M Miyashita

Randomized Controlled Trial of Zoledronic Acid plus Chemotherapy versus Chemotherapy Alone as Neoadjuvant Treatment of HER2-Negative Primary Breast Cancer (JONIE Study)

Purpose Zoledronic acid (ZOL) is a nitrogen-containing bisphosphonate that induces osteoclast apoptosis and inhibits bone resorption by inhibiting the mevalonate pathway. Its benefit for the prevention of skeletal complications due to bone metastases has been established. However, the antitumor efficacy of ZOL, although suggested by multiple preclinical and clinical studies, has not yet been clinically proven. We performed the present randomized Phase 2 trial to investigate the antitumor effect of ZOL with chemotherapy (CT). Methods Asian patients with HER2-negative invasive breast cancer were randomly assigned to either the CT or CT+ZOL (CTZ) group. One hundred and eighty-eight patients were randomized to either the CT group (n = 95) or the CTZ group (n = 93) from March 2010 to April 2012, and 180 patients were assessed. All patients received four cycles of FEC100 (fluorouracil 500 mg/m2, epirubicin 100 mg/m2, and cyclophosphamide 500 mg/m2), followed by 12 cycles of paclitaxel at 80 mg/m2 weekly. ZOL (4 mg) was administered three to four times weekly for 7 weeks to the patients in the CTZ group. The primary endpoint was the pathological complete response (pCR) rate, which was defined as no invasive cancer in the breast tissue specimen. Safety was assessed in all patients who received at least one dose of the study drug. Results This randomized controlled trial indicated that the rates of pCR in CTZ group (14.8%) was doubled to CT group (7.7%), respectively (one-sided chi-square test, p = 0.068), though the additional efficacy of zoledronic acid was not demonstrated statistically. The pCR rate in postmenopausal patients was 18.4% and 5.1% in the CTZ and CT groups, respectively (one-sided Fisher’s exact test, p = 0.071), and that in patients with triple-negative breast cancer was 35.3% and 11.8% in the CTZ and CT groups, respectively (one-sided Fisher’s exact test, p = 0.112). Thus the addition of ZOL to neoadjuvant CT has potential anticancer benefits in postmenopausal patients and patients with triple-negative breast cancer. Further investigation is warranted. Trial Registration University Hospital Medical Information Network. UMIN000003261.

Low dose capecitabine plus weekly paclitaxel in patients with metastatic breast cancer: a multicenter phase II study KBCSG-0609

PurposeThe combination of capecitabine and paclitaxel (XP) has demonstrated synergistic antitumor activity in preclinical models. The purpose of this phase II study was to evaluate the efficacy and safety of a monthly XP regimen in patients with metastatic breast cancer (MBC).MethodsEligible patients had received one or fewer prior chemotherapy regimens for MBC. Patients received oral capecitabine of low dose (828 mg/m2 twice daily, days 1–21) plus paclitaxel (80 mg/m2, i.v., over 60 min, days 1, 8 and 15) every 28 days until disease progression or unacceptable toxicity. The primary endpoint was overall response rate (ORR). Progression-free survival (PFS), overall survival (OS) and safety were secondary endpoints. An exploratory analysis of efficacy according to hormone receptor (HR) status was performed.ResultsForty-four patients were enrolled, and 43 patients were evaluable. ORR was 46.5 %. PFS and OS were 8.3 and 22.9 months, respectively. ORR was 45.5 % in patients with HR-positive tumors and 50 % in HR-negative cases. The most frequently observed grade 3/4 adverse events were neutropenia (27.9 %), leukopenia (11.6 %), hand-foot syndrome (HFS, 9.3 %) and fatigue (7.0 %). There were no discontinuations due to HFS.ConclusionsMonthly XP was an effective and well-tolerated regimen for the first- or second-line treatment for MBC.

Abstract PD3-7: Disease-free survival and Ki67 analysis of a randomized controlled trial comparing zoledronic acid plus chemotherapy with chemotherapy alone as a neoadjuvant treatment in patients with HER2-negative primary breast cancer (JONIE-1 study)

Background : Zoledronic acid (ZOL) has been found to have a synergistic anti-proliferative effect when used in combination with antitumor drugs. We suggested that the addition of ZOL to neoadjuvant chemotherapy (CT) has potential anti-cancer benefit in postmenopausal patients with triple-negative breast cancer in JONIE-1 Trial (50% pCR rate in ZOL+CT: CTZ versus 0% in CT, p = 0.029). We analyzed the disease-free survival (DFS) as a secondary endpoint and baseline Ki67 levels between two groups. Methods : Women with Stage IIA-IIIB HER-2-negative breast cancer were randomly assigned 1:1 to CTZ group or CT group, CT was FEC100 q3w × 4 cycles followed by weekly paclitaxel for 12 cycles and ZOL 4mg was administered every 3-4 weeks. Among 188 patients recruited between March 2010 and April 2012 excluding 10 from the primary assessment, 178 patients were assessed. The aims of this study were to compare the relative efficacy or CTZ with the efficacy of CT in prolonging DFS in all patients and also to compare the pCR rates between baseline Ki67 high (20% and >20%) with Ki67 low ( Results : During a mean follow-up period of 34.4 months, breast cancer specific events (recurrence and death) occurred 17 participants, 7 in CTZ group and 10 in CT group. The 1-year, 2-year, and 3-year DFS rates were 97.7%, 88.4%, and 88.4% in CTZ versus 100%, 84.8%, and 81.1% in CT, respectively. In the ER positive cohort studied for Ki67 consist of 109 patients, 40 were in Ki67 low group and 69 were in Ki67 high group. Among Ki67 low group, number of pCR was none out of 18 in CTZ and 1 out of 22 in CT ( p = .550). Among Ki high group, that was 6 out of 38 in CTZ and 3 out of 31 ( p = .352). Conclusion : We could not find a modest improvement in disease-free survival compared the addition of ZOL to neoadjuvant CT with CT alone. Ki67 study for central analysis has been under investigation. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr PD3-7.

Abstract P1-13-07: Chemotherapy, but not body mass index has impact on joint symptoms in postmenopausal Japanese breast cancer patients treated with anastrozole: A prospective multicenter cohort study of patient-reported outcomes

Background: Endocrine treatment-related adverse events have a strong impact on patients’ quality of life and sometimes result in treatment discontinuation. Since joint symptoms are the most frequently recognized side-effect of aromatase inhibitors, evaluation of associated risk factors may well be important. Among high body mass index (BMI) and chemotherapy have been associated with the development of joint symptoms in patients enrolled in ATAC trials. To determine the impact of these factors on treatment-emergent joint symptoms in Japanese breast cancer treated with adjuvant anastrozole, we conducted a prospective cohort study based on patient-reported outcomes (PROs). Patients and Methods: Postmenopausal Japanese women with estrogen receptor-positive breast cancer and treated with adjuvant anastrozole were enrolled in this prospective cohort study (SAVS-JP, UMIN000002455). A total of 416 patients were recruited from 30 centers for PRO assessment at their after-care appointments between August 2009 and April 2012. Patients completed the self-report questionnaire at baseline, 3, 6, 9 and 12 months. Symptoms were assessed as four categories (none, Grade 1: somewhat, Grade 2: quite a bit, Grade 3: very much). Pre-existing symptoms were only included if they worsened from baseline. The endpoint of this study was the frequencies of treatment-related joint symptoms, which included reports of arthralgia, decrease of joint motion, and joint stiffness. Results: We obtained PROs from 391 (94.0%) of the 416 patients at baseline and at one or more points during treatment, so that 391 patients were analysed. Joint symptoms at baseline were reported by 134 (34.3%) patients and new or worsening symptoms were experienced by 258 (66.0%) patients. The symptoms were graded as: grade 1, 53.1%; grade 2, 37.6%; grade 3, 9.3%. Mean time to onset of joint symptoms was 5.4 months, and nearly 80% had developed symptoms by 6 months. Twelve patents discontinued treatment during the first year and two patients withdrew due to joint symptoms. Patients with joint symptoms were significantly younger (age: 63.1; standard deviation: 7.9) than those without symptoms (age: 65.8: 8.4; p = 0.0045). We categorized BMI into three groups (low: Discussion: The incidence of anastrozole-associated joint symptoms was more than 60%, with most women having developed symptoms by 6 months. The PROs may disclose higher prevalence rates than physician ratings for symptoms published in pivotal clinical trials. We found that younger age and adjuvant chemotherapy, but not high BMI, were significantly associated with joint symptoms. These data should prove useful for counseling before initiating treatment with adjuvant aromatase inhibitors for postmenopausal Japanese women. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-13-07.

Abstract P3-07-50: Early and accurate prediction of pathological response by magnetic resonance imaging and ultrasonography in patients undergoing neoadjuvant chemotherapy for operable breast cancer

Background: Neoadjuvant chemotherapy (NAC) reduces tumor size, and increases the frequency of breast-conserving surgery in operable breast cancers. Response predictions to NAC are made based on diagnostic imaging. Although various studies have reported the optimal timing for diagnostic imaging, this still remains unclear. Purpose: To identify the optimal timing of diagnostic imaging for the response prediction to NAC, and to evaluate the accuracy of response prediction. Methods: We evaluated 146 cases enrolled in the JONIE-1 study (a randomized controlled trial comparing zoledronic acid plus chemotherapy with chemotherapy alone as a NAC in patients with HER2-negative primary breast cancer). The chemotherapy regimen was FEC100×4 courses followed by weekly paclitaxel 80×12 courses (± zoledronic acid). Statistical analysis of the association between the tumor reduction ratio and the histopathological response and the prediction of pathological complete response (pCR) was performed using JMP software. The maximum tumor diameter was evaluated using magnetic resonance imaging and ultrasound on each patient 3 times (before NAC, after FEC treatment, after NAC) and tumor reduction ratios were calculated. Results: The average age of the patients was 49.8 years old. The menopause status was pre-menopause in 84 patients, and post-menopause in 58 patients. Regarding the subtype classification, 116 patients were of the luminal type (Lum) and 26 patients were triple negative (TN), and the Ki-67 labeling index had a median of 25% (1%-93%). Pathological examination demonstrated that 16 patients had pCR(11.3%, Lum, 9;TN: 7), and 126 patients had non-pCR (88.7%, Lum:107; TN:19). Seven patients had clinical-CR (4.8%, Lum: 4; TN: 3) at post-FEC, and 26 patients (17.8%, Lum: 20; TN: 6) at post-NAC. The prediction of pCR at post-FEC and post-NAC was evaluated by single variable analysis, resulting in an AUC (0.75645) p=0.0017 at post-FEC, and AUC (0.76563) p=0.0001 at post-NAC. The sensitivity / specificity / positive predictive value / negative predictive value were 0.625 / 0.873 / 0.385 / 0.948 at post-FEC, 0.250 / 0.976 / 0.571 / 0.911 at post-NAC, respectively. In TN cases, the values were 0.714 / 0.947 / 0.833 / 0.900 in post-FEC, and 0.429 / 1.000 / 1.000 / 0.826 in post-NAC. Conclusions: Diagnostic imaging evaluation performed after FEC treatment was useful for the prediction of pCR. Furthermore, the reliability was high in Triple Negative Sub type, but is affected by the existence of residual tumors in Luminal type. Citation Format: Kaise H, Ishikawa T, Miura D, Hasegawa Y, Horiguchi J, Hayashi M, Takao S, Kim SJ, Tanino H, Miyashita M, Konishi M, Shigeoka Y, Yamagami K, Suzuki M, Taguchi T, Akazawa K, Kohno N. Early and accurate prediction of pathological response by magnetic resonance imaging and ultrasonography in patients undergoing neoadjuvant chemotherapy for operable breast cancer. [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 P3-07-50.

Abstract P1-12-04: Factors influencing on discontinuation of adjuvant anastrozole in postmenopausal Japanese breast cancer patients: Results from a prospective multicenter cohort study of patient-reported outcomes

Background: Adjuvant five-year treatment with aromatase inhibitors is standard for postmenopausal women with estrogen receptor positive breast cancer. However, aromatase inhibitor-related adverse events including joint symptoms and vasomotor symptoms have a strong impact on patients9 quality of life and sometimes result in treatment discontinuation. The aim of this study is to determine risk factors for discontinuation of endocrine therapy in Japanese postmenopausal breast cancer patients treated with adjuvant anastrozole in a prospective cohort study based on patient-reported outcomes (PROs). Patients and Methods: A total of 391 postmenopausal Japanese women with estrogen receptor-positive breast cancer and treated with adjuvant anastrozole were enrolled from 28 centers in this prospective cohort study (SAVS-JP, UMIN000002455). PROs assessment was obtained at baseline, 3, 6, 9 and 12 months which included joint and vasomotor symptoms. Long-term adherence of anastrozole was obtained form 364 out of 391 patients (median follow-up: 44 months, range: 5-105months). We analyzed the relationship of discontinuation of anastrozole with joint and vasomotor symptoms induced by treatment, and patients’ characteristics. Results: Among 364 patients, 64 (17.6%) discontinued, 297 (81.6%) are ongoing and 3 (0.8%) have completed five-year anastrozole treatment. The reasons for discontinuation were recurrence: 20 (31.3%), secondary malignancies: 5 (7.8%), death from non-breast cancer: 1 (1.6%) and adverse events: 38 (59.4%). These 38 patients who stopped treatment caused by adverse events were compared with other 323 patients. Joint and vasomotor symptoms were categorized into grade 0 (no symptom or no change from baseline), grade 1+2 (mild+moderate) and grade 3 (severe). Grades of joint symptoms were significantly associated with discontinuation of anastrozole (Grade 0: 9.7%, grade 1+2: 7.8%, grade 3: 25.0%, p=0.02). Patients with longer time after menopause (16 years or longer) were significantly higher frequency of discontinuation as compared with shorter time after menopause (0-15years) (14.9% vs 8.0%, p=0.04). Univariate analysis revealed that grade 3 joint symptoms (odds ratio: 3.67, 95% confidence interval: 1.34-10.04, p=0.01) and longer time after menopause (OR: 2.01, 95%CI: 1.01-4.00, p=0.04) were significant risk factors for discontinuation. By multivariate analysis, both grade 3 joint symptoms and long time after menopause were independently associated with discontinuation. Conclusion: In the present study, we have identified that grade 3 joint symptoms and longer time after menopause were risk factors for discontinuation of adjuvant anastrozole. These data might give us useful information for counseling in patients with adjuvant aromatase inhibitors for postmenopausal Japanese women. Citation Format: Chiyomi Egawa, Shintaro Takao, Kazuhiko Yamagami, Masaru Miyashita, Masashi Baba, Shigetoshi Ichii, Muneharu Konishi, Yuichiro Kikawa, Junya Minohata, Toshitaka Okuno, Keisuke Miyauchi, Kazuyuki Wakita, Hirofumi Suwa, Takashi Hashimoto, Masayuki Nishino, Takashi Matsumoto, Toshiharu Hidaka, Yutaka Konishi, Yoko Sakoda, Akihiro Miya, Masahiro Kishimoto, Hidefumi Nishikawa, Seishi Kono, Ikuo Kokufu, Isao Sakita, Koushiro Kitatsuji, Koushi Oh, Yasuo Miyoshi. Factors influencing on discontinuation of adjuvant anastrozole in postmenopausal Japanese breast cancer patients: Results from a prospective multicenter cohort study of patient-reported outcomes [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-12-04.

Abstract P6-07-39: Prognostic Value of Body Mass Index in Japanese Breast Cancer Patients: A Collaborative Study by the Kobe Breast Cancer Oncology Group and Hokkaido Cancer Center

Background: Many recent clinical trials conducted in Western populations suggest that obesity is a prognostic factor after primary treatment in postmenopausal breast cancer patients. However, the incidence of obesity differs substantially between Asian and Western breast cancer patients. Moreover, few studies have reported the relationship between body mass index (BMI) and postsurgical prognosis in Asian breast cancer patients. A previous retrospective analysis of Japanese populations revealed that obesity might be a prognostic risk factor in Japanese breast cancer patients. Methods: We retrospectively analyzed BMI and clinical outcomes after primary treatment in Japanese breast cancer patients of Hanshin and Hokkaido areas. We reviewed the clinical data (height, weight, BMI, estrogen receptor [ER] status, progesterone receptor status [PgR], human epidermal growth factor receptor 2 [HER2] status, and outcome) of 1,222 primary breast cancer patients with clinical stage I-III disease who were operated on between Jan 2004 and Dec 2005 at Kobe Breast Cancer Oncology Group (KBCOG) and Hokkaido Cancer Center (median follow-up period, 74 months). The patients were categorized into 4 groups: underweight (BMI, 2 ), normal (18.5–24.9 kg/m 2 ), overweight (25–29.9 kg/m 2 ), and obesity (>30.0 kg/m 2 ). Patient characteristics, excluding age and menopausal status, were well-balanced across groups. The correlations of BMI with disease-free survival (DFS) and overall survival (OS) were analyzed using the Cox hazards model. Results: The normal, underweight, overweight, and obesity groups contained 832 (68.1%), 92 (7.5%), 253 (20.7%), and 45 (3.7%) patients, respectively. Breast cancer recurred in 184 patients (15.0%); 75 patients died due to breast cancer recurrence, 29 died of other diseases, and 6 died of unknown causes. The univariate hazard ratio (HR) values for disease-free survival and overall survival in the overweight group were significantly lower than those in the normal group. However, there were no statistical significant differences among four groups by the multivariate analysis. We added subgroup analysis with classifications by ER and PgR status to speculate the cause for these unexpected results. Although there were no statistically significant differences, HRs for DFS and OS in the obesity group were higher than those in the normal group among ER− and/or PgR-positive patients. However, HRs for DFS and OS tended to be higher in the underweight groups and lower in the overweight groups in ER− and PgR-negative populations. Conclusions: The incidence of obesity in the Japanese population is much lower than that in the Western population. Although results of this study were slightly different from recent findings, obesity might be a risk factor for DFS and OS in ER-positive Japanese breast cancer patients, similar to that in Western countries. In underweight patients, ER− and PgR-negative status might indicate poor prognosis. However, this study was a retrospective analysis of a limited, heterogeneous patient group. A large-scale cohort study in the Japanese population is, therefore, recommended. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-07-39.