OS events were 28 (6.5%) and 41 (9.3%), respectively. On Kaplan-Meier analysis, 2-year DFS was 87.3% for the arm with X and 80.5% for no X (HR:0.688, 98.66%CI: 0.479-0.989, log-rank P=0.001). The tendency for improvement of OS by adding X was also confirmed; 2-year OS was 96.2% and 93.9%, respectively (HR: 0.658, 95%CI: 0.407-1.065, log-rank P=0.086). In the experimental arm with X, grade 3/4 toxicities included HFS (11%), neutropenia (9%), diarrhea (3%), and fatigue (1%); all were controllable. No SAE was related to X administration. Because the study met the primary endpoint, an independent data monitoring committee recommended discontinuation of the study.

Conclusions: The clinical utility of X in the adjuvant setting for breast cancer pts has been proven to improve the prognosis based on the pathological response-guided strategy. Tolerability was consistent with the established safety profile of X in mBC. The benefit to risk balance of the addition of 8 cycles of X to standard adjuvant therapy seems to be satisfied. This evidence might allow the development of personalized individualized treatment based on the response to primary systemic therapy.

This research will be presented at a press conference at the 2015 San Antonio Breast Cancer Symposium, moderated by SABCS Co-director Virginia Kaklamani, MD, leader of the Breast Cancer Program at the Cancer Therapy & Research Center and professor of medicine at the UT Health Science Center San Antonio, Wednesday, Dec. 9, 7:30 a.m. CT in Room 217D of the Henry B. Gonzalez Convention Center. Reporters who cannot attend the press conference in person can call in using the following information:

  • United States/Canada (toll-free): 866-297-6395
  • International (toll): 1-847-944-7317
  • Conference code number: 41320575

To interview Masakazu Toi, contact Julia Gunther at or 267-250-5441.

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