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Background/Aim: There are few reports about the administration of nivolumab plus ipilimumab to hemodialysis patients and their efficacy and safety have not been established yet. Case Report: A 74-year-old male, who was receiving hemodialysis, was presented with metastatic renal cell carcinoma (mRCC). Two years later, more metastases were found, hence, immunotherapy involving nivolumab plus ipilimumab was initiated. After two doses of immunotherapy, interstitial pneumonia was observed. Thus, steroid pulse therapy was administered immediately. Subsequently, computed tomography (CT) findings and symptoms improved markedly. One month later, a CT scan showed a nodular shadow and an air cavity. A fungal infection was strongly suspected, so an antifungal drug was administered. Conclusion: Combination immunotherapy with nivolumab plus ipilimumab was demonstrated to be effective in a hemodialysis patient with mRCC.

Background: Docetaxel + Trastuzumab (H) + Pertuzumab (P) provided progression-free survival (PFS) and overall survival (OS) benefits in HER2-positive advanced or metastatic breast cancer (AMBC) in the CLEOPATRA study as a first-line therapy. However, long-term administration of docetaxel at a dose of 75 mg/m2 every 3 weeks in AMBC patients (pts) is difficult due to the toxicities. Eribulin mesylate (E) is a well-tolerated microtubule inhibitor, and we have reported the efficacy and safety of EHP regimen as first- and second-line therapy for AMBC in a multicenter, phase II study (JBCRG-M03/UMIN000012232). In this M06 study, we address the clinical question as to which is the better chemotherapy partner for HP as first line regimen, in terms of efficacy, toxicity and QOL. Methods: JBCRG-M06 is a multicenter open-label randomized phase III study for HER2-positive AMBC pts who have received no prior chemotherapy except for the HER2- Antibody-Drug Conjugate (ADC). Pts will be randomized 1:1 to E (1.4mg/m2 on day 1 and 8) + H (8 mg/kg loading dose followed by 6 mg/kg) +P (840 mg loading dose followed by 420 mg) q3wks or standard taxanes (docetaxel 75mg/m2 on day1 or paclitaxel 80mg/m2 on day 1, 8 and 15) + HP q3wks. Stratification factors for randomization are; presence of visceral metastases, number of prior taxanes on perioperative adjuvant treatment, and treatment with prior anti-HER2-ADC. Primary endpoint is PFS and secondary endpoints include overall response rate, duration of response, OS, patient-reported outcomes (PRO) relating to QOL and peripheral neuropathy, new-metastases free survival, and safety. Translational research to search for biomarker for individual precision therapy will be performed. Main eligibility criteria are as follows: pts with HER2-positive AMBC, female aged 20-70 years old, ECOG PS of 0-1, LVEF ≥ 50% at baseline and adequate organ function. Pts who had progressive MBC within 6 months after the end of primary adjuvant systemic chemotherapy are excluded. The sample size was calculated by type1 error (2-sided) of 0.05 and 80% power to estimate the noninferiority margin 1.33 with an expected median PFS of 14.2 months. The target number of pts is 480 recruited over the duration of 3-years. The first patient in was achieved on August 2017. (ClinicalTrials.gov Identifier:NCT03264547). Citation Format: Masuda N, Yamashita T, Saji S, Araki K, Ito Y, Takano T, Takahashi M, Tsurutani J, Koizumi K, Kitada M, Kojima Y, Sagara Y, Tada H, Iwasa T, Kadoya T, Iwatani T, Hasegawa H, Morita S, Ohno S. A phase III trial to compare eribulin mesylate + trastuzumab (H) + pertuzumab (P) with paclitaxel or docetaxel + HP for HER2-positive advanced or metastatic breast cancer (JBCRG-M06/ EMERALD) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT2-07-05.

Background:It is unclear how to define responsiveness to endocrine therapy (ET) during the clinical course of advanced breast cancer (ABC), especially in evaluation of the effect of sequential ET. Objective:The goal of the study was to evaluate the efficacy of second line treatment of physician's choice (2nd-line TPC) for estrogen receptor-positive (ER+) and HER2-negative postmenopausal ABC with very low or low sensitivity to initial ET. Methods:A multicenter prospective observational cohort study was performed for 2nd-line TPCs. ABC with low sensitivity to initial ET was defined as recurrence within 5 years (yrs) during adjuvant ET or progression within 9 months (mo.) of initial ET. Similarly, ABC with very low sensitivity to initial ET was defined as recurrence within 2 yrs during adjuvant ET or progression within 3 mo. of initial ET. The expected clinical benefit rate (CBR: defined as patients who achieved CR, PR or SD for 24 weeks) was 50%. The null hypothesis of a CBR of 30% was tested with a one-sided α of 5%. 90% confidence intervals (CIs) were calculated for hypothesis tests. Results: A total of 56 patients (pts) were enrolled, but 7 were ineligible and one discontinued before starting the protocol treatment. The median age was 66 yrs (range: 41-88) and the median BMI was 23.4 kg/m2 (16.4-31.9). All pts were ER+ and 80% were PgR+. Most of pts had a baseline PS of 0 or 1, 90% had invasive ductal carcinoma, and 10% had invasive lobular carcinoma. Postoperative recurrence was detected in 84% and these pts had a median duration of adjuvant ET of 30.5 mo. (5.3-58.9). De novo stage IV ABC was present in 16%, with a median duration of first-line ET of 5 mo. (2.3-10.8). Adjuvant chemotherapy including anthracycline- and/or a taxane-containing regimen was administered in 58% (29/49). As adjuvant ET before initial recurrence, 34 pts received non-steroidal aromatase inhibitors (AIs) (88.0%), 1 received a steroidal AI (2.3%), and 3 received a selective estrogen receptor modulator (SERM). As first line ET in de novo stage IV, 7 pts (14%) were treated with AIs or a SERM (1 case). 2nd-line TPCs were also used, with 40 pts receiving fulvestrant (82%), 5 receiving SERMs (10%), 3 receiving a mTOR inhibitor plus a steroidal AI (6%), and one patient receiving an AI alone. The overall CBR was 44.9% (90% CI: 34.6-57.6, p=0.009), and CBR was similar across following subgroups (PgR+: n=39, 51.3%, 90% CI: 39.6-65.2, p=0.0016; very low sensitivity group: n=17, 58.8%, 90% CI: 42.0-78.8, p=0.003; non-visceral metastases: n=25, 40%, 90% CI; 34.1-65.9, p=0.0175). However, there were not statistically significant CBR in PgR- (n=10, 20.0%, 90% CI; 8.73-50.7, p=0.617), fulvestrant subgroup (n=40, 40.0 %, 90% CI; 29.2-54.2, p=0.063), low sensitive group (n=32, 37.5%, 90% CI; 26.0-53.6, p=0.1326), and visceral metastases (n=24, 48%, 90%CI; 28.2-60.3 p=0.072). The median PFS was 7.1 mo. (95% CI: 5.6-10.6). Conclusion:This study shows that 2nd line ETs was effective and might be a valid option in the sequence of treatments for postmenopausal women with ABC with low sensitivity to initial ET. It was suggested that PgR and visceral metastasis were significant predictive factors for CBR. Citation Format: Araki K, Fujisawa T, Sakamaki K, Kikawa Y, Iwamoto T, Sangai T, Shien T, Takao S, Nishimura R, Takahashi M, Aihara T, Mukai H, Taira N. Sequential second line endocrine therapy is still an effective strategy for postmenopausal ER+ and HER2- advanced breast cancer with low sensitivity to initial endocrine therapy [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-13-09.

Background/Aim: Recently, it was reported that the use of androgen deprivation therapy (ADT) is significantly associated with an increased risk of acute kidney injury (AKI) in patients with newly diagnosed non-metastatic prostate cancer. This study aimed to investigate the incidence of early renal dysfunction in Japanese prostate cancer patients receiving ADT and the factors associated with it. Patients and Methods: A total of 135 patients who had been pathologically diagnosed with prostate cancer and had received ADT for at least 6 months were eligible for study inclusion. The estimated glomerular filtration rate (eGFR) before treatment, and at 1, 3, and 6 months of ADT were evaluated retrospectively. We assessed renal function using eGFR and investigated the rate of change in the eGFR (ΔeGFR) during ADT. Univariate and multivariate logistic analyses were carried out to identify clinical factors that were significantly associated with renal dysfunction after 6 months ADT. Results: A total of 110 cases were evaluated in this study. The incidence of renal dysfunction after 6 months ADT was 63% (69/110). The mean ΔeGFR after 1, 3, and 6 months of ADT were –0.6%, –3.1% and –1.7%, respectively (p

Objectives. To determine whether an alkaline phosphatase (ALP) flare after androgen deprivation therapy (ADT) is associated with the treatment response in castration-resistant prostate cancer (CRPC) and predicts the prognosis of metastatic prostate cancer (PCa) patients. Methods. One hundred and nineteen patients diagnosed with metastatic PCa between 2008 and 2017 were retrospectively studied. The ALP flare ratio was calculated as the ratio of ALP levels 1 month after beginning ADT to ALP levels at diagnosis. The association of the ALP flare ratio with the prostate-specific antigen (PSA) response to CRPC treatment (second-generation androgen receptor targeted therapy (ART) or docetaxel), time to CRPC, and overall survival (OS) were investigated. Results. The time to CRPC and OS was significantly longer in patients with an ALP flare ratio less than 1.33 compared to a ratio more than 1.33. No difference in PSA response was seen regarding the ALP flare ratio in both ART and docetaxel treatment. Second-generation ART-treated patients with a low ALP flare ratio showed longer OS than those with a higher ALP flare ratio ( p = 0.0367 ). However, no difference was seen between a high and low ALP flare ratio ( p = 0.8054 ) in docetaxel-treated patients. The ALP flare ratio was the most significant prognostic factor for OS ( p < 0.0001 ). Conclusions. A higher ALP flare ratio after first-line ADT was a significant prognostic factor in metastatic PCa, especially in patients treated with second-generation ART for CRPC. Chemotherapy for patients with a higher ALP flare ratio 1 month after induction of ADT may be a clinically relevant decision.

Purpose Second-line endocrine therapy (ET) for estrogen receptor (ER)-positive and human epidermal growth factor 2 (HER2)-negative metastatic breast cancer (MBC) is offered based on the response to first-line ET. However, no clinical trials have evaluated the efficacy and safety of secondary ETs in patients with poor responses to initial ET. This study evaluated the efficacy of second-line ET in ER-positive and HER2-negative postmenopausal MBC patients with low or very low sensitivity to initial ET. Methods This multicenter prospective observational cohort study evaluated the response of 49 patients to second-line ETs in postmenopausal MBC patients with low or very low sensitivity to initial ET. The primary endpoint was the clinical benefit rate (CBR) for 24 weeks. Results Of the 49 patients assessed, 40 (82%) received fulvestrant in the second line, 5 (10%) received selective estrogen receptor modulators, 3 (6%) received aromatase inhibitors (AIs) alone, and 1 received everolimus with a steroidal AI. The overall CBR was 44.9% [90% confidence interval (CI): 34.6–57.6, p = 0.009]; CBR demonstrated similar significance across the progesterone receptor-positive (n = 39, 51.3%, 90% CI: 39.6–65.2, p = 0.002), very low sensitivity (n = 17, 58.8%, 90% CI: 42.0–78.8, p = 0.003), and non-visceral metastases (n = 25, 48.0%, 90% CI: 34.1–65.9, p = 0.018) groups. The median progression-free survival was 7.1 months (95% CI: 5.6–10.6). Conclusion Second-line ET might be a viable treatment option for postmenopausal patients with MBC with low and very low sensitivity to initial ET. Future studies based on larger and independent cohorts are needed to validate these findings.

Although peripheral blood-based parameters (PBBPs) are reported as prognostic indicators in patients with breast cancers, their utility has not been studied in human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer (ABC). Tumor-infiltrating lymphocytes (TILs) might be a predictive factor in patients with HER2-positive ABC treated with pertuzumab and trastuzumab (PT) plus docetaxel. We aimed to evaluate whether PBBPs could have predictive value in HER2-positive ABC treated with pertuzumab and trastuzumab (PT) combined with eribulin (ERI) or nab-paclitaxel (Nab-PTX). Data from 51 patients included in two single-arm, phase II trials were included in this retrospective-prospective study; the ERI + PT (N = 30) and Nab-PTX + PT (N = 21) combinations were registered under clinical trials number UMIN000012375 and UMIN000006838, respectively. We assessed PBBPs using prospectively collected data and investigated the association with progression-free survival (PFS); we evaluated absolute lymphocyte count (ALC), neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR). The cutoff values for ALC, NLR, and PLR were set at 1000 or 1500 cells/μL, 2, and 250, respectively. PFS was significantly improved in patients with ALC ≥1500/μL compared to those with ALC 1000–

Although eribulin and nab-paclitaxel are chemotherapy agents widely used for locally advanced or metastatic breast cancer (MBC), their predictive factors remain unknown. Because the absolute neutrophil-to-lymphocyte ratio (NLR) is a significant prognostic factor for early-stage breast cancer, we investigated its usefulness in terms of the eribulin or nab-paclitaxel treatment efficacy for MBC.A total of 85 patients with MBC treated with eribulin (n = 59) or nab-paclitaxel (n = 26) were recruited. NLR values were collected at baseline, after 1 cycle, after 2 cycles, and at the end of treatment. The NLR cutoff value was set at 3.The progression-free survival (PFS) of patients with an NLR 3 at baseline (median, 242 days; n = 24) was significantly better than that of patients with an NLR of ≥ 3 (median, 98 days; n = 35; hazard ratio, 0.37, 95% confidence interval, 0.18-0.71; P = .0032). Similarly, the overall survival was marginally significantly better in patients with an NLR 3 who were treated with eribulin (P = .058). However, the NLR was not significantly associated with PFS or overall survival for patients treated with nab-paclitaxel. No significant association was found between the NLR during treatment and PFS in the eribulin group. The significance of the NLR for the efficacy of eribulin was consistent, irrespective of estrogen receptor status, previous anthracycline or endocrine use, and the number of previous chemotherapy regimens.A low NLR at baseline was significantly associated with improved PFS in patients treated with eribulin but not in those treated with nab-paclitaxel. Therefore, the baseline NLR might be clinically useful for selecting patients who would benefit from eribulin.

Background: Tumor-infiltrating lymphocytes might be a one of predictive outcome of human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer (ABC) patients (pts) who treated with trastuzumab and pertuzumab (TP) plus docetaxel. Although peripheral blood-based parameter (PBBP) is reported as a prognostic indicator of patients with early breast cancers, utility of PBBP has not been studied in HER2-positive ABC. Objective:The aim of our study was to determine whether PBBP is significant for predictive efficacy in HER2-positive ABC treated with TP combined with eribulin (ERI) or nab-paclitaxel (Nab-PTX). Methods: The 51 patients' data from two single arm phase II trials was included in this retrospective-prospective study; ERI + TP (n=30) or Nab-PTX + TP (n=21) registered with UMIN000012375 or UMIN000006838, respectively. We assessed the PBBP in prospectively collected data and investigated their association with progression-free survival (PFS). In consideration of PBBP, we evaluated absolute lymphocyte count (ALC), neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR). The cutoff values of ALC, NLR, and PLR were set at 1000 cells/μL, 2, and 250, respectively. Results:Median age at baseline was 58 years (range: 31-77). Median number of previous chemotherapy was 3 (range: 1-10). Pts had multiple metastases, 53% with LNs, 35% with bone, 25% with lung, 20% with liver, and 6% with brain. The objective response rate (CR+PR) and clinical benefit rate (CR+PR+ more than 6 month SD) were 37% (n=19) and 59% (n=30), respectively. The median PFS of all pts was 301 days (range: 21-1281). The PFS of pts with ALC-High was significantly better than those of ALC-low (hazard ratio (HR): 2.74, 95% confidence interval (CI): 1.28 to 5.86; p= .0097). Furthermore, improved PFS was obtained in pts with ALC greater than 1500 cells/μL compared with less than 1000 cells/uL (HR: 4.05, 95% CI: 1.60 to 11.6; p= .0029). Significant associations seem to exist irrespective of number of previous chemotherapy. Since we combined different studies for evaluating PBBP, ERI and Nab-PTX were calculated separately. Marginally significant associations between ALC and PFS were obtained both in ERI (HR: 2.18, 95% CI: 0.87 to 5.60; p=.0973) and Nab-PTX (HR: 3.26, 95% CI: 0.80 to 12.4; p=.0939). The PFS of NLR-low pts was significantly better than those of NLR-high (HR: 2.29, 95% CI: 1.01 to 5.90; p= .0477), but this statistical difference was inferior to those of ALC. There was no significant association between PLR and PFS. Conclusions: Pre-treatment ALC-High was significantly correlated with favorable PFS of pts treated with TP irrespective of combination chemotherapy in HER2-positve ABC. Prolonged PFS of TP combination therapy might be obtained mediating through host systemic onco-immunity. These data obtained here suggest that a usefulness of ALC for selecting pts who might have clinical benefit from TP combination therapy for heavily treated HER2-positve ABC. Citation Format: Araki K, Ito Y, Fukada I, Kobayashi K, Ohno S, Miyagawa Y, Imamura M, Kira A, Takatsuka Y, Egawa C, Suwa H, Miyoshi Y. Predictive impact of absolute lymphocyte counts for progression-free survival in HER2-positive advanced breast cancer treated with pertuzumab and trastuzumab plus eribulin or nab-paclitaxel [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-09-31.

Purpose To evaluate the association between tumor shrinkage patterns shown with magnetic resonance (MR) imaging during neoadjuvant chemotherapy (NAC) and prognosis in patients with low-grade luminal breast cancer. Materials and Methods This retrospective study was approved by the institutional review board and informed consent was obtained from all subjects. The low-grade luminal breast cancer was defined as hormone receptor-positive and human epidermal growth factor receptor 2-negative with nuclear grades 1 or 2. The patterns of tumor shrinkage as revealed at MR imaging were categorized into two types: concentric shrinkage (CS) and non-CS. Among 854 patients who had received NAC in a single institution from January 2000 to December 2009, 183 patients with low-grade luminal breast cancer were retrospectively evaluated for the development set. Another data set from 292 patients who had received NAC in the same institution between January 2010 and December 2012 was used for the validation set. Among these 292 patients, 121 patients with low-grade luminal breast cancer were retrospectively evaluated. Results In the development set, the median observation period was 67.9 months. Recurrence was observed in 31 patients, and 16 deaths were related to breast cancer. There were statistically significant differences in both the disease-free survival (DFS) and overall survival (OS) rates between patterns of tumor shrinkage (P < .001 and P < .001, respectively). Multivariate analysis demonstrated that the CS pattern had the only significant independent association with DFS (P = .001) and OS (P = .009) rate. In the validation set, the median follow-up period was 56.9 months. Recurrence was observed in 20 patients (16.5%) and eight (6.6%) deaths were related to breast cancer. DFS rate was significantly longer in patients with the CS pattern (72.8 months; 95% confidence interval [CI]: 69.9, 75.6 months) than in those with the non-CS pattern (56.0 months; 95% CI: 49.1, 62.9 months; P ≤ .001). The CS pattern was associated with an excellent prognosis (median OS, 80.6 months; 95% CI: 79.3, 81.8 months vs 65.0 months; 95% CI: 60.1, 69.8 months; P = .004). Multivariate analysis demonstrated that the CS pattern had the only significant independent association with DFS (P = .007) and OS (P = .037) rates. Conclusion The CS pattern as revealed at MR imaging during NAC had the only significant independent association with prognosis in patients with low-grade luminal breast cancer. © RSNA, 2017.

Background The efficacy and safety of continuing multiple anti-HER2 therapies in advanced breast cancer (ABC) patients remains unclear. This study investigated eribulin in combination with pertuzumab and trastuzumab for both taxane- and trastuzumab-pretreated HER2-positive ABC patients. Methods In a single-institute, single-arm, open-label, phase II trial, HER2-positive ABC patients who had previously received taxanes and trastuzumab were treated with eribulin in combination with pertuzumab and trastuzumab. The pharmacokinetics of eribulin in this combination were assessed in 6 patients. Tumor assessments were conducted every 6 weeks for the first 6 cycles and every 12 weeks thereafter. The primary endpoint was objective response rate (ORR). Results A total of 30 patients (median age, 58 years; range, 31–76) were enrolled, with a median number of previous chemotherapy regimens of 3.5 (range: 1–9) in the metastatic setting. Pharmacokinetic parameters of eribulin in this combination were similar to previous reports of eribulin monotherapy. ORR was 34.8% (95% CI: 16.4–57.3, n = 23), and median progression-free survival was 42.6 weeks (95% CI: 20.3–51.9, n = 30). Clinical benefit rate was 60.9% (95% CI: 16.4–57.3). The most common grade 3/4 adverse event was neutropenia in 20 patients (66.7%). A dose reduction of eribulin was required in 27 patients due to adverse events, particularly grade 3 neutropenia. Conclusions Eribulin in combination with pertuzumab and trastuzumab was well tolerated in heavily pretreated patients. Eribulin may be a viable treatment option when used in combination with pertuzumab and trastuzumab for HER2-positive ABC patients (UMIN Clinical Trial Registry identification number, UMIN000012375).

Background Trastuzumab (Tmab), pertuzumab (Pmab), and taxane has been a standard first-line treatment for recurrent or metastatic human epidermal growth factor (HER2)-positive breast cancer (HER2+ mBC) but has some safety issues due to taxane-induced toxicities. This has led to ongoing efforts to seek less toxic alternatives to taxanes that are equally effective when used in combination with Tmab plus Pmab. This study aims to show the non-inferiority of eribulin, a non-taxane microtubule inhibitor, against taxane, as a partner for dual HER2 blockade. Methods/design This multicenter, randomized, open-label, parallel-group, phase III study will involve a total of 480 Japanese women with HER2+ mBC who meet the following requirements: (1) age 20–70 years; (2) no prior cytotoxic chemotherapy (excluding trastuzumab-emtansine) for mBC; (3) ≥ 6 months after prior neoadjuvant or adjuvant cytotoxic chemotherapy; (4) presence of any radiologically evaluable lesion; (5) left ventricular ejection fraction ≥ 50%; (6) Eastern Cooperative Oncology Group performance status score of 0 or 1; (7) adequate organ function; and (8) life expectancy of at least 6 months. They will be randomized 1:1 to receive eribulin (1.4 mg/m2 on days 1 and 8) or taxane (docetaxel 75 mg/m2 on day 1 or paclitaxel 80 mg/m2 on days 1, 8, and 15) in combination with Tmab (8 mg/kg then 6 mg/kg) plus Pmab (840 mg then 420 mg) on day 1 of each 21-day cycle. The treatment will be continued until disease progression or unmanageable toxicity. The primary endpoint is progression-free survival as per investigator according to RECIST v1.1 criteria. Key secondary endpoints include objective response rate, overall survival, quality of life and safety. Non-inferiority will be tested with two margins of 1.33 and 1.25 in a stepwise manner. If non-inferiority is shown with a margin of 1.25, superiority will then be tested. Discussion If this study shows the non-inferiority, or even superiority, of Tmab, Pmab, and eribulin against the existing taxane-containing regimen, this new regimen may become a standard first- or second-line treatment option for HER2+ mBC in Japan. Trial registration ClinicalTrials.gov, ID: NCT03264547. Registered on 28 June 2017.

The combination chemotherapy regimen of eribulin (ERI) and trastuzumab (TRA)—the ERI-TRA regimen—has been shown to be highly tolerable for patients with recurrent or metastatic human epidermal growth factor receptor 2 (HER2)-positive breast cancer. However, no sufficient clinical evidence is available for the long-term safety profile of the regimen. We report on three patients in the Phase I combination study of the regimen, for whom the regimen could be conducted over the long term. Patient #1 was a 68-year-old woman and underwent the regimen until cycle 23. Patient #2 was a 61-year-old woman and underwent the regimen until cycle 27. Patient #3 was a 59-year-old woman and underwent the regimen until cycle 22. All these patients had undergone TRA-based combination therapy before the onset of the regimen. Any new categories of adverse events did not occur in association with the long-term combination chemotherapy. Neutropenia experienced by these patients was reversible and easily manageable by dose adjustment (interruption/delay and reduction). Neither increase in the risk of cardiomyopathy nor the worsening of peripheral neuropathy greater than grade 1 was found. The present regimen was suggested to be a novel chemotherapeutic option for patients with HER2-positive recurrent or metastatic breast cancer. The fact that the long-term ERI-TRA regimen was successfully conducted for these patients can be supplementary clinical information that is beneficial for clinical oncologists.

Background Multiple anti-HER2 therapies have improved the outcome for patients with HER2-positive breast cancer. However, optimal management has yet to be established for lapatinib (LAP)- and trastuzumab (Tmab)-resistant disease progression. Data from our institution were reviewed to contribute to the search for best practices. Patients and Methods Between June 2009 and March 2013, 74 HER2-positive advanced breast cancer (ABC) patients were treated with LAP with capecitabine (LAPCAP). Patients re-treated with Tmab-based chemotherapies were identified, with a focus on baseline characteristics, chemotherapies, and efficacy. The study focused on the clinical outcomes of 50 patients re-treated with Tmab after LAPCAP-resistant disease progression (LAPCAP-PD), with an assessment of tumor response and clinical benefit (CB). Progression-free survival (PFS) was used as a predictive surrogate marker for the efficacy of Tmab rechallenge. Results All patients were pretreated with Tmab- and LAP-based chemotherapies. At a median follow-up of 7.9 months, PFS was 4.6 months, and overall survival was 33.7 months after LAPCAP-PD. Rechallenges with Tmab-based chemotherapies included gemcitabine (GEM) in 23 patients, vinorelbine in 14, taxanes in 5, endocrine treatments in 2, and others. The CB rate was 32%, including complete response for 1, partial response for 3, and > 6 months of stable disease for 12. Although the median PFS was longer for patients treated with microtubule inhibitors (MTIs) than with GEM, various chemotherapies had different efficacy regardless of whether or not previous LAPCAP had CBs. Conclusion Tmab rechallenge combined with not only MTIs but also an antimetabolite agent is effective against some LAPCAP-PD HER2-positive ABC.

Tocilizumab (TCZ) is a humanized antihuman interleukin-6 (IL-6) receptor antibody used for the treatment of inflammatory diseases such as rheumatoid arthritis (RA). While TCZ could act as a therapeutic agent, it has a potential for inducing adverse drug events including psoriasis-like eruption. Seven cases with specific reference to TCZ-induced psoriasis eruption have been reported worldwide so far. In these cases, treatments with the same dosage of TCZ were either maintained or discontinued. Herein, we report a case involving a 74-year-old man diagnosed with rheumatoid factor-positive and anti-citrullinated protein antibody-positive RA with comorbidity of atopic dermatitis. TCZ was administered intravenously with oral methotrexate. After the third infusion, the patient developed TCZ-induced psoriasis-like eruptions, which were resolved by shortening the dose interval. Eruption recurrence was not observed after frequent TCZ subcutaneous injection. Our case may help physicians manage TCZ-induced psoriasis-like eruption.

We aimed to confirm the efficacy of fulvestrant in Japanese postmenopausal advanced/recurrent breast cancer (ABC) patients, and investigate factors contributing to time-to-treatment failure (TTF) prolongation.This retrospective study included 194 ABC patients who received fulvestrant (500 mg) from January 2012 to December 2014.TTF (efficacy measure), overall survival (OS), factors prolonging TTF and adverse events were evaluated.The median age was 65 (42 - 90) years. Overall, TTF was 5.48 months. In patients without prior chemotherapy (n = 59), OS was significantly longer (p = 0.0131) than in patients with prior chemotherapy (n = 135). There was no strong correlation between TTF with fulvestrant and other endocrine therapies, total duration of endocrine therapy and maximum duration of endocrine therapy. TTF was significantly longer in patients with less than two prior chemotherapy regimens (p = 0.0093), de novo metastatic disease (p = 0.0124) and without liver metastasis (p = 0.0024). We observed one case each of pulmonary infarction and psychiatric disorder.Fulvestrant is effective for ABC patients and may show greater efficacy in patients with few prior chemotherapy regimens, de novo metastatic disease and absence of liver metastasis. Prior endocrine therapy duration might not be a predictive factor for fulvestrant TTF in heavily treated ABC patients.

Fulvestrant 500 mg is currently approved for the treatment of postmenopausal women with hormone receptor-positive metastatic breast cancer after failure of prior endocrine therapies.A total of 117 postmenopausal women with metastatic breast cancer, who experienced progression after previous endocrine therapies, were treated with fulvestrant 500 mg between January 2012 and June 2014. Clinical response, time to progression (TTP) and adverse events were investigated.Ninety-nine patients had recurrent breast cancer and 18 patients had stage IV disease. Patients had received a median of two endocrine therapies and a median of two chemotherapies, prior to fulvestrant. There were 10 patients with partial response, 39 patients with long stable disease, 18 patients with stable disease, and 50 patients with progressive disease, so that the objective response rate was 8.5 %, with a clinical benefit rate of 41.9 %. The median TTP was 6.1 months. The absence of liver metastases, a small number of previous chemotherapies, and the longer duration of first-line endocrine therapy were positively correlated with TTP in univariate analysis. In multivariate analysis, a significant association was observed between TTP and duration of first-line endocrine therapy. Serious adverse events were observed in one patient with pulmonary embolism and in one patient with psychiatric symptoms.Fulvestrant 500 mg is an effective and well-tolerated treatment for postmenopausal women with metastatic breast cancer that had progressed after prior endocrine therapies. Patients with acquired resistance to endocrine therapies might be good candidates for fulvestrant therapy regardless of the number of prior endocrine treatments.

Pulmonary tumor thrombotic microangiopathy (PTTM) is a rare cancer-related complication leading to hypoxia, pulmonary hypertension, and heart failure. The standard treatment for PTTM is not established. However, imatinib, a tyrosine kinase inhibitor of platelet-derived growth factor receptor (PDGFR), may cause regression of pulmonary hypertension and pulmonary artery remodeling in PTTM. We report a case of a 61-year-old woman in whom PTTM developed during chemotherapy for metastatic breast cancer. Although imatinib alleviated pulmonary hypertension, she died because of progression of metastatic breast cancer 54 days after her initial admission to our hospital. It would be advisable to conduct a well-designed clinical trial using chemotherapy regimens combined with imatinib for PTTM.

Background Although the prognosis for operable breast cancers is reportedly worse if serum carcinoembryonic antigen (CEA) and cancer antigen 15-3 (CA15-3) levels are above normal, the usefulness of this prognosis is limited due to the low sensitivity and specificity; in addition, the optimal cutoff levels remain unknown. Methods A total of 1076 patients who were operated for breast cancers (test set = 608, validation set = 468) without evidence of metastasis were recruited, and their baseline and postoperative serum CEA and CA15-3 levels were analyzed. The optimal cutoff values of CEA and CA15-3 for disease-free survival (DFS) were 3.2 ng/mL and 13.3 U/mL, respectively, based on receiver operating characteristic curve and area under the curve analyses. Results The DFS of patients with high CEA levels (CEA-high: n = 191, 5-year DFS 70.6%) was significantly worse (p

A phase 1 study of pazopanib alone or in combination with lapatinib was conducted to assess the safety, tolerability, and pharmacokinetics of these oral tyrosine kinase inhibitors in Japanese patients with solid tumors.In part A (monotherapy), 7 patients initially received pazopanib 800 mg/day, the recommended dose for non-Japanese patients. Then, 3 patients received pazopanib 400 mg/day on day 1 followed by 800 mg/day from day 2 onward. Three other patients received pazopanib 1,000 mg/day. In part B (combination therapy), 17 patients received pazopanib plus lapatinib (pazopanib/lapatinib) at once-daily doses of 400/1,000 mg (4 patients), 800/1,000 mg (3 patients), 400/1,500 mg (3 patients), and then 600/1,250 mg (7 patients).There was no dose-limiting toxicity during the study. In part A, most drug-related adverse events were grade 2 or lower, including neutropenia/neutrophil count decreased, thrombocytopenia/platelet count decreased, diarrhea, hypertension, aspartate aminotransferase increased, and lipase increased. In part B, rash, decreased appetite, and serum thyroid-stimulating hormone increased also occurred. In all dose groups, the plasma concentrations after multiple doses of pazopanib exceeded the target trough concentration for inhibition of vascular endothelial growth factor receptor-2 activity (20 μg/mL).The pharmacokinetic profiles of pazopanib and lapatinib in Japanese patients were not apparently different from those reported in non-Japanese patients. There were no consistent trends in pharmacokinetic drug interactions between pazopanib and lapatinib. Pazopanib monotherapy at 800 and 1,000 mg once daily and pazopanib plus lapatinib once daily at any doses studied were well tolerated in Japanese patients.

Introduction Pulmonary tumor thrombotic microangiopathy (PTTM) is rare, cancer-related pulmonary complication leading to hypoxia, pulmonary hypertension, and heart failure. The standard treatment for PTTM is not established. However, imatinib, a tyrosine kinase inhibitor of the PDGF receptor, may cause regression of pulmonary hypertension and pulmonary artery remodeling in PTTM. Case descriptions We report two cases of PTTM who received an anti-PDGF agent of imatinib for PTTM developed during chemotherapy for metastatic breast cancer. Case 1: 61-year-old woman who underwent resection of the left breast and axillary lymph node dissection and received adjuvant chemotherapy (CAF followed by docetaxel), then endocrine therapy for 5 years. Twelve years after surgery, multiple bone and mediastinal lymph node metastases occurred. She was under treatment with eribulin for one year but admitted because of rapid progressing dyspnea. Case 2: 45-year-old woman with metastatic breast cancer in multiple bones was under treatment for 5 years. Receiving capecitabine, she suffered from dyspnea for 2 months, she was admitted to our hospital with diagnosis of severe hypoxia. In both cases, the wedged pulmonary arterial blood cell sampling revealed cytologically malignant cells which confirmed the diagnosis of PTTM. They were treated with imatinib, which alleviated pulmonary hypertension. However, they died due to progression of metastatic breast cancer. Discussion and Evaluation Single use of imatinib did not showed sufficient efficacy. It is necessary to conduct a well-designed clinical trial using chemotherapies combined with imatinib for PTTM. Conclusions Imatinib, which alleviated pulmonary hypertension, could be a new strategy for pulmonary tumor thrombotic microangiopathy in patient with metastatic breast cancer.

Introduction: Gastric metastasis of breast invasive ductal carcinoma is rare. We present a case of a patient developing aggressive recurrence of early breast invasive ductal carcinoma with gastric metastasis in the third year of adjuvant hormonal therapy. A rarely observed increase in human epidermal growth factor receptor 2 (HER2) overexpression was also observed at the recurrent metastatic sites, and this situation strongly influenced therapeutic management. Case presentation: A 49-year-old Japanese female with prolonged back pain was examined by abdominal ultrasound to eliminate the possibility of abdominal malignancy; she was found to have multiple tumors in the liver. Contrast-enhanced computed tomographic (CT) imaging was performed for thorough examination, revealing multiple tumors in abdominal lymph nodes and in the lungs in addition to the liver. An integrated positron emission tomographic CT scan showed metabolically active foci distributed throughout the body, including the thoracic and lumbar vertebrae, para-aortic lymph nodes, liver, and stomach. At the age of 46, the patient had undergone a lumpectomy without axillary lymph node dissection for early breast invasive ductal carcinoma (pT1N0M0 Stage I), and the cancer was positive for both estrogen and progesterone receptors while not overexpressing HER2. Currently, however, biopsies from gastric and liver tumors showed adenocarcinoma with histological and immunohistochemical properties similar to those of the previous breast invasive ductal carcinoma, indicating metastatic breast cancer. Interestingly, HER2 was overexpressed in the metastatic foci, and the difference in expression status influenced the choice of treatment. Conclusions: Aggressive recurrence of early breast invasive ductal carcinoma with gastric metastasis is rare. Furthermore, HER2 expression status differed between primary and metastatic foci, and reassessment of expression status was helpful for informing decisions on optimal treatment strategy.

S-1 plus cisplatin is the standard chemotherapy for recurrent gastric cancer. While depression and delirium are frequent in cancer patients, hypomania during chemotherapy is rare. We describe a rare case of hypomania during S-1 plus cisplatin treatment for recurrent gastric cancer. A 66-year-old woman, with no previous psychiatric disorder, received S-1 plus cisplatin for recurrent gastric cancer. She showed peculiar behavior. Physical examination, urine, blood and imaging findings were normal. There was no gastric cancer progression. During psychiatric consultation, she behaved inappropriately. However, she behaved normally while performing daily activities. She manifested a persistently elevated, expansive or irritable mood, clearly different from her usual non-depressed state, meeting hypomania diagnostic criteria. Her condition did not require chemotherapy discontinuation or additional medication. During the second and subsequent S-1 plus cisplatin cycles, symptoms were stable. Cancer patients often have adjustment disorders, depression and delirium, but rarely hypomania. Our patient showed no significant changes in blood biochemistry and brain and whole body imaging. While S-1 plus cisplatin-induced hypomania cannot be excluded, hypomanic symptoms did not improve during the chemotherapy rest period, nor was there deterioration during subsequent cycles, suggesting drug-induced mania to be unlikely. Possible onset mechanisms include manic defense phenomena, common with stressful life events. There are no reports of recurrent gastric cancer patients experiencing hypomania during S-1 or S-1 plus cisplatin therapy, i.e. our patient represents a rare course. Clinicians should recognize psychosis or mood disorders during gastric cancer treatment. Further accumulation of such rare cases might elucidate pathological mechanisms underlying hypomania in cancer patients.

Reversible posterior leukoencephalopathy syndrome (RPLS) is a serious neurologic disease characterized by visual disturbance, seizures, headache, and altered mental status associated with white matter changes, particularly in the occipital lobes. RPLS has been attributed to chemotherapy, including modified FOLFOX6 regimens consisting of 5-fluorouracil, oxaliplatin, and leucovorin. Although the mechanism of development of RPLS remains unclear, impaired cerebral blood flow autoregulation and endothelial dysfunction seem to be involved. In particular, endothelial dysfunction has been implicated in the pathophysiology of RPLS associated with platinum agents. Platinum-based chemotherapy is thought to have a direct toxic effect on the vascular endothelium, leading to capillary leakage, disruption of the blood–brain barrier, and axonal swelling, triggering vasogenic edema. Much progress has been made in chemotherapy for colorectal cancer, and the increasing use of molecular-targeted agents is expected to further improve the outcome of therapy. RPLS has recently been associated with such molecular-targeted therapy, particularly in patients concurrently receiving platinum agents. This finding is consistent with previous reports suggesting that RPLS occurs more often in patients receiving platinum-based therapy than in those receiving molecular-targeted agents. Because platinum agents are the most widely used in cancer chemotherapy, clinicians should strongly suspect RPLS in patients receiving treatment with this class of drug.

Objective: To evaluate the safety and efficacy of combination chemotherapy with 5-fluorouracil (5-FU), leucovorin, irinotecan and oxaliplatin (FOLFOXIRI) in Japanese patients with advanced colorectal cancer. Methods: This phase I dose-finding study was designed to determine the maximum tolerated dose (MTD), recommended dose (RD) or both of FOLFOXIRI. Patients with UDP-glucuronosyltransferase (UGT) 1A1*6/*6, *28/*28 and *6/*28 genotypes were excluded, because these UGT1A1 genotypes are linked to severe neutropenia in Japanese. Results: A total of 10 Japanese patients with advanced colorectal cancer were studied. The MTD of FOLFOXIRI in these Japanese patients was 165 mg/m2 irinotecan, 85 mg/m2 oxaliplatin and 2,400 mg/m2 5-FU. Accordingly, the RD of FOLFOXIRI was determined to be 150 mg/m2 irinotecan, 85 mg/m2 oxaliplatin and 2,400 mg/m2 5-FU. Toxic effects, evaluated until the completion of 4 cycles, were manageable. Grade 3–4 neutropenia occurred in 27% of cycles, but there was no febrile neutropenia. Among the 9 assessable patients, the objective response rate was 89%. Conclusions: We thus determined the RD of FOLFOXIRI in Japanese patients with advanced colorectal cancer who do not have UGT1A1*28/*28, *6/*6 or *6/*28 genotypes. Our results indicate that FOLFOXIRI is a well-tolerated regimen for these Japanese patients.

Purpose Sagopilone has recently been identified and preferentially used for the treatment of taxane-resistant cancer. The purpose of this dose-escalation study was to investigate the safety, tolerability, and pharmacokinetics (PK) of sagopilone in refractory solid tumors. Methods A total of 17 Japanese patients received sagopilone in this Phase I study. Sagopilone was given as a 30-min intravenous infusion once every 3 weeks (one course) with an initial dose of 12.4 mg/m2 up to 22.0 mg/m2 for a maximum of 6 courses. Results The maximum tolerated dose (MTD) was determined to be 16.5 mg/m2. The major dose-limiting toxicity (DLT) was peripheral sensory neuropathy. The PK data demonstrated that sagopilone did not accumulate after repeated administration. Two patients had stable disease (SD) over a period of 12 weeks. Conclusions Our study demonstrated clinically favorable safety, tolerability, and efficacy of sagopilone, which will help define the treatment of advanced tumors in more extensive clinical trials.

Trastuzumab is known for its clinical activity in women with HER2-overexpressing breast cancer. Randomized clinical trials have shown significant improvement in disease-free and overall survival with trastuzumab administered in conjunction with adjuvant chemotherapy for early-stage HER2-positive breast cancer. However, there is no direct evidence of clinical benefit from adjuvant trastuzumab in patients with node-negative, HER2-overexpressing, small (T1a-b) breast cancers. Previous literature shows that most breast cancers with node-negative small tumors have a good prognosis, but HER2-overexpressing disease might still be worse in this population. Some recent retrospective studies showed that an adjuvant trastuzumab-based regimen has a better prognostic effect, even in patients with node-negative, HER2-overexpressing, small breast cancers, although absolute survival differences were small. On the basis of the available literature, we believe that trastuzumab should be considered for patients with minimal HER2-overexpressing disease, although tools for accurate selection of patients at risk of relapse still need to be developed.

Background we investigated the maximum tolerated dose (MTD) of combination therapy with docetaxel, cisplatin, and S-1 (TPS) in patients with locally advanced or recurrent/metastatic head and neck cancer (HNC). Patients and methods treatment consisted of docetaxel (Taxotere) at doses of 50, 60, and 70 mg/m(2); cisplatin at 70 mg·m(2)/day on day 1; and S-1 twice daily on days 1-14 at doses of 40, 60, and 80 mg·m(2)/day, repeated every 3 or 4 weeks. Results forty patients were enrolled. MTD was not reached until level 4. Subjects at expanded dose were limited to patients with locally advanced disease. Two dose-limiting toxic effects (DLTs) were observed at dose level 5 (TPS: 70/70/80 mg·m(2)/day, every 3 weeks), namely one grade 3 infection and one grade 3 hyperbilirubinemia, establishing this as the MTD. Of 12 patients treated at dose level 6 (TPS: 70/70/60 mg·m(2)/day, every 3 weeks), 2 DLTs were seen. Six achieved a complete response and 22 a partial response, giving a response rate of 70%. Conclusions TPS was well tolerated. The recommended phase II dose as induction chemotherapy for locally advanced HNC was determined as 70/70/60 mg·m(2)/day every 3 weeks. Antitumor activity was highly promising and warrants further investigation.

Differences in efficacy and toxicity between UDP-glucuronosyltransferase (UGT) 1A1*1/*1 and *1/*6 or *1/*28 genotypes remain unclear in Japanese patients. Patients with advanced colorectal cancer who received irinotecan combined with 5-fluorouracil plus l-leucovorin (FOLFIRI) as first-line therapy were divided into two groups: those with UGT1A1*1/*1 genotype and those with UGT1A1*1/*6 or *1/*28 genotype. Efficacy and toxicity were compared between these groups retrospectively. Forty-two patients (24 *1/*1 and 18 *1/*6 or *1/*28) were evaluated. The response rate was 48% in *1/*1 group and 56% in *1/*6 or *1/*28 group (P = 0.847). Median progression-free survival was 8.6 months in *1/*1 group and 8.5 months in *1/*6 or *1/*28 group (P = 0.888). No hematologic or non-hematologic toxic effects were clearly related to UGT1A1*1/*6 or *1/*28 during the first cycle or throughout the entire course of chemotherapy. There were no significant differences in the efficacy or toxicity of FOLFIRI between patients with UGT1A1*1/*1 genotype and those with UGT1A1*1/*6 or *1/*28 genotype. Our results suggest that patients with the latter genotypes can receive FOLFIRI at the same dose of irinotecan as those with the UGT1A1*1/*1 genotype receive.

611 Background: Hypertension (HT) is an established risk factor for developing renal cell carcinoma (RCC), and a relationship between the renin-angiotensin system and RCC has been emphasized. However, information about the impact of HT on treatment outcomes of patients after RCC surgery is limited. The present study aimed to clarify the impact of HT on the recurrence and survival of patients with RCC after surgery. Methods: Relationships between HT and clinical data including treatment outcomes were retrospectively analyzed in 149 patients (male, n = 112; female, n = 37; median age, 63 y; range, 29-86 y at the time of surgery) who underwent surgery between 2010 and 2016 at our hospital. Data were statistically analyzed using JMP version 9.0. Results: During a median follow-up period of 30.9 months, 28 and 16 patients experienced recurrence and died, respectively. Patients (n = 15) with Stage IV RCC were excluded from the analysis of recurrence. Five-year overall (OS) and recurrence-free (RFS) survival rates of the entire cohort were 80.8% and 76.1%, respectively. Kaplan-Meier analysis did not uncover a relationship between HT and OS, but the RFS rate was significantly lower for patients with HT than without HT (P = 0.0468). Tumor stage and the prevalence of proteinuria were significantly higher in the group with HT. The prevalences of vessel invasion (P = 0.0582) and low pre-surgical hemoglobin values (P = 0.0585) tended to be significantly higher for patients with HT. Conclusions: Patients with HT had significantly worse RFS rates, a more advanced stage of disease at the time of surgery, and a tendency towards a higher rate of vessel invasion. Further investigations are warranted to determine how HT promotes cancer progression.

To investigate the effects of genetic polymorphisms on morphine-induced adverse events in cancer patients. We examined the relation of morphine-related adverse events to polymorphisms in UDP-glucuronosyltransferase (UGT) 2B7, ATP-binding cassette, sub-family B, number 1 (ABCB1), and μ-opioid receptor 1 genes in 32 Japanese cancer patients receiving oral controlled-release morphine sulfate tablets. The T/T genotype at 1236 or TT/TT diplotype at 2677 and 3435 in ABCB1 was associated with significantly lower frequency of fatigue (grades 1–3) (P = 0.012 or 0.011, Fisher’s exact test). The UGT2B7*2 genotype was associated with the frequency of nausea (grades 1–3) (P = 0.023). The frequency of nausea was higher in patients without UGT2B7*2 allele than others. The diplotype at 2677 and 3435 in ABCB1 was associated with the frequency of vomiting (grades 1–3) (P = 0.011). No patient whose diplotype was consisted of no GC allele at 2677 and 3435 suffered from vomiting. Our findings suggest that pharmacogenetics can be used to predict the risk of morphine-induced adverse events.

Sorafenib is a novel oral multikinase inhibitor that targets Raf serine/threonine and receptor tyrosine kinases, and inhibits tumor cell proliferation and angiogenesis. We have conducted a phase I study of sorafenib to determine the safety, tolerability, pharmacokinetics, and potential efficacy of this agent in 31 Japanese patients with advanced refractory solid tumors. Sorafenib (100–600 mg) was given as a single dose followed by a 7-day wash-out period, and then administrated twice daily (bid). The most frequent drug-related adverse events were rash/desquamation (61%), hand–foot skin reactions (39%), diarrhea (36%), and elevations of serum lipase (36%) and amylase (26%) levels. Dose-limiting toxicities (DLTs) were grade 3 diarrhea at 200 mg bid and grade 3 fatigue at 600 mg bid. Grade 3 and 4 pancreatic enzyme elevations were observed at 200–600 mg bid, but they were not deemed dose-limiting because they were asymptomatic and were not associated with pancreatitis or chronic damage to the pancreas. The AUC and Cmax of sorafenib increased linearly with dose up to 400 mg bid. Partial responses were observed in one of 10 patients with non-small cell lung cancer and one of three patients with renal cell carcinoma. In conclusion, sorafenib 400 mg bid was well tolerated in Japanese patients with advanced refractory solid tumors. The recommended dose for future clinical trials is 400 mg bid. (Cancer Sci 2008; 99: 1492–1498)

The relationships between serum level of testosterone (T) and prostate cancer (PCa) are complex. The present study evaluated whether presence of PCa alters serum T levels. Subjects were 125 patients with clinically localized PCa treated using radical prostatectomy (RP), for whom pretreatment T levels were recorded. We investigated clinical and pathological factors such as pretreatment serum T level, age, pretreatment prostate-specific antigen, Gleason score and pathological stage. Serum T and human luteinizing hormone (LH) levels before and after RP were then compared in 118 of the 125 patients. Mean pretreatment T level was significantly higher in patients with organ-confined PCa (pT2; 4.03+/-1.50 ng ml(-1)) than in patients with nonorgan-confined cancer (pT3; 3.42+/-1.06 ng ml(-1); P=0.0438). No association existed between pretreatment serum T level and pathological Gleason score. After RP, serum T level (5.60+/-1.90 ng ml(-1)) was significantly elevated compared to preoperative level (3.89+/-1.43 ng ml(-1); P0.0001). In parallel, significant increases were seen in postoperative serum LH level (6.86+/-3.64 ng ml(-1)) compared to preoperative level (5.11+/-2.47 ng ml(-1); P=0.0001). In contrast, differences in serum T levels according to pathological stage disappeared postoperatively (P=0.5513). Significant increases in serum T and LH levels were seen after RP, compared to preoperative levels in parallel. This study suggests that serum T levels are altered by the presence of PCa, supporting the possibility that PCa may inhibit serum T levels with negative feedback in the hypothalamic-pituitary axis.

Relationships between androgenic hormones and prostatic tissue growth are complex. It is certainly true that the prostate will not develop without androgens and the gland will atrophy if androgen support is withdrawn. The hormonal hypothesis remains one of the most important hypotheses in the etiology of prostate cancer (PCa), and efforts are continuing to improve the understanding of androgen actions in PCa. Although evidence from epidemiological studies of associations between circulating levels of androgens and PCa risk has been inconsistent, the traditional view that higher testosterone (T) levels represent a risk factor for PCa appears to have little evidentiary support. Reinvestigation of the relationship between T and PCa seems important and necessary if a new, clinically and scientifically rewarding concept is to be constructed. The present review considers the metabolism and intraprostatic action of T, epidemiological evidence, and the association between T and PCa risk.

ATP-binding cassette, sub-family C, number 2 (ABCC2) is involved in the biliary excretion of irinotecan and its metabolites, SN-38 and SN-38 glucuronide. Effects of the ABCC2 genotype on the pharmacokinetics (PK) of irinotecan and the metabolites were examined in Japanese patients with metastatic colorectal cancer receiving irinotecan plus infusional 5-fluorouracil/leucovorin (FOLFIRI). ABCC2 genotypes (-1549G>A, -1023G>A, -1019A>G, -24C>T, 1249G>A and 3972C>T) and haplotypes were analyzed for 67 patients with cancer. PK was also examined in a subset of 31 patients receiving FOLFIRI. Relationship between the ABCC2 genotypes or diplotypes and area under the time-concentration curve (AUC) of irinotecan and the metabolites normalized by irinotecan dose was analyzed. The lower AUC of irinotecan was seen in patients with A/A or G/A genotypes at 1249 of the ABCC2 gene than others (p=0.011, Mann-Whitney U teat). AUC of SN-38 in patients with A/A or G/A genotypes at -1023 was significantly lower than that in others (p=0.018). The haplotype I included -1023A (GAACGC) was the most frequent one with the allele frequency of 0.366. The AUC of SN-38 observed in patients with diplotypes harboring at least one haplotype I was lower than that observed in others (p=0.023). The haplotype IV consisted of 1249 (GGACAC) and was the fourth most frequent one with the allele frequency of 0.127. Patients with diplotypes carrying at least one haplotype IV showed lower AUC of irinotecan than others (p=0.011). Thus, ABCC2 genotype is one of the predictors of the variability of irinotecan PK in Japanese patients with metastatic colorectal cancer receiving FOLFIRI.

Purpose There is a significant difference in the mean tumor size between very young breast cancer patients and their elder counterparts. A simple comparison may show obvious prognostic differences. We investigated the prognostic impact of age by reducing the influence of the tumor size, which is thought to be a confounding factor. Patients and methods We investigated 1,880 consecutive pT1-4N0-3M0 breast cancer patients treated at less than 45 years of age between 1986 and 2002 and conducted a case–control study of breast cancer subjects less than 30 years of age. Each patient (Younger than 30) was matched with a corresponding control subject (Elder counterpart) based on an age 15 years above the patient’s age, a similar tumor size and a status of being within 1 year after surgery. In addition, we assessed 47 patients with pregnancy-associated breast cancer (PABC). The levels of hormone receptors were measured using an enzyme immunoassay (EIA), and receptor-positive cases were divided into “weakly” and “strongly” positive groups based on the median value. Years from the last childbirth (YFLC) was categorized as “recent” and “past” at the time point of 8 years. Results There were fewer past YFLC cases, more partial mastectomy cases, a higher rate of scirrhous carcinoma or solid-tubular carcinoma in the Younger than 30 group than in the Elder counterpart group. The rates of a PgR-negative status in the Younger than 30 and Elder counterpart groups were 45.1 and 29.9%, respectively, As for the relationship between the PgR-negative rate and YFLC, the rates of a PgR-negative status in the past YFLC, nulliparous, recent YFLC and PABC groups were 31.9, 37.7, 44.4 and 65.7%, respectively. On the other hand, the rates of strongly positive cases were 42.6, 30.2, 22.2 and 8.6%, respectively. The 10-year recurrence-free survival rates in the Younger than 30, Elder counterpart and PABC groups were 61.7, 65.6 and 54.1%, respectively. The differences between the groups were not significant. In a multivariate analysis, independent prognostic facers included the number of lymph node metastases (4–9, HR:3.388, 95% CI 1.363–8.425, p = 0.0086, over 10, HR: 6.714, 2.033–22.177, p = 0.0018), solid-tubular carcinoma (HR 3.348, 1.352–8.292, p = 0.0090), scirrhous carcinoma (HR 2.294, 1.013–5.197, p = 0.0465) and past YFLC (HR 0.422, 0.186–0.956, p = 0.0387). An age younger than 30 was not found to be an independent prognostic factor. Conclusions The prognosis of the very young women was the same as their elder counterparts with a matched tumor size, and age was not identified to be an independent prognostic factor according to the multivariate analysis. Recent childbirth probably influences the prognosis of patients younger than 30 years of age with breast cancer by lowering hormonal sensitivity.

Taxane drugs play a central role in chemotherapy for breast cancer. However, previous studies have reported that taxanes are relatively ineffective in patients with operable luminal breast cancer compared with other subtypes. Between January 2000 and August 2008, 293 patients with metastatic breast cancer were treated with taxanes in The Cancer Institute Hospital of The Japanese Foundation for Cancer Research and were included in the present study. The patients were divided into 4 subtypes based on the immunohistochemically evaluated estrogen receptor (ER), progesterone receptor (PgR) and human epidermal growth factor receptor 2 (HER2) status. The clinicopathological features, response rate (RR) and time to progression (TTP) were analyzed retrospectively. In total, 159 patient tissues were classified as luminal type (ER+ and/or PgR+ and HER2-), 28 patient tissues were classified as luminal-HER2 type (ER+ and/or PgR+ and HER2+), 57 patient tissues were classified as HER2 type (ER-, PgR- and HER2+), and 49 patient tissues were classified as triple-negative type (ER-, PgR- and HER2-). Among the 4 subtypes, the clinical benefit rate was 51.6, 78.6, 71.9 and 40.8%, respectively. There were significant differences in TTP between subtypes (median TTP, 8.3 months in luminal, 14.1 months in luminal-HER2, 10.6 months in HER2, and 4.2 months in triple-negative; P

Objectives To identify the prognostic factors in patients with recurrent renal cell carcinoma after nephrectomy, various factors were assessed, with special attention to serum immunosuppressive acidic protein (IAP) and its doubling time. Methods Age, sex, stage, grade, histopathologic type, primary tumor size, site and number of metastatic organs, time to recurrence, IAP levels before nephrectomy and at the diagnosis of recurrence, and IAP doubling time just before recurrence were analyzed in 125 patients with recurrent renal cell carcinoma after nephrectomy. Results Univariate analysis identified stage, grade, histopathologic type, primary tumor size, time to recurrence, IAP level at the diagnosis of recurrence, and IAP doubling time as significant prognostic factors. After exclusion of confounding factors, multivariate analysis showed that IAP doubling time was the most potent independent prognostic factor. Patient survival rates dichotomized according to IAP doubling time were compared at 100-day intervals from 100 to 700 days and 1000 and 2000 days. The maximal difference in survival rate was found when the cutoff level in the IAP doubling time was set at 200 days. Conclusions The results of our study have shown that the IAP doubling time is a potent prognostic factor in patients with recurrent renal cell carcinoma. Periodic checkups with serum IAP level monitoring are recommended to predict prognosis after recurrence.

Pharmacogenetic testing for UDP-glucuronosyltransferase (UGT) 1A1*28, a promoter variant of the UGT1A1 gene, is now carried out clinically to estimate the risk of irinotecan-associated toxicity. We studied the clinical significance of UGT1A1*6 and UGT1A1*27, two variants in exon 1 of the UGT1A1 gene that are found mainly in Asians. The study group comprised 46 Japanese patients who received various regimens of chemotherapy including irinotecan at doses from 50 to 180 mg/m(2). Pharmacogenetic relationships were explored between the UGT1A1 genotype and the ratio of the area under the plasma concentration-time curve (AUC) of the active metabolite of irinotecan (SN-38) to that of SN-38 glucuronide (SN-38G), used as a surrogate for UGT1A1 activity (AUC(SN-38)/AUC(SN-38G)). No patient was homozygous for UGT1A1*28, and none had UGT1A1*27. Two were heterozygous for UGT1A1*28. Two were homozygous and 15 heterozygous for UGT1A1*6, all of whom were wild type with respect to UGT1A1*28. Two patients were simultaneously heterozygous for UGT1A1*28 and UGT1A1*6, present on different chromosomes. The other 25 patients had none of the variants studied. The two patients simultaneously heterozygous for UGT1A1*28 and UGT1A1*6 and the two patients homozygous for UGT1A1*6 had significantly higher AUC(SN-38)/AUC(SN-38G) ratios than the others (P = 0.0039). Concurrence of UGT1A1*28 and UGT1A1*6, even when heterozygous, altered the disposition of irinotecan remarkably, potentially increasing susceptibility to toxicity. Patients homozygous for UGT1A1*6 should also be carefully monitored. UGT1A1 polymorphisms in the coding region of the UGT1A1 gene should be genotyped in addition to testing for UGT1A1*28 to more accurately predict irinotecan-related toxicity, at least in Asian patients.

Multiple myeloma (MM) is a fatal disease that affects plasma cells. Patients with MM have 1 or more osteolytic lesions in their bone tissues, where insulin-like growth factors (IGFs; IGF-I and IGF-II) are mainly stored. The role of bone-derived IGFs in the development of MM has not been extensively studied because reliable animal models are lacking. We established an animal model using a human MM cell line, RPMI8226, in nonobese diabetic/severe-combined immunodeficient (NOD/SCID) mice implanted with human adult bone (HAB) fragments. Treatment with an anti-human IGF-neutralizing monoclonal antibody, KM1468, inhibited the IGF-I-stimulated phosphorylation of type-I IGF receptors (IGF-IR) in RPMI8226 cells and the activation of the downstream PI3-K/Akt signaling pathway in vitro. KM1468 inhibited IGF-I-mediated RPMI8226 cell growth in a dose-dependent manner. In the NOD/SCID-HAB model, treatment with KM1468 significantly inhibited the growth of RPMI8226 cells (p

This study is aimed to identify clinical predictors, other than HER2 overexpression, for the response to lapatinib plus capecitabine (LAPCAP) in patients with HER2-positive advanced breast cancer (HER2ABC). Data from our medical records of 76 patients from June 2009 to March 2013 were analyzed. Evaluations of these patients with HER2ABC treated with LAPCAP included baseline characteristics, dose modifications, efficacy, and incidence of adverse events (AEs). With a median follow-up of 20 months, the median number of prior therapies for ABC before LAPCAP was 2 (range 0–13), and 66 patients had previously received trastuzumab. For LAPCAP, the overall response rate was 21 %, and the clinical benefit rate was 60 %. During the initial 12-month observation period, 93 % of patients had AEs. The most common AE was hand-foot syndrome (HFS) in 55 patients. Progression-free survival (PFS) was better in patients who had HFS than in those who did not (p = 0.0002). Since HFS is a well-known AE associated with CAP, whether CAP dose affected PFS or not was investigated, but no positive relationship was found. Since several studies with EGFR-targeted agents have suggested a positive correlation between cutaneous toxicities and outcomes, whether the incidence of any AEs affected PFS or not was explored among 76 patients. HFS, diarrhea, and rash were significant favorable factors (p = 0.0002, 0.0088, and 0.0011). The median PFS of patients who had all three AEs was 13.2 months, compared with 2.6 months for those who did not (p = 0.00000174). Mucocutaneous toxicities may be predictors of the response to LAP in patients with HER2ABC.

Objective: To investigate the risk of bladder cancer with pioglitazone, the data of diabetic patients treated at Teikyo Chiba Medical Center were analyzed retrospectively. Methods: From February 2009 to October 2011, 720 patients were treated with pioglitazone, and 742 patients were not treated with pioglitazone at Teikyo University Chiba Medical Center. The numbers of newly diagnosed bladder cancers from February 2009 to December 2013 in these patients and the occurrence of bladder cancer among type 2 diabetes mellitus patients were identified. The duration of diabetes, sex, age, smoking, and medication for diabetes were obtained from the medical records. The occurrence of bladder cancer was defined as incident cases after the initiation of pioglitazone. Statistical significance was analyzed by Fisher’s exact test. Results: About 2% of diabetic patients had bladder cancer. The incidence of bladder cancer was not different between the pioglitazone group (15/720, 2.0%) and the no pioglitazone group (14/742, 1.9%). No oral diabetes medication was related to the risk of bladder cancer. However, use of insulin was significantly related to bladder cancer risk (hazard ratio [HR]: 2.83; 95% confidence interval [CI]: 1.15–6.84; p=0.0246), and sex was also significantly related to bladder cancer (HR: 6.001; 95% CI: 1.397–43.06; p=0.0137). The duration of diabetes and smoking were not associated with bladder cancer risk. Conclusion: In this study, use of pioglitazone was not related to bladder cancer risk, while use of insulin was related

Renal cell carcinoma (RCC) is capable of metastasizing to several organs. Synchronous isolated contralateral adrenal metastasis of the primary RCC is, however, very rare. Herein we report a case of RCC with a huge solitary metastasis to the contralateral adrenal gland that was surgically treated. We scheduled nephrectomy for the left primary RCC and adrenalectomy for the right adrenal tumor. However, at surgery we found a huge right adrenal tumor that had invaded the right kidney, right renal vein, and inferior vena cava. Therefore right nephrectomy was performed simultaneously with resection and reconstruction of the inferior vena cava. Pathological findings demonstrated that the left renal tumor and right adrenal tumor had the same histology. Although the patient required hemodialysis, he remains well at six months postoperatively. So far, there have been only two cases of a solitary contralateral metastatic adrenal tumor that was larger than the primary RCC, thus the present case is the third one.

Background Pathological complete response (pCR) with neoadjuvant chemotherapy (NAC) has been regarded as a surrogate endpoint for disease-free survival (DFS) and overall survival (OS) of patients with breast cancer. No consensus regarding the definition of pCR has been established; there are several definitions according to a variety of classifications. Eradication of cancer cells in both breast and lymph nodes has been better associated with improved prognosis than in the breast alone. Even in patients diagnosed as having clinically node-negative cancer before NAC, postoperative pathological examination often shows axillary lymph node metastases. Patients and Methods Of the 771 patients with breast cancer who underwent NAC in the Cancer Institute Hospital between January 2000 and May 2009, 146 patients preoperatively diagnosed as having node-negative breast cancer were retrospectively evaluated. We have made the definition of clinically lymph node-negative (N0) as follows: first, ultrasonography before NAC did not show any lymphadenopathy. Second, a cytological procedure confirmed negative study for each patient when ultrasonography suggested lymphadenopathy. Results The median observation period was 79.7 months, and the median age of the subjects was 51 years. Pathological examination at the time of the surgery showed lymph node metastases (ypN+) in 46 patients (31.5%). Histological therapeutic effects revealed ypT0/is in 9 patients (6.2%) and ypTinv in 137 (93.8%). Multivariate analysis demonstrated that younger age (49>), large tumor size, NG3, and ypN+ were significant poor prognostic factors for DFS (p = 0.020, p = 0.008, P = 0.022 and p = 0.010, respectively). Moreover, ypN+ was the only significant poor prognostic factor for OS (p = 0.022). The predictive factors of ypN+ in clinically lymph node–negative breast cancer were ypTinv (p = 0.036) and the luminal type (HR+ and HER2-) (p = 0.029). Conclusion The prognosis of clinically lymph node negative breast cancer depended on ypN+, which was associated with ypTinv and luminal subtype.

BACKGROUND: In neoadjuvant chemotherapy (NAC) for early breast cancer, the pathological response rate in estrogen receptor (ER)-positive tumors has been low in comparison with those of ER-negative tumors. Therefore, surrogate makers other than the pCR rate are needed during NAC for luminal breast cancer. Using MRI, we analyzed the patterns of tumor shrinkage after NAC as a surrogate prognostic factor in low grade luminal breast cancer. METHODS: Of 854 patients who had received NAC in a single institute from Jan. 2000 to Dec. 2009, 183 patients with low grade luminal breast cancer were retrospectively evaluated for this study. They were defined as ER and/or PgR positive in more than 10% of cancer cells and HER2 negative (IHC 0, 1+ or FISH Citation Format: Fukada I, Araki K, Kobayashi K, Gomi N, Horii R, Akiyama F, Takahashi S, Iiwase T, Ohno S, Ito Y. The pattern of tumor shrinkage is associated with prognosis in low grade luminal early breast cancer during neoadjuvant chemotherapy. [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 P4-02-13.

546 Background: Diabetes mellitus is one of the major risk factor for renal cell carcinoma (RCC) development. Although, in various cancers, the relationship between diabetes mellitus and worse prognosis is pointed out, the association between RCC prognosis and diabetes mellitus is under discussion. We sought to determine the association between diabetes mellitus with outcome of sunitinib treatment in metastatic RCC (mRCC) patients. Methods: A retrospective study of sunitinib-treated mRCC patients was performed. 69 patients who had been treated with sunitinib in Japanese two institutions (Teikyo University Chiba Medical Center and Chiba University) were entered. Kaplan-Meier and the log-rank test were performed to investigate the association between the pretreatment status of diabetes mellitus and the outcome of the patients who received the treatment with sunitinib. Results: Between 2008 and 2015, 69 mRCC patients were treated with sunitinib. 53 (76.8%) patients received sunitinib treatment as the first line molecular target drug. 15 (21.7%) patients were diagnosed as diabetes mellitus at the time of sunitinib treatment. Median time to treatment failure (TTF) was 7.1 months, cancer specific survival (CSS) was 33.9 months for all patients. With regard to TTF, there was no difference between diabetic and non-diabetic patients, 9 months for diabetic patients and 7.1 months for non-diabetic patients respectively (P = 0.3271). CCS was significantly shorter for diabetic patients, 11 months for diabetic patients and 39.4 months for non-diabetic patients respectively (P = 0.0469). When focusing on HbA1c, CSS was significant longer for the patients with HbA1c under 6.5% than the patients with HbA1c was 6.5 or more, median CSS was 44.5 months and 11.3 months, respectively (P = 0.0055). Conclusions: Diabetes mellitus did not influence the TTF of sunitinib treatment for mRCC patients. Diabetes mellitus may negatively affect the CSS of sunitinib-treated mRCC. Clinicians should consider controlling patient’s HbA1c status at the initiation of sunitinib treatment for mRCC.

S-1 is an oral anticancer agent that combines tegafur, a prodrug of 5-fluorouracil (5-FU), and 5-chloro-2,4-dihydroxypyridine (CDHP), an inhibitor of dihydropyrimidine dehydrogenase. We examined the effects of aging on the pharmacokinetics of the components of S-1. The median area under the concentration-time curve (AUC) of active 5-FU did not significantly differ between 10 patients 75 years or older and 53 patients younger than 75 years (P = 0.598, Mann-Whitney U test). It is interesting to note that the median oral clearance of tegafur in patients 75 years or older was significantly lower than that in patients younger than 75 years (P = 0.011). Furthermore, the median AUC of CDHP was significantly higher in patients 75 years or older than in those younger than 75 years (P = 0.004). This effect was caused by reduced renal function in the elderly, because CDHP is excreted in the urine by glomerular filtration. The opposing effects of aging on the oral clearance of tegafur and the AUC of CDHP may offset each other, leading to unchanged systemic exposure of 5-FU.

Polymorphisms of the UDP-glucuronosyltransferase (UGT) 1A1 gene, such as UGT1A1*28 and UGT1A1*6, can cause severe neutropenia and diarrhea in patients who receive irinotecan [1, 2]. Homozygosity for UGT1A1*28 is associated with less efficient glucuronidation of SN-38, the active metabolite of irinotecan, resulting in increased plasma SN-38 concentrations. Four pharmacogenetic trials have demonstrated an association between UGT1A1*28 genotype and irinotecan-induced hematologic toxicity, diarrhea, or both [3]. In response to these findings, the United States Food and Drug Administration has approved genetic testing for UGT1A1*28 and recommends that the initial dose of irinotecan is reduced by at least one level in patients who are homozygous for UGT1A1*28, albeit the effectiveness of such testing remains to be confirmed prospectively. UGT1A1*6 is also associated with severe irinotecan-related toxicity [4]. Given that the area under the time versus concentration curve ratio (SN-38 glucuronide/SN-38) seen in patients homozygous for UGT1A1*28 and *6 are almost equal [4], the impact of these variants on glucuronidation capacity of UGT1A1 for SN-38 is almost the same. The distribution of genotypes associated with these polymorphisms varies considerably among ethnic groups. UGT1A1*28 is found in Japanese and whites, but the allele frequency in Japanese is lower than that in whites [2, 4]. UGT1A1*6 is found in Japanese, but not in whites [4]. Homozygosity for UGT1A1*28 or UGT1A1*6 and heterozygosity for both UGT1A1*6 and UGT1A1*28 are associated with severe irinotecan-related neutropenia in Japanese patients [1, 4]. The Ministry of Health, Labour and Welfare in Japan has therefore recently approved genetic testing for UGT1A1*28 and *6. The value of genetic testing for UGT1A1 depends on genotype frequency and the association of genetic variants with irinotecan-induced toxicity. The higher the frequency of toxicity-related polymorphisms, the greater is the number of patients who would benefit from genetic testing. Large prospective studies are needed to accurately estimate the distribution of UGT1A1 polymorphisms in a given population. We have carried out the largest prospective study to date, examining the distributions of UGT1A1*28 and UGT1A1*6 genotypes in 300 Japanese patients (male/female, 172 of 128) with various solid tumors (200 colorectal, 43 gastric, 15 ovarian, 14 breast, 10 lung, and 18 others). All patients gave written informed consent, and the study protocol was approved by the Institutional Review Board of Saitama Medical University. Genotyping was carried out as described elsewhere [5]. UGT1A1*28 and UGT1A1*6 were in Hardy–Weinberg equilibrium (P > 0.05). Only 2 of 300 patients were UGT1A1*28 homozygotes (0.7%) (Table 1). The frequency of homozygosity for UGT1A1*28 was much lower than that in other prospective studies in Japan (2.3%, 4 of 176) [4]. The frequency of UGT1A1*6 homozygosity was 5.7% (Table 1), higher than that reported previously (2.8%) [4]. Eleven patients were both heterozygous for UGT1A1*6 and UGT1A1*28 (3.7%). The combined frequency of patients with two ‘risk alleles’ (i.e. *28/*28, *6/*6, and *6/*28) was 10.1% (95% confidence interval, 6.8% to 14.0%). Such patients might be at increased risk for irinotecan-related neutropenia. Given the genotype frequencies of UGT1A1*28 and UGT1A1*6, genetic testing for UGT1A1 might not be essential for identifying homozygotes for UGT1A1*28, but useful for identifying homozygotes for UGT1A1*6 as well as heterozygotes for UGT1A1*6 and UGT1A1*28, thereby avoiding severe irinotecan-induced toxicity in Japanese patients. The present results and considerations are likely to have application across East Asia. Prospective evaluations of genetic testing for UGT1A1 polymorphisms, encompassing both medical aspects and cost effectiveness, appear to be warranted, especially in East Asian countries including Japan. Table 1. Genotype frequencies of UGT1A1*28 and UGT1A1*6 in Japanese