Long-term survival analysis of addition of carboplatin to neoadjuvant chemotherapy in HER2-negative breast cancer.

PURPOSE: Addition of carboplatin (CBDCA) to neoadjuvant chemotherapy (NAC) in triple-negative breast cancer (TNBC) has improved pathological complete response (pCR) rates in previous studies. We present long-term survival outcomes (disease-free survival [DFS], pre-planned secondary endpoint; overall survival [OS], post hoc exploratory endpoint) of our randomized study of the addition of CBDCA to NAC for HER2-negative breast cancer. METHODS: Patients with stage II/III, HER2-negative breast cancer (N = 179) were randomly assigned to receive CP-CEF (four 3-week cycles of CBDCA [area under the curve, 5 mg/mL/min, day 1] and weekly paclitaxel [wPTX, 80 mg/m2, day 1, 8, 15] followed by four 3-week cycles of cyclophosphamide, epirubicin, and 5-fluorouracil [CEF, 500/100/500 mg/m2]) or P-CEF (four cycles of wPTX followed by four cycles of CEF) as NAC. DFS and OS were analyzed at each population of pCR status and assigned treatment arm. RESULTS: Of 179 patients, 154 were available for long-term follow-up. At a median follow-up of 6.6 years (range, 0.7-8.0 years), patients who achieved pCR [n = 42, 23.5% (CP-CEF: n = 28, P-CEF: n = 16)] had longer DFS and OS than non-pCR patients [DFS; HR 0.15 (0.04-0.61), P = 0.008, OS; log-rank P = 0.003]. Addition of carboplatin to NAC significantly improved DFS and OS in the subset of patients with TNBC [DFS: HR, 0.22 (0.06-0.82), P = 0.015; OS: HR, 0.12 (0.01-0.96), P = 0.046], but not in the subset of patients with hormone receptor-positive disease or among all patients. CONCLUSIONS: Addition of carboplatin to neoadjuvant chemotherapy significantly improved DFS and OS in patients with TNBC but not in those with hormone receptor-positive, HER2-negative breast cancer.

The utility of DHL-HisZnNa, a novel antioxidant, against anticancer agent-induced alopecia in breast cancer patients: a multicenter phase II clinical trial.

PURPOSE: Chemotherapy-induced alopecia (CIA) is a distressing adverse effect of anticancer drugs; however, there are currently no mechanisms to completely prevent CIA. In this study, we performed a clinical trial to examine whether sodium N-(dihydrolipoyl)-l-histidinate zinc complex (DHL-HisZnNa), an alpha-lipoic acid derivative, prevents CIA in patients with breast cancer. METHODS: Between July 2014 and May 2015, we performed a multi-center, single arm, clinical trial involving 103 breast cancer patients who received adjuvant chemotherapy at three medical institutions in Japan. During chemotherapy, a lotion containing 1% DHL-HisZnNa was applied daily to the patients' scalps. The primary endpoint was the incidence of grade 2 alopecia; the secondary endpoints were the duration of grade 2 alopecia, alopecia-related symptoms, and drug-related adverse events. Alopecia was evaluated by three independent reviewers using head photographs taken from four angles. RESULTS: Safety analysis was performed for 101 patients who started the protocol therapy. After excluding one patient who experienced disease progression during treatment, 100 patients who received at least two courses of chemotherapy underwent efficacy analysis. All original 101 patients developed grade 2 alopecia, the median durations of which were 119 days (112-133 days) and 203 days (196-212 days) in the groups treated with four and eight courses of chemotherapy, respectively. Mild or moderate adverse events potentially related to DHL-HisZnNa were observed in 11 patients. Alopecia-related symptoms were observed in 53 patients (52%). CONCLUSIONS: The application of 1% DHL-HisZnNa to the scalp did not prevent CIA. However, this drug may promote recovery from CIA. TRIAL REGISTRATION NUMBER: UMIN000014840.

Feasibility study of contralateral risk-reducing mastectomy with breast reconstruction for breast cancer patients with BRCA mutations in Japan.

BACKGROUND: Contralateral risk-reducing mastectomy (CRRM) for breast cancer patients with BRCA mutations has been reported to not only reduce breast cancer incidence but also to improve survival. The National Comprehensive Cancer Network guidelines recommend providing CRRM to women with BRCA mutations who desire CRRM after risk-reduction counseling. However, in Japan, CRRM cannot be performed generally because it is not covered by health insurance. Thus, we conducted a feasibility study to confirm the safety of CRRM. METHODS: CRRM with bilateral breast reconstructions were performed for breast cancer patients with BRCA mutations. The primary endpoint was early adverse events within 3 months, and secondary endpoints were late adverse events. RESULTS: Between August 2014 and November 2016, ten patients were enrolled. The median age was 37.5 years, and five of the patients had the BRCA1 mutation while five had the BRCA2 mutation. Six patients received neoadjuvant chemotherapy. Eight patients selected silicone breast implants, and two patients selected transverse rectus abdominis myocutaneous flap reconstruction. Pathological findings showed no evidence of occult breast cancers in any of the patients. At a median of 25.5 months follow-up time, CRRM-related early adverse events were hematoma (subsequently removed by re-operation; grade 2, n = 1), wound infection (grade 2, n = 1), skin ulceration (grade 1, n = 2) and wound pain (grade 1, n = 1). Overall, there were no grade 3 or more severe adverse events. CONCLUSION: Our results confirm that CRRM with reconstruction could be performed safely.

Rainbow of KIBOU (ROK) study: a Breast Cancer Survivor Cohort in Japan.

BACKGROUND: Although there are a large number of epidemiological studies investigating the etiological role of lifestyle factors in breast cancer, there are few studies on the association between lifestyle factors and breast cancer prognosis. To investigate the influence of lifestyle factors such as diet and physical activity, use of complementary and alternative medicine, and psychosocial factors on prognosis, we designed a large-scale cohort study of female breast cancer patients in Japan. METHODS: The planned sample size is 7200. The cohort is being conducted in collaboration with several clinical trials, a cancer registry, and daily practice. Information on clinical factors, treatment, and follow-up will be obtained from the clinical trials and participating hospitals. A self-administered questionnaire is given to subjects before, immediately after, or 1 to 5 years after surgery. Blood and tissue samples are also collected. The primary endpoint is disease-free survival. The secondary endpoints are overall survival and health-related quality of life. The follow-up period will be at least 5 years after the last participant is enrolled. Recruitment began in November 2007. CURRENT STATUS: As of April 2017, there are 5852 patients enrolled in the study along with 1430 biological samples and the study is still ongoing. The number of subjects enrolled in the study is already the largest in the world. CONCLUSIONS: The ROK study will provide much important evidence for breast cancer survivorship.

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.

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.

Evaluation of trastuzumab without chemotherapy as a post-operative adjuvant therapy in HER2-positive elderly breast cancer patients: randomized controlled trial [RESPECT (N-SAS BC07)].

OBJECTIVE: This trial is conducted to investigate the benefit of trastuzumab monotherapy compared with a combination therapy of trastuzumab and chemotherapy in women over 70 years with human epidermal growth factor receptor type-2-positive primary breast cancer. METHODS: Inclusion criteria are the following: histologically diagnosed as invasive breast cancer and received curative operation for primary breast cancer; Stage I, IIA, IIB or IIIA/M0; and baseline left ventricular ejection fraction is ≥55%. Patients are randomized to receive either trastuzumab (8 mg/kg loading dose, 6 mg/kg every 3 weeks for 1 year) plus chemotherapy selected from regimens specified on the protocol or trastuzumab monotherapy. The primary endpoint is disease-free survival. Secondary endpoints are overall survival, relapse-free survival, safety, health-related quality of life, comprehensive geriatric assessment and cost effectiveness. RESULTS: Patients recruitment has been commenced in October 2009. Enrollment of 300 patients is planned during the 4-year recruitment period. CONCLUSIONS: We hereby report the study concept.

Oral uracil and tegafur compared with classic cyclophosphamide, methotrexate, fluorouracil as postoperative chemotherapy in patients with node-negative, high-risk breast cancer: National Surgical Adjuvant Study for Breast Cancer 01 Trial.

PURPOSE: The primary aim of this study was to compare the effectiveness of oral uracil-tegafur (UFT) with that of classical cyclophosphamide, methotrexate, and fluorouracil (CMF) given as postoperative adjuvant treatment to women with node-negative, high-risk breast cancer. PATIENTS AND METHODS: Women with node-negative, high-risk breast cancer were randomly assigned to receive either 2 years of UFT or six cycles of CMF after surgery. The primary end point was relapse-free survival (RFS). Overall survival (OS), toxicity, and quality of life (QOL) were secondary end points. The hypothesis was that UFT was not inferior to CMF in terms of RFS. RESULTS: Between October 1996 and April 2001, a total of 733 patients were randomly assigned to receive either treatment. The median follow-up time was 6.2 years. The RFS rates at 5 years were 88.0% in the CMF arm and 87.8% in the UFT arm. OS rates were 96.0% and 96.2%, respectively. The hazard ratios of the UFT arm relative to the CMF arm were 0.98 for RFS (95% CI, 0.66 to 1.45; P = .92) and 0.81 for OS (95% CI, 0.44 to 1.48; P = .49). The toxicity profiles differed between the two groups. The QOL scores were better for patients given UFT than those given CMF. CONCLUSION: RFS and OS with oral UFT were similar to those with classical CMF. Given the higher QOL scores, oral UFT is a promising alternative to CMF for postoperative adjuvant chemotherapy in women with node-negative, high-risk breast cancer.

Breast cancer risk and erythrocyte compositions of n-3 highly unsaturated fatty acids in Japanese.

Dietary intake of fish rich in n-3 highly unsaturated fatty acids (HUFAs), such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), has been proposed to decrease cancer risk. In contrast to results from laboratory studies, however, protective effects for breast cancer have proved equivocal in epidemiological studies. In the present case-control study, we examined associations between breast cancer risk and fatty acid compositions in erythrocyte membranes as biomarkers for those intakes. Dietary information and blood samples were collected from 103 incident breast cancer cases and 309 non-cancer controls (matched by age and season) and erythrocyte fatty acids were measured using accelerated solvent extraction and gas-liquid chromatography. Dietary intake of n-3 HUFAs demonstrated a negative association with risk (the highest to the lowest tertile, odds ratio (OR), 0.51; 95% confidence interval (CI), 0.27-0.98; p(trend)<0.05), but there was no association with those of saturated fatty acids (SFAs) and meat. Moreover, risk was inversely associated with erythrocyte compositions of EPA (OR, 0.27; 95% CI, 0.14-0.53; p(trend)<0.0001), DHA (OR, 0.06; 95% CI, 0.02-0.16; p(trend)<0.0001) and n-3 HUFAs (OR, 0.11; 95% CI, 0.05-0.24; p(trend)<0.0001), and positively with that of SFAs (OR, 12.29; 95% CI, 4.94-30.57; p(trend)<0.0001) and the ratio of SFAs/n-3 HUFAs (OR, 14.65; 95% CI, 5.67-37.82; p(trend)<0.0001). In conclusion, we showed that erythrocyte compositions of specific fatty acids derived from fish intake, as biomarkers, are associated with lower risk of breast cancer, but further studies are needed to investigate mechanisms linked to the etiology.