B-W Park

Abstract S1-07: 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)

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 center9s 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 (O9Brein-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. Citation Format: Toi M, Lee S-J, Lee ES, Ohtani S, Im Y-H, Im S-A, Park B-W, Kim S-B, Yanagita Y, Takao S, Ohno S, Aogi K, Iwata H, Kim A, Sasano H, Yokota I, Ohashi Y, Masuda N. 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). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr S1-07.

Abstract P3-12-03: Adjuvant capecitabine in breast cancer patients with pathologic residual disease after neoadjuvant chemotherapy: First safety analysis of CREATE-X (JBCRG-04)

Background Patients (pts) without pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC) have a poor prognosis compared with pts achieving a pCR with NAC. It is not clear whether further systemic chemotherapy is beneficial for pts with no pCR. CREATE-X (UMIN000000843) is an ongoing collaborative Korean (KRN)/Japanese (JPN) prospective multicenter open-label randomized phase III trial evaluating this clinical question using capecitabine (X) in pts with no pCR after NAC. We report first safety results, focusing on hand-foot syndrome (HFS), the timing of radiotherapy (RT) and hormone therapy (HT), and differences between KRN and JPN pts. Methods Pts with residual invasive cancer after anthracycline- and/or taxane-containing NAC were randomized to standard post-surgical treatment (RT, HT as appropriate) with or without 8 cycles of X (1250 mg/m2 bid, days 1–14 q3w). RT was given before or after X. Pts with hormone receptor (HR)-positive disease received HT either with or after X, according to each center9s prespecified standard practice. After evaluation of the tolerability of 6 cycles of X in the first 50 pts, the independent data monitoring committee recommended extending X to 8 cycles. Results Between Feb 2007 and Jul 2012, 910 pts were enrolled (304 in Korea, 606 in Japan). At the time of data cut-off (May 20, 2013), data were available from 866 pts. Median age was 48 years in both arms. In the investigational arm, RT was given before X in 260 pts and after X in 33 pts; 73 pts received prophylactic vitamin B6 (VB6). In HR-positive pts HT was given with X in 200 pts and after X in 24 pts. The relative dose intensity of X was 85.7% in JPN pts and 95.2% in KRN pts. Grade (G) 3/4 neutropenia, HFS (G3 only), fatigue, and diarrhea were significantly (p Conclusions Addition of 8 cycles of X to standard adjuvant therapy is feasible and tolerable, resulting in a modest yet acceptable increase in toxicities. The timing of RT and HT administration relative to X influenced the incidence of adverse events. HFS was more common in JPN than KRN pts, although further investigation of the potential cause of this difference is required. These findings should be interpreted in light of efficacy data, expected in 2015. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-12-03.

Abstract P2-05-03: Mouse double minute 2 nuclear expression as a prognostic marker in patients with breast cancer

BACKGROUND: Mouse double minute 2 (Mdm2) is a negative regulator of tumor suppressor, p53, thus Mdm2 expression may play a role in cancer development and prognosis, however, the definite role of Mdm2 in breast cancer is unclear. The aim of the study is to evaluate the correlation between Mdm2 expression and prognosis of breast cancer. METHODS: Mdm2 expression was determined from immunohistochemistry of tissue microarrays of 865 patients with breast cancer who underwent surgery. Clinicopathologic characteristics and survival data were analyzed using a univariate and multivariate analysis. Mdm2 expression was categorized into 3 groups: negative; no Mdm2 expression in nucleus and cytoplasm, cytoplasm-positive; cytoplasmic expression of Mdm2, nucleus-positive; nuclear with or without cytoplastimc expression of Mdm2. RESULTS: Negative, cytoplasm-positive, and nucleus-positive groups were observed in 59.2%, 10.9%, and 29.9% of patients, respectively. Nucleus-positive group was associated with young age, high grade, negativity of estrogen and progesterone receptor, HER2 positivity, and high Ki-67 index. With median 86.0 follow-up months, nucleus-positive group showed poorer disease-free survival and overall survival than negative and cytoplasm-positive groups. In multivariate analysis, cytoplsmic expression of Mdm2 was not significantly associated with survival, whereas nuclear expression of Mdm2 was related to poor prognosis. (HR, 1.44; 95% CI, 1.041–1.993 for DFS; HR, 1.546; 95% CI, 1.060–2.255 for OS) CONCLUSIONS: Nuclear expression of Mdm2 was an independent prognostic factor in patients with breast cancer. Patterns of Mdm2 expression in tumor cell should be rendered in the evaluation of Mdm2 in breast cancer. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-05-03.

P3-14-18: Primary Tumor Response to Neoadjuvant Chemotherapy Is Significantly Associated with Nodal Pathological Complete Response in Breast Cancer Patients with Cytologically Proven Axillary Node Metastasis.

Background: Axillary node status is the most significant factor for the prediction of outcome in breast cancer patients whether they received neoadjuvant chemotherapy or not. However, a reliable method to predict nodal response to neoadjuvant chemotherapy is not established yet. The aim of this study was to identify the predictive factors of axillary pathological complete response (pCR) after neoadjuvant chemotherapy in breast cancer patients with cytologically proven axillary lymph node metastases. Patients and methods: A total of 123 patients with axillary metastases confirmed by ultrasound-guided fine-needle aspiration biopsy were subsequently treated with four cycles of anthracycline (60mg/m2) plus cyclophosphamide (600mg/m2) followed by doxetaxel (75-100mg/m2) between August 2008 and March 2011. After neoadjuvant chemotherapy, all patients underwent a definite breast surgery with complete axillary lymph node dissection. Clinicopathological parameters were evaluated using a chi-square test and logistic regression model in association with node pCR. Results: The mean age at diagnosis was 47.9 years in all patients. Eighty-one (65.9%) patients were preoperative clinical T2 stage, 74 (60.2%) showed estrogen receptor (ER)-positivity, and 36 (29.3%) demonstrated HER2−positivity. A pCR of the axilla and breast was determined in 56 (46%) and 40 (31.7%) patients, respectively. Breast Pcr rate is significantly associated with age≤50 at diagnosis, ER(−),PR(−) and higher Ki-67 proliferation. Axillary pCR rate is significantly associated with age at diagnosis of 50 or less, smaller primary tumor size at diagnosis, tumor responsiveness to neoadjuvant chemotherapy, estrogen hormone receptors-negativity, higher Ki-67 proliferative index at diagnosis, and subtypes of HER2−enriched or triple negative breast cancer. When these factors entered logistic regression model, tumor response( SD+PD vs CR+PR: OR 8.603, P=0.007), Ki67((−) vs (+): OR 7.157, p=0.009), ER status((+) vs (−) : OR 4.943, P=0.036), pre-operation tumor size(>2cm vs ≤2cm: OR 5.116, p=0.044), HER2 status( (−) vs (+): OR 5.029,p=0.046) remained to be significant for the prediction of axillary pCR, favorable nodal response. Conclusion: Our study suggests that primary tumor response to neoadjuvant chemotherapy is significantly associated with favorable nodal response. The factors of tumor and nodal response were similar. There are many issues remained to be determined yet. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-14-18.

Abstract P3-10-03: The Implication of Androgen Receptor Expression in Breast Cancers

Purpose: To evaluate the implication of androgen receptor (AR) expression in patients with breast cancer. Methods: Immunohistochemically AR expression was investigated in 931 invasive breast cancers prepared in tissue microarray blocks that were collected in between November 1999 and August 2005. The clinicopathological features, disease-free (DFS) and overall survival (OS) were analyzed using chi-square test, Kaplan-Meier methods, and Cox9s models. Tumors with ≥10% nuclear-stained cells were considered to be positive for AR, estrogen receptor (ER), and progesterone receptor (PR) expression and 3+ with immunohistochemical staing or FISH + were considered positive for HER2 expression. Results: The positive expression of AR, ER, PR, and HER2 was 58.1%, 72.2%, 61.4%, and 24.7% of all patients, respectively. AR expression was significantly associated with an older age at diagnosis (p=0.007), smaller tumor size (P Conclusions: AR expression is significantly associated with favorable clinicopathological features and better outcomes in ER-positive cancers but tumors with molecular apocrine features showed a trend of poorer outcome with AR expression. These results suggest that AR expression could be an additional marker for endocrine responsiveness in ER-positive tumors and a target molecule for the molecular apocrine tumors. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-10-03.

Abstract P3-10-11: Clinical Significance of Progesterone Receptor and HER2 Status in Estrogen Receptor-Positive, Operable Breast Cancer with Adjuvant Tamoxifen: Consistent Prognostic Impact of HER2 Status Over Time

Purpose: To evaluate prognostic factors in estrogen receptor (ER)-positive, operable breast cancer, focusing on the progesterone receptor (PR) and HER2 over time. Patients and Methods: A total of 819 patients with ER-positive, operable breast cancer were enrolled. All received adjuvant tamoxifen. Prognostic value of the PR status and HER2 status was evaluated using Cox regression before and after 5 years post-surgery. Results: PR and HER2 status were inversely correlated (P = .014). PR-negativity was a time-dependent poor prognostic factor for recurrence before 5 years post-surgery (P = .049), but not after 5 years post-surgery (P = .566). However, HER2 overexpression and younger age (35 years or less) were consistent prognostic factors for recurrence over all time periods, whereas N stage and histologic grade, which are known prognostic factors, were no longer informative after 5 years post-surgery, except for N3 disease. Conclusion: In ER-positive, operable breast cancer, the prognostic impact of PR status along with N stage and histologic grade were strong for the first 5 years post-surgery, but disappeared thereafter. However, HER2 overexpression was a consistent poor prognostic factor, suggesting that an alternative adjuvant strategy, possibly involving incorporation of prolonged HER2-targeted therapy should be evaluated for HER2-overexpressing tumors. Figure available in online version. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-10-11.