Reiki Nishimura

The combination of PD-L1 expression and decreased tumor-infiltrating lymphocytes is associated with a poor prognosis in triple-negative breast cancer

This study included patients with primary triple-negative breast cancer (TNBC) who underwent resection without neoadjuvant chemotherapy between January 2004 and December 2014. Among the 248 TNBCs studied, programmed cell death ligand-1 (PD-L1) expression was detected in 103 (41.5%) tumors, and high levels of tumor-infiltrating lymphocytes (TILs) were present in 118 (47.6%) tumors. PD-L1 expression correlated with high levels of TILs, but was not a prognostic factor. Patients with TILs-high tumors had better overall survival than those with TILs-low tumors (P = 0.016). There was a strong interaction between PD-L1 expression and TILs that was associated with both recurrence-free survival (P = 0.0018) and overall survival (P = 0.015). Multivariate Cox proportional hazards model analysis showed that PD-L1-positive/TILs-low was an independent negative prognostic factor for both recurrence-free survival and overall survival. Our findings suggest that PD-L1-positive/TILs-low tumors are associated with a poor prognosis in patients with TNBC, and that it is important to focus on the combination of PD-L1 expression on tumor cells and TILs present in the tumor microenvironment. These biomarkers may be useful for stratification of TNBCs and for predicting prognosis and developing novel cancer immunotherapies.

Efficacy of goserelin plus anastrozole in premenopausal women with advanced or recurrent breast cancer refractory to an LH-RH analogue with tamoxifen: Results of the JMTO BC08-01 phase II trial

The aim of the present study was to assess the efficacy and tolerability of a luteinizing hormone-releasing hormone (LH-RH) analogue plus an aromatase inhibitor following failure to respond to standard LH-RH analogue plus tamoxifen (TAM) in premenopausal patients. Premenopausal women with estrogen receptor (ER)-positive and/or progesterone-receptor positive, advanced or recurrent breast cancer refractory to an LH-RH analogue plus TAM received goserelin (GOS) in conjunction with anastrozole (ANA). The primary endpoint was the objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), clinical benefit rate (CBR) and safety. Between September 2008 and November 2010, 37 patients were enrolled. Thirty-five patients (94.6%) had ER-positive tumors, and 36 (97.3%) had human epidermal growth factor receptor (HER) 2-negative tumors. Thirty-six (97.3%) had measurable lesions and 1 (2.7%) had only bone metastasis. The ORR was 18.9% [95% confidence interval (CI), 8.0–35.2%], the CBR was 62.2% (95% CI, 44.8–77.5%) and the median PFS was 7.3 months. Eight patients had adverse drug reactions but none resulted in discontinuation of treatment. GOS plus ANA is a safe effective treatment for premenopausal women with hormone receptor-positive, recurrent or advanced breast cancer. The treatment may become viable treatment in the future, particularly when TAM is ineffective or contraindicated. Further studies and discussion are warranted.

Oral combination chemotherapy with capecitabine and cyclophosphamide in patients with metastatic breast cancer: A phase II study

Capecitabine (Xeloda, X) and cyclophosphamide (C) can be given orally and they have synergistic effects with nonoverlapping toxicities in preclinical studies. A phase I study of the XC combination therapy was conducted in patients with metastatic breast cancer (MBC) and determined the recommended dose and schedule of 1657u2009mg/m2/day capecitabine and 65u2009mg/m2/day cyclophosphamide given orally for 2 weeks at a 3-week interval. A phase II study of the oral XC regimen was then conducted. This study enrolled patients with HER2-negative MBC who were earlier treated with anthracyclines. XC was given at the recommended doses on a 3-week schedule for at least six courses unless disease progression or unacceptable toxicities occurred. The primary endpoint was the response rate. Progression-free survival, overall survival, and adverse events were investigated as secondary endpoints. Forty-eight patients with the median age of 58 (range 32–72 years) years were registered. Three patients withdrew by choice before starting the treatment. A complete response was obtained in two of the 45 evaluable patients, and partial response in 14, resulting in an overall response rate of 35.6%. The median progression-free survival and overall survival were 199 (115–231) days and 677 (437∼) days, respectively. Grade 3 neutropenia and leukopenia developed in 11%, and that of anemia and thrombocytopenia in 2% patients. Nonhematological toxicities were mild. Hand--foot syndrome was observed in 14 patients but no one had grade 3–4 toxicity. Oral XC combination is effective with acceptable toxicities in patients with MBC.

A case control study on risk factors involved in inflammatory breast recurrence after breast-conserving surgery

Recurrence that poses the biggest problem after breast-conserving surgery is local recurrence. Particularly, in the case of inflammatory breast recurrence which is rare but has a specific pathologic nature, it is important to elucidate the pathology and risk factors and to consider appropriate countermeasures. In the present study, we classified 133 cases of recurrence following breast-conserving surgery, collected from 18 key hospitals/institutes in Japan. Recurrence types were divided into three groups, namely, inflammatory breast recurrence, noninflammatory breast recurrence and distant metastasis only, and the risk factors involved in recurrence were investigated by the case control study allotting 2 controls to each case. The study population consisted of 9 cases of the inflammatory type, 64 cases of the noninflammatory type and 60 cases of distant metastasis. The significant risk factor for inflammatory breast recurrence was positive lymph node metastasis, which was significantly more frequent in lymphatic invasion-positive cases unlike in the distant metastasis group. The positive surgical margin and nonradiation therapy which have been shown to be significant risk factors for noninflammatory breast recurrence were entirely unrelated with inflammatory breast recurrence. In addition, the inflammatory-type recurrence time was as short as about 12 months irrespective of whether radiation therapy was performed or not. The inflammatory type was accompanied with local wide extension (cancerous embolus of the dermal lymphatic vessels), and distant metastasis (lymphangitis carcinomatosa) at the time of recurrence, and further surgery was impossible in most cases, with a significantly poorer prognosis than the other recurrence types. These findings suggest that this recurrence corresponds to the so-called ‘occult’ case of primary inflammatory breast carcinoma. We think it important to predict this recurrence by close pathological examination, particularly in patients with lymph node metastasis, and to consider appropriate measures.

Weekly Paclitaxel in the Treatment of Advanced or Metastatic Breast Cancer Previously Treated or Not Treated with Docetaxel: A Phase II Study

Background: Paclitaxel has been approved for 3-weekly administration in Japan. Recent reports suggest that weekly paclitaxel can achieve a higher tumor response and lower toxicity. Methods: This study was designed to investigate the usefulness and tolerability of weekly paclitaxel by 1-hour infusion in patients with metastatic breast cancer who were previously treated with docetaxel or other anticancer agents. Results: Thirty-five patients were enrolled. The overall response rate was 41.2% (14/34, 95% confidence interval: 24.6–59.3%). The median time to progression and the median survival time were 218.5 and 624 days, respectively. One patient developed dyspnea, probably induced by a hypersensitivity reaction. The most common hematological toxicities were leukopenia and neutropenia, although no patients developed grade 4 leukopenia or neutropenia and G-CSF support was not required. Conclusions: Weekly paclitaxel could be safely administered and achieved a relatively high response rate. Weekly paclitaxel would be a good candidate second-line therapy for recurrent or advanced breast cancer.

Endocrine therapies for patients with recurrent breast cancer: predictive factors for responses to first- and second-line endocrine therapies.

Breast cancer patients have been treated with four different hormonal agents, antiestrogen, progestin, luteinizing hormone-releasing hormone agonist and aromatase inhibitor, during the past 7 years in Japan. To investigate the efficacy of these agents for the treatment of recurrent breast cancer patients, we conducted a retrospective multi-institute survey in Japan. The clinico-pathological data of 131 patients, who received endocrine therapy as first-line treatment between 1993 and 1998, were collected from seven institutes. The median age of the patients was 55 (range 27–92) years, 75% of their primary tumors were estrogen receptor (ER)-positive or unknown, and 95% of the dominant metastatic sites were bone, soft tissue or lungs. The objective response rate to first-line endocrine therapy was 42.7%, and that to second-line therapy 42.5% (17 of 40 patients). Multiple regression analyses of predictive factors for a response to first- and second-line endocrine therapies indicated two independent factors, ER status of the primary tumors and dominant site of metastasis, for the former, and one independent factor, a response to first-line endocrine therapy, for the latter. Analysis of relationships between sequences of use of hormonal agents and objective response rates revealed that the choice of first-line hormonal agent did not influence the overall efficacy of first- and second-line endocrine therapies. Overall survival after first recurrence in patients with tumors exhibiting an objective response or stable disease to first-line endocrine therapy was significantly better than that in patients with tumors exhibiting progressive disease (p < 0.01). These findings suggest that an adequate selection of recurrent breast cancer patients referring the ER status, dominant site of metastasis and a prior response to endocrine therapy may contribute to better clinical outcomes of the patients.

BRCAness as a Biomarker for Predicting Prognosis and Response to Anthracycline-Based Adjuvant Chemotherapy for Patients with Triple-Negative Breast Cancer.

Background Triple-negative breast cancer (TNBC) is a heterogeneous tumor that encompasses many different subclasses of the disease. In this study, we assessed BRCAness, defined as the shared characteristics between sporadic and BRCA1-mutated tumors, in a large cohort of TNBC cases. Methods The BRCAness of 262 patients with primary TNBCs resected between January 2004 and December 2014 was determined through the isolation of DNA from tumor tissue. Classification of BRCAness was performed using multiple ligation-dependent probe amplification (MLPA). The tumor subtypes were determined immunohistochemically using resected specimens. Results Of the 262 TNBCs, the results of the MLPA assays showed that 174 (66.4%) tumors had BRCAness. Patients with BRCAness tumors were younger than patients with non-BRCAness tumors (P = 0.003). There was no significant difference between the two groups regarding their pathological stages. The BRCAness group had a significantly shorter recurrence-free survival (RFS) compared with the non-BRCAness group (P = 0.04) and had a shorter overall survival (OS) although this did not reach statistical significance. Adjuvant treatments with anthracycline-based regimens provided significantly greater benefits to the BRCAness group (P = 0.003 for RFS, and P = 0.03 for OS). Multivariate Cox proportional hazard model analysis showed that BRCAness was an independent negative prognostic factor, and the anthracycline-based adjuvant chemotherapy was an independent positive prognostic factor for both RFS and OS in TNBC. Conclusions The 66.4% patients of TNBCs showed BRCAness. BRCAness is essential as a biomarker in the subclassification of TNBCs and might be of use for predicting their prognosis. Furthermore, this biomarker might be a predictive factor for the effectiveness of anthracycline-based adjuvant chemotherapy for patients with TNBCs.

Role of HER2-Related Biomarkers (HER2, p95HER2, HER3, PTEN, and PIK3CA) in the Efficacy of Lapatinib plus Capecitabine in HER2-Positive Advanced Breast Cancer Refractory to Trastuzumab

Objective: The aim of this study was to investigate the correlation between human epidermal growth factor receptor 2 (HER2)-related biomarkers and the treatment outcomes using lapatinib plus capecitabine (LC) and to evaluate the influence of the estrogen receptor (ER) status in trastuzumab-refractory HER2-positive advanced breast cancer. Method: Eighty patients were enrolled in this study. Total HER2, p95HER2, and total HER3 expression were quantified using the VeraTag assays. PTEN (phosphatase and tensin homolog) and p95 expression was evaluated using immunohistochemistry and PIK3CA mutation using direct sequencing. Results: The response rate to LC was 30%, clinical benefit rate was 51.3%, and the median progression-free survival (PFS) was 174.5 days. ER negativity significantly correlated with higher HER2 and p95HER2. The lower HER2 and PIK3CA mutations were often observed in the nonresponders. A high p95HER2 expression correlated with longer PFS especially in the high HER2- and ER-positive cases. Patients without the PIK3CA mutation showed longer PFS in the same subset. Overall survival after LC significantly correlated with the number of recurrence organs. Conclusion: LC therapy is effective in trastuzumab-refractory HER2-positive breast cancer. Moreover, the biomarker expression differed depending on ER status, and a high p95HER2 expression and wild-type PIK3CA gene correlated with longer PFS especially in the ER-positive cases.

Outcomes of trastuzumab therapy in HER2-positive early breast cancer patients.

BackgroundPrevious large trials with trastuzumab (TZM) showed improved outcome in patients with HER2-positive early-stage breast cancer. However, the efficacy and safety of TZM in Japanese patients have not been fully evaluated. We have therefore conducted an observational study in Japan.MethodsThis was a retrospective and a prospective observational study in which data on women with histologically confirmed HER2-positive invasive breast cancer who received TZM for stage I–IIIC disease were collected from 56 institutions that participated in the Japan Breast Cancer Research Group and the efficacy of each treatment regimen analyzed.ResultsA total of 2,024 patients treated between July 2009 and June 2011 were initially enrolled in this study; in August 2013, the patient cohort comprised 2,009 patients. Of these, 142 (7.5xa0%) were aged ≥70 years, 1,097 (58.1xa0%) had clinically node-negative (cN0) breast cancer, and 883 (47.4xa0%) were estrogen receptor-positive. Treatment options were neoadjuvant therapy (662 patients) and adjuvant therapy with TZM (1,228 patients). Three-year overall survival (OS) rates in the entire cohort and in the neoadjuvant and adjuvant cohorts, respectively, were 98.9 [95xa0% confidence interval (CI) 98.2–99.3], 98.3 (95xa0% CI 96.8–99.1 %), and 99.2xa0% (95xa0% CI 98.4–99.6), respectively. Three-year disease-free survival (DFS) rates in the entire cohort and in the neoadjuvant and adjuvant cohorts, respectively were 94.2 (95xa0% CI 93.0–95.2), 94.8 (95xa0% CI 93.0–95.9), and 93.1 (95xa0% CI 90.7–94.9 %), respectively. Multivariate analysis showed that age and nodal status negatively correlated with DFS. Age was the only factor which correlated with OS rate. Adverse events (AEs) associated with TZM and grade 3/4 AEs were reported in 356 (18.8xa0%) and 14 (0.6 %) patients, respectively. Grade 3/4 cardiac toxicities were reported in 11 patients.ConclusionBased on data from our patient cohort of Japanese women with HER2-positive early-stage breast cancer, the efficacy and safety of systemic therapy with TZM are comparable to data from previously conducted large trials. Progress in anti-HER2 therapy for patients aged ≥70 years who have a poorer prognosis is needed.

An all-oral combination of capecitabine (X) and cyclophosphamide (C): Findings from a phase I study and an additional feasibility study in patients (pts) with metastatic breast cancer (MBC)

849 Background: Both X and C have single-agent activity in MBC. A combination of X and C is reported to show a synergistic effect in xenograft models. We performed a phase I study to determine the maximum tolerated doses (MTD) and recommended phase II doses (RD) for an all-oral combination of XC. Methods: Eligible pts had histologically confirmed MBC, age 20–75, ECOG PS ≥2, ≥1 prior chemotherapy regimen, and adequate bone marrow, renal, hepatic, and cardiac function. X and C were administered bid on days 1 -14 every 3 weeks. In the phase I study, toxicity was evaluated after 2 cycles of therapy. Dose limiting toxicity (DLT) was defined as grade (G) 4 hematological toxicity, G 3/4 non-hematological toxicity, and >1 week treatment delay at day 1 of cycle 2. X and C were administered at 3 dose levels: DL1 (X/C 1225/65mg/m2/day); DL2 (X/C 1657/65mg/m2/day); and DL3 (X/C 1657/100mg/m2/day). Results: 9 pts (6 at DL1 and 3 at DL2) were enrolled in the phase I study. 8 pts had received ≥2 prior-chemotherapies (5 ...