Naohito Yamamoto

Dofequidar Fumarate (MS-209) in Combination With Cyclophosphamide, Doxorubicin, and Fluorouracil for Patients With Advanced or Recurrent Breast Cancer

PURPOSE To evaluate the efficacy and tolerability of dofequidar plus cyclophosphamide, doxorubicin, and fluorouracil (CAF) therapy in comparison with CAF alone, in patients with advanced or recurrent breast cancer. Dofequidar is a novel, orally active quinoline derivative that reverses multidrug resistance. PATIENTS AND METHODS In this randomized, double-blind, placebo-controlled trial, patients were treated with six cycles of CAF therapy: 28 days/cycle, with doxorubicin (25 mg/m2) and fluorouracil (500 mg/m2) administered on days 1 and 8 and cyclophosphamide (100 mg orally [PO]) administered on day 1 through 14. Patients received dofequidar (900 mg PO) 30 minutes before each dose of doxorubicin. Primary end point was overall response rate (ORR; partial or complete response). In total, 221 patients were assessable. RESULTS ORR was 42.6% for CAF compared with 53.1% for dofequidar + CAF, a 24.6% relative improvement and 10.5% absolute increase (P = .077). There was a trend for prolonged progression-free survival (PFS; median 241 days for CAF v 366 days for dofequidar + CAF; P = .145). In retrospectively defined subgroups, significant improvement in PFS in favor of dofequidar was observed in patients who were premenopausal, had no prior therapy, and were stage IV at diagnosis with an intact primary tumor. Except for neutropenia and leukopenia, there was no statistically significant excess of grade 3/4 adverse events compared with CAF. Treatment with dofequidar did not affect the plasma concentration of doxorubicin. CONCLUSION Dofequidar + CAF was well tolerated and is suggested to have efficacy in patients who had not received prior therapy.

Docetaxel Followed by Fluorouracil/Epirubicin/Cyclophosphamide as Neoadjuvant Chemotherapy for Patients with Primary Breast Cancer

OBJECTIVE This multicenter, open-label, single-arm, Phase II study assessed the efficacy of a neoadjuvant chemotherapy with docetaxel (75 mg/m(2) q3w) followed by 5-fluorouracil 500 mg/m(2), epirubicin 100 mg/m(2) and cyclophosphamide 500 mg/m(2) q3w in patients with early-stage breast cancer. METHODS Women with resectable breast cancer (T1c-3 N0 M0 or T1-3 N1 M0) were enrolled. Before surgery, patients received four cycles of docetaxel followed by four cycles of 5-fluorouracil, epirubicin, and cyclophosphamide. The primary endpoint was the pathological complete response (pCR) rate defined for the breast alone, assessed by a central review committee. Secondary endpoints included clinical response and safety. RESULTS One hundred and thirty-seven patients were enrolled. Of the 132 patients assessable for pathologic response, 23% (95% confidence interval, 16-31%) experienced a pathological complete response and 6% (95% confidence interval, 3-12%) had a near pathological complete response (few remaining cancer cells), resulting in a quasi-pathological complete response of 29% (95% confidence interval, 21-37%). Clinical response rate following the initial docetaxel regimen was 64%. The overall clinical response rate after completion of 5-fluorouracil, epirubicin, and cyclophosphamide was 79%; breast-conserving surgery was performed in 79% of patients. More patients with triple-negative disease (estrogen/progesterone receptors negative; human epidermal growth factor 2 negative) experienced a pathological complete response [14/29, (48%); 95% confidence interval, 29-68%] versus those with other molecular subtypes. The safety profile was acceptable. CONCLUSIONS Eight cycles of neoadjuvant chemotherapy-docetaxel followed by 5-fluorouracil, epirubicin, and cyclophosphamide-are tolerable and conferred high rates of pathological complete response and breast-conserving surgery. Patients with triple-negative disease were more likely to achieve pathological complete response versus other subtypes, suggesting that selecting appropriate neoadjuvant chemotherapy based on molecular subtype could be possible.

The relationship between skeletal-related events and bone scan index for the treatment of bone metastasis with breast cancer patients.

AbstractThe aim of the present study was to investigate the relationships between the automated bone scan index (aBSI) and skeletal-related events (SRE) in breast cancer patients with bone metastasis. A computer-aided software (BONENAVI™) that was developed using an Artificial Neural Network (Artificial Neural Network) was used for the present analysis.Forty-five patients diagnosed with bone metastasis due to breast cancer from April 2005 through March 2013 were retrospectively analyzed. Before and after the time of initial treatment, aBSI, Artificial Neural Network score, and hotspot number were calculated, and the relationships between these scores and SRE were analyzed.Twenty cases showed decreased (improved) aBSI values after initial treatment (Group A), and 25 cases showed unchanged/increased (worsened) aBSI values (Group B). Chi-square analysis revealed a significant difference in incident numbers of SRE between the two groups—one case in Group A and 12 in Group B (P < 0.001). Event-free survival was significantly shorter in Group B (hazard ratio: 8.31, 95% CI: 1.33–12.14, log-rank test; P < 0.05). The groups were also divided by the results of 2 radiologists’ visual scan interpretations, and no significant differences were shown in the number of SRE (P = 0.82, P = 0.10). When correlation analyses were performed between aBSI and bone metabolic or tumor markers, alkaline phosphatase was significantly correlated with aBSI at the time of initial treatment (R = 0.69, P < 0.05).In conclusion, aBSI is proposed as a useful and objective imaging biomarker in the detection of breast-cancer patients with bone metastasis at high risk of SRE.

Final Results of a Safety and Efficacy Trial of Preoperative Sequential Chemoradiation Therapy for the Nonsurgical Treatment of Early Breast Cancer: Japan Clinical Oncology Group Study JCOG0306

Objective: To explore the possibility of nonsurgical treatment of primary breast cancers by a sequential treatment of chemotherapy and radiotherapy. Methods: We conducted a safety and efficacy trial of chemotherapy and radiation therapy sequentially as primary therapy in patients with stage I-IIIA breast cancer. All patients underwent mastectomy or lumpectomy 12-16 weeks after the completion of radiation therapy to maximize the effect of radiation therapy. The primary endpoint was the pathological complete response (pCR) rate. Results: Between June 2004 and April 2005, one hundred eight patients were enrolled. Thirty six percent of the entire population achieved a pCR, which could not reject the null hypothesis. The pCR rate was 57% in patients with hormone receptor (HR)-negative/HER-2-positive tumors and 52% in patients with triple-negative tumors. While 7% of the HR-negative/HER2-positive patients recurred, a higher incidence of recurrence (24%) was observed in triple-negative tumors in a follow-up of 4.5 years. The rate of breast-conserving surgery was 88.9% (96/108). Conclusion: The pCR rate was not high enough, even though preoperative sequential chemoradiation therapy did not increase the risk of operative complications and could achieve a high rate of breast-conserving surgery.

Randomized Phase II Study of Primary Systemic Chemotherapy and Trastuzumab for Operable HER2 Positive Breast Cancer

BACKGROUND In primary systemic therapy in patients with human epidermal growth factor receptor 2 positive (HER2(+)) breast cancer, improvements in pathologic complete response (pCR) rate have been achieved by administering trastuzumab. PATIENTS AND METHODS Patients with stage II or IIIA HER2(+) operable breast cancer were randomly assigned to receive four 3-weekly cycles of FEC (5-fluorouracil 500 mg/m(2), epirubicin 100 mg/m(2), cyclophosphamide 500 mg/m(2)) followed by 4 cycles of 3-weekly trastuzumab (8 mg/kg week 1 and then 6 mg/kg) with either 12 weekly doses of paclitaxel 80 mg/m(2) (FEC-PH) or 4 cycles of 3-weekly docetaxel 75 mg/m(2) (FEC-DH). RESULTS Between March 2007 and June 2008, 102 patients were enrolled. Forty-nine patients receiving FEC-PH and 47 receiving FEC-DH were assessable for efficacy and safety. Eighty-four patients completed treatment and underwent surgery. There was no significant difference in the pCR rate between the 2 groups (46.9% [95% CI, 33.7%-60.6%] with FEC-PH vs. 42.6% [95% CI, 29.5%-56.8%] with FEC-DH; P = .67). Analysis by hormone receptor (HR) status showed pCR rates of 54.2% (32/59) in HR(-) tumors and 29.7% (11/37) in HR(+) tumors (P = .02). Among HR(-) tumors, the pCR rates were 65.4% and 45.5% in patients treated with FEC-PH and FEC-DH, respectively (P = .13). CONCLUSIONS There was no significant difference in pCR rate between FEC-PH and FEC-DH. Both regimens achieved higher pCR rates in HR(-) than HR(+) breast cancer, and there was a trend toward higher pCR in HR(-) tumors with FEC-PH compared with FEC-DH. Further investigation is warranted to explore the relationship between efficacy and HR status.

The Japanese Breast Cancer Society Clinical Practice Guideline for systemic treatment of breast cancer

1. For operable, postmenopausal, hormone receptorpositive, HER2-negative breast cancer, preoperative endocrine therapy may be considered for the purpose of breast conservation (Grade C1). 2. Preoperative endocrine therapy improves the breast conservation rate in premenopausal breast cancer as well as postmenopausal breast cancer. However, it is not generally recommended since evidence is scarce (Grade C2).

Randomized phase II study of three doses of oral TAS-108 in postmenopausal patients with metastatic breast cancer

This randomized phase II study was intended to identify the optimal dose of TAS‐108, a novel steroidal antiestrogen, for the treatment of breast cancer in postmenopausal Japanese women. The potential clinical effects of TAS‐108 on the uterus, bone, serum lipids, and hormones were also investigated. Postmenopausal women with hormone receptor‐positive metastatic breast cancer who had previously received one or two endocrine therapies were randomly assigned to one of the three possible dose levels of TAS‐108 (40, 80 or 120 mg/day). Oral TAS‐108 was given daily, and the efficacy and safety of the three doses were evaluated. A total of 97 patients (33, 32, and 32 in the 40‐, 80‐, and 120‐mg groups, respectively) were treated with TAS‐108. The clinical benefit rate was 30.3% for the 40‐mg, 25.0% for the 80‐mg, and 25.0% for the 120‐mg group. The 40‐mg group achieved the prespecified target threshold. TAS‐108 at all dose levels was well tolerated and appeared to have no harmful effects in terms of the variables examined in this study. We conclude that the optimal dose of TAS‐108 among the three doses is 40 mg, once daily, for further studies. JAPIC Clinical Trials Information number: Japic CTI – 121754.

Carcinomatous Pericarditis in 3 Breast Cancer Patients with Long-Term Survival

With advances in drug treatment of breast cancer, the number of patients experiencing cardiac toxicity or carcinomatous pericarditis is expected to increase. These conditions can cause cardiac tamponade, which is a potentially fatal condition requiring prompt diagnosis and treatment. We experienced 3 breast cancer patients with cardiac tamponade due to carcinomatous pericarditis who survived for prolonged periods after treatment with pericardiocentesis and intrapericardial instillation. The 3 women were 68, 46 and 46 years old, respectively, and receiving treatment for recurrent breast cancer after surgery. They developed dyspnea and cough and were diagnosed with cardiac tamponade by echocardiography. Pericardiocentesis was performed, and cytology of the effusion confirmed the diagnosis of carcinomatous pericarditis. Intrapericardial instillation of cisplatin reduced the cardiac effusion, ameliorating symptoms. The patients died 13, 31 and 14 months later, respectively. In our clinical review of 13 other cases of cardiac tamponade due to breast cancer, 85% achieved local control after the aforementioned local treatments, which were considered to be effective. Although the overall prognosis was poor with a median survival time of only 4 months, some patients were able to survive more than 1 year after local treatment with subsequent systemic therapy.

Radiofrequency Ablation of Breast Cancer: A Retrospective Study

&NA; In this study, feasibility of RFA procedure and related safety and ipsilateral breast tumor recurrence (IBTR) were examined. RFA in breast cancer is a safe and promising minimally invasive treatment for tumors ≤ 2 cm in diameter. Combination of ultrasound‐guided RFA of breast cancer with concurrent sentinel lymph node biopsy could potentially become state‐of‐the‐art breast‐conservative therapy for early breast cancer. Purpose: To validate the safety and efficacy of percutaneous radiofrequency ablation (RFA) of breast carcinomas. Methods: This retrospective study was conducted by the Breast Cancer Society for Minimally Invasive Therapy following approval from institutional review boards, and with the written informed consent of patients. A total of 386 patients with breast cancer treated with RFA at 10 institutions between July 2003 and June 2009 were identified and included in the analysis. Patients underwent a standard RFA procedure with ultrasound guidance and were followed up every 6 to 12 months. In this study, feasibility of RFA procedure and related safety and ipsilateral breast tumor recurrence (IBTR) were examined. Fisher exact or χ2 test evaluated associations between clinicopathological factors and IBTR, and local recurrence‐free survival was estimated using the Kaplan‐Meier method. Results: RFA‐related adverse events included local pain in 9 patients, skin burns in 15, and nipple retraction in 7. Patients were followed for a median of 50 months. IBTR was more frequently observed in patients with initial tumor sizes > 2 cm (3 of 30, 10%) than in those with initial tumors ≤ 2 cm (8 of 355, 2.3%; P = .015). IBTR‐free rates 5 years after RFA were 97%, 94%, and 87% in patients with initial tumor sizes ≤ 1.0 cm, 1.1 to 2.0 cm, and > 2.0 cm, respectively. Conclusions: RFA in breast cancer is a safe and promising minimally invasive treatment for tumors ≤ 2 cm in diameter. Further studies are needed to optimize the technique and evaluate its future role as local therapy.

Randomized phase II study of nab-paclitaxel as first-line chemotherapy in patients with HER2-negative metastatic breast cancer

Weekly administration of nanoparticle albumin‐bound paclitaxel (nab‐paclitaxel) has been shown to be a safe and effective treatment for metastatic breast cancer (MBC) in clinical studies. We conducted a multicenter, randomized, open‐label phase II study to compare the efficacy and safety of weekly nab‐paclitaxel and docetaxel in Japanese patients with human epidermal growth factor receptor 2‐negative MBC. The primary endpoint was progression‐free survival (PFS). Patients were randomized to receive nab‐paclitaxel (150 mg/m2 nab‐paclitaxel once per week for 3 of 4 weeks; n = 100) or docetaxel (75 mg/m2 docetaxel every 3 weeks; n = 100). The median PFS by independent radiologist assessment was 9.8 months (90% confidence interval [CI]: 8.5–11.2) for nab‐paclitaxel and 11.2 months (90% CI: 8.4–13.8) for docetaxel (hazard ratio: 1.25, P = 0.363), and the median overall survival was 42.4 months and 34.0 months, respectively. The overall response rate was 56.1% for nab‐paclitaxel and 52.5% for docetaxel. Adverse events in both treatment arms were similar to previous reports. Neutropenia was the most common adverse event in both arms, with 35.0% of patients in the nab‐paclitaxel arm and 89.0% in the docetaxel arm experiencing grade 4 neutropenia. Grade 3 peripheral sensory neuropathy occurred in 22.0% of patients in the nab‐paclitaxel and 5.0% in the docetaxel arm. In this study, although weekly nab‐paclitaxel 150 mg/m2 did not show superiority in PFS compared with docetaxel, efficacy outcomes were similar in patients treated with weekly nab‐paclitaxel and docetaxel.