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Supplementary Figure 1: Expression of signalling proteins in MCF10A-AKT1WT and MCF10A-AKT1E17K cells grown in the presence or absence of doxycycline; Supplementary Figure 2: Colony formation in soft agar using MCF10A cells expressing AKT1E17K, AKT1WT, ERBB2V659E or RFP under a tet-inducible promoter in the presence or absence of 1 μg/mL doxycycline; Supplementary Figure 3: Histograms showing the frequencies of colonies of various diameters; Supplementary Figure 4: Detection of AKT1E17K mutation in HBC-x2 xenograft tissue; Supplementary Figure 5: Effect of AKT inhibitors, AZD5363 and MK-2206 on AKT pathway biomarkers and growth of MGH-U3 cells in vitro.

AKT1E17K mutations occur at low frequency in a variety of solid tumors, including those of the breast and urinary bladder. Although this mutation has been shown to transform rodent cells in culture, it was found to be less oncogenic than PIK3CA mutations in breast epithelial cells. Moreover, the therapeutic potential of AKT inhibitors in human tumors with an endogenous AKT1E17K mutation is not known. Expression of exogenous copies of AKT1E17K in MCF10A breast epithelial cells increased phosphorylation of AKT and its substrates, induced colony formation in soft agar, and formation of lesions in the mammary fat pad of immunodeficient mice. These effects were inhibited by the allosteric and catalytic AKT inhibitors MK-2206 and AZD5363, respectively. Both AKT inhibitors caused highly significant growth inhibition of breast cancer explant models with AKT1E17K mutation. Furthermore, in a phase I clinical study, the catalytic Akt inhibitor AZD5363 induced partial responses in patients with breast and ovarian cancer with tumors containing AKT1E17K mutations. In MGH-U3 bladder cancer xenografts, which contain both AKT1E17K and FGFR3Y373C mutations, AZD5363 monotherapy did not significantly reduce tumor growth, but tumor regression was observed in combination with the FGFR inhibitor AZD4547. The data show that tumors with AKT1E17K mutations are rational therapeutic targets for AKT inhibitors, although combinations with other targeted agents may be required where activating oncogenic mutations of other proteins are present in the same tumor. Mol Cancer Ther; 14(11); 2441–51. ©2015 AACR.

Background: Bone Modifying Agents (BMAs) have been used to prevent skeletal-related events (SRE) in cancer patients with bone metastases. In this meta-analysis, efficacy and adverse events (AEs) were studied based on a de-escalation strategy in which the BMA dosing interval was prolonged from 4 to 12 weeks.Methods: PubMed, Cochrane, ICHUSHI, and CINAHL were searched for articles on BMA dosing intervals from outcomes measured were the incidence of SRE and related various AEs. A quantitative meta-analysis was performed using a random-effects model to calculate relative risk ratios (RR) and 95% confidence intervals (CI).Result: The meta-analysis included three randomized controlled studies (RCTs) of Zoledronic acid hydrate (ZA) (n = 2,663) and six RCTs (n = 141) on BMA other than zoledronic acid. There was no difference in the incidence of SREs when comparing dosing frequency of 12 versus 4 weeks for BMA (RR = 1.21, 95% CI [0.82-1.78], p = 0.33). Further, AEs related to treatment discontinuation were significantly less frequent with ZA given every 12 weeks than when given every 4 weeks (RR = 0.51 [0.30-0.89], p = 0.02). In particular, renal dysfunction leading to grade ≥3 or discontinuation of treatment with ZA occurred significantly less frequently with every 12-week dosing (RR = 0.33 [0.12-0.91], p = 0.33). Conclusion: The meta-analysis showed no influence of BMA de-escalation on the incidence of SRE, nevertheless, AEs appeared to reduce with the usage of ZA.

Objective Few reports have analyzed the diagnostic process of carcinoma of unknown primary site (CUP) or have focused on the frequency of nonmalignant lesions among patients with suspected malignant diseases. The aim of this study was to investigate the incidence and characteristics of nonmalignant diseases that tend to be mistaken for malignant diseases. Patients We retrospectively analyzed the medical records of patients with suspected CUP who were referred to the National Cancer Center Hospital (Tokyo, Japan) between April 2007 and December 2014. All patients underwent a thorough history and physical examination as well as radiological and ultrasonography imaging tests for the CUP diagnostic work up. Results Among 830 patients with suspected CUP, 46 were diagnosed with nonmalignant diseases, and 780 were diagnosed with a malignant neoplasm (409 neoplasms with detected primary site and 371 CUP neoplasms). Four patients discontinued the diagnostic workup because they refused further examinations or had a poor general status. The final diagnosis of the 46 patients with nonmalignant disease comprised 10 benign tumors, 10 benign diseases, and 26 with no evidence of disease. The nonmalignant tumors comprised three hemangiomas, two schwannomas, two uterine myomas, two pseudomyxoma peritonei, one lymphangioma, one meningioma, and one poroma. Conclusion The incidence of nonmalignant diseases among patients with suspected CUP was 46 out of 830 patients in our institution. It is important to perform a thorough pathological examination in the CUP diagnostic workup. To confirm a diagnosis, some patients may need to visit specialized institutions, especially those with liver and bone lesions.

Olaratumab, a monoclonal antibody targeting human platelet‐derived growth factor receptor α, plus doxorubicin significantly improved overall survival in patients with advanced soft‐tissue sarcoma (STS) in a prior phase 1b/2 randomized trial. Subsequent exposure‐response analysis suggested that higher olaratumab exposures earlier might improve outcomes in patients at risk of early disease progression. This phase 1 study (3 treatment cohorts; minimum 6 patients each) investigated the safety, pharmacokinetics and antitumor activity of olaratumab plus doxorubicin in Japanese patients with STS. Patients received olaratumab 15 mg/kg on Days 1 and 8 during each 21‐day cycle until disease progression. Patients in Cohort 3 received a 20 mg/kg loading dose of olaratumab in Cycle 1. Doxorubicin was administered for up to 6 cycles. Patients in Cohort 1 received doxorubicin 25 mg/m2 on Days 1, 2 and 3. Patients in Cohorts 2 and 3 received doxorubicin 75 mg/m2 on Day 1. One patient in Cohort 2 experienced a dose‐limiting toxicity of Grade 3 febrile neutropenia. Most treatment‐emergent adverse events were of mild and moderate severity, and were known doxorubicin toxicities. Olaratumab serum concentrations in Cohort 3 reached a steady‐state exceeding the target level in Cycle 1. Partial response was confirmed in 4 patients (2 each in Cohorts 2 and 3). Olaratumab plus doxorubicin had an acceptable safety profile in patients with STS. A loading dose of olaratumab 20 mg/kg was effective for achieving minimum serum concentrations above the target trough level in Cycle 1.

Taselisib is a potent and selective phosphatidylinositide 3‐kinase (PI3K) inhibitor. The present article reports the first study of taselisib administration in Japanese patients. The aim of this 2‐stage, phase I, multicenter, open‐label, dose‐escalation study was to evaluate the safety, pharmacokinetics, and preliminary efficacy of taselisib as monotherapy in Japanese patients with advanced solid tumors (stage 1), and as part of combination therapy in Japanese patients with hormone receptor (HR)‐positive locally advanced or recurrent breast cancer (stage 2). In stage 1, oral taselisib tablets 2, 4, and 6 mg/d were given in 28‐day cycles. In stage 2, successive cohorts of patients received oral taselisib tablets (2 or 4 mg/d) with i.m. fulvestrant 500 mg. Nine and 6 patients were enrolled in stage 1 and stage 2, respectively. Taselisib was well tolerated. No dose‐limiting toxicities were experienced in any cohort of patients and no deaths were observed. The most common treatment‐related adverse events in stage 1 and stage 2, respectively, were rash (55.6%, 66.7%), diarrhea (44.4%, 66.7%), and stomatitis (44.4%, 66.7%). Taselisib was rapidly absorbed after dosage; its half‐life was 12.9‐32.0 hours in stage 1 and 16.1‐26.5 hours in stage 2. Two patients achieved partial response (PR), 5 patients had stable disease (SD) and 2 patients had progressive disease (PD) in stage 1, and 1 patient had PR and 3 patients had SD in stage 2. All patients with PR were positive for PIK3CA gene mutations. These preliminary data suggest that taselisib may be effective in patients with PIK3CA‐mutated solid tumors or HR‐positive advanced breast cancer.

Background The efficacy and safety of eribulin in patients with locally advanced or metastatic breast cancer has been demonstrated in phase III trials. However, as patients receiving eribulin in daily practice do not necessarily meet all the eligibility criteria of clinical trials, data for such patients are limited. Methods We identified patients with locally advanced or metastatic breast cancer, treated with eribulin monotherapy between July 2011 and December 2015 at the National Cancer Center Hospital, Tokyo, Japan. Patients who would have met the following eligibility criteria from the EMBRACE trial were included in the eligible group, and the rest were included in the ineligible group: 1) Eastern Cooperative Oncology Group Performance status 0–2; 2) adequate function of principal organs; and 3) absence of active infection. We compared the relative dose intensity (RDI), tumor response, progression-free survival (PFS), overall survival (OS), and adverse events between the groups. Nominal and continuous values were compared using the Fisher’s exact test and Mann-Whitney U test, respectively. Survival outcomes were determined using Kaplan-Meier estimation, and between-group differences were assessed using the log-rank test. Results Of the 203 patients included, 34 were classified into the ineligible group and 169 into the eligible group. Initial dose reduction and treatment discontinuation due to adverse events (AEs) were more common in the ineligible group (initial dose reduction: 23.5% in the ineligible group vs. 7.7% in the eligible group, p = 0.011; treatment discontinuation due to AEs: 11.8% vs. 3.0%, p = 0.045). However, RDI (66% vs. 71%, p = 0.130), response rate (15.6% vs. 18.1%, p = 1.000), PFS (3.7 months vs. 4.0 months, p = 0.913), OS (11.5 months vs. 16.1 months, p = 0.743), AEs requiring hospitalization (5.9% vs. 6.5%, p = 1.000), and grade 3/4 AEs were similar in both groups. PFS, OS, AEs requiring hospitalization, and discontinuation due to AEs in the eligible group were comparable to those found in previous phase III trials. Conclusion The safety and efficacy of eribulin monotherapy was demonstrated in a broader patient population than that eligible for clinical trials. Eribulin may be a treatment option in these patients with locally advanced or metastatic breast cancer, considering dose reduction and pre-existing dysfunctions. Electronic supplementary material The online version of this article (10.1186/s12885-017-3846-8) contains supplementary material, which is available to authorized users.

ObjectiveThe aim of this study was to assess the use of the pathological response to neoadjuvant chemotherapy (NAC) for predicting disease prognosis in patients with advanced ovarian cancer who received neoadjuvant dose-dense weekly paclitaxel and carboplatin (dd-TC) therapy.MethodsWe retrospectively investigated patients with advanced epithelial ovarian, tubal, or peritoneal carcinoma treated at our hospital from July 2004 to October 2014. Patients received dd-TC therapy as NAC followed by interval debulking surgery (IDS). Specimens resected during IDS were divided into 4 groups based on pathological response: grade 1, most tumor cells appeared to be viable; grade 2a, most tumor cells had disappeared, whereas the remaining tumor cells were vacuolated or degenerated; grade 2b, small numbers of viable tumor cells were observed; and grade 3, small aggregations of macrophages were seen.ResultsSixty-eight patients were enrolled. The median number of NAC cycles was 3 (range, 2–6), and 51 patients (75.0%) achieved complete resection at IDS. Regarding pathological response, 7 (10.3%) patients were classified as grade 1, 11 (16.2%) as grade 2a, 46 (67.7%) as grade 2b, and 4 (5.9%) as grade 3. In univariate and multivariate analyses, grades 2b and 3 pathological responses were significant favorable prognostic factors for progression-free survival (P = 0.028; hazard ratio, 0.48; 95% confidence interval, 0.26–0.92).ConclusionsAlthough the pathological complete response rate to NAC was low in this study, both complete and good pathological responses to NAC might be favorable prognostic factors for PFS in patients with advanced ovarian cancer who receive dd-TC.

A growing number of studies suggest critical tumor suppressor roles of the SWI/SNF chromatin remodeling complex in a variety of human cancers. The recent discovery of SMARCA4-deficient thoracic sarcomas has added to the list of tumor groups with the SMARCA4 inactivating mutation. To better characterize these tumors and establish their nosological status, we undertook a clinicopathological and molecular analysis of 12 SMARCA4-deficient thoracic sarcomas and compared them with three potentially related disease entities. Eleven men and one woman with SMARCA4-deficient thoracic sarcomas (aged 27-82 years, median 39 years) were included in the study. Most of the patients had heavy smoking exposure and pulmonary emphysema/bullae. The primary tumors were large and involved the thoracic region in all cases and simultaneously affected the abdominal cavity in 3 cases. The patients followed a rapid course, with a median survival of 7 months. Histologically, all tumors showed diffuse sheets of mildly dyscohesive, relatively monotonous, and undifferentiated epithelioid cells with prominent nucleoli. Immunohistochemically, all tumors demonstrated a complete absence (8 cases) or diffuse severe reduction (4 cases) of SMARCA4 expression. Cytokeratin, CD34, SOX2, SALL4, and p53 were expressed in 6/12, 10/12, 10/12, 10/12, and 7/10 cases, respectively. SMARCA2 expression was deficient in 11/12 cases, and none (0/8) expressed claudin-4. Targeted sequencing was performed in 5 cases and demonstrated the inactivating SMARCA4 mutation in each case and uncovered alterations in TP53 (5/5), NF1 (2/5), CDKN2A (2/5), KRAS (1/5), and KEAP1 (1/5), among others. Comparative analysis supported the distinctiveness of SMARCA4-deficient thoracic sarcomas as they were distinguishable from 13 malignant rhabdoid tumors, 15 epithelioid sarcomas, and 12 SMARCA4-deficient lung carcinomas based on clinicopathological and immunohistochemical grounds. SMARCA4-deficient thoracic sarcomas constitute a unique, highly lethal entity that requires full recognition and differentiation from other epithelioid malignancies involving the thoracic region.

Ewing sarcoma/peripheral primitive neuroectodermal tumor (ES/PNET) is an aggressive bone tumor. Bone marrow aspiration and biopsy (BMAB) has been recognized as the gold standard for assessing bone marrow status. While the latest guideline suggests the need to omit bone marrow aspiration in patients with no findings on 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) based on one retrospective report, there is no study using 18F-FDG PET/computed tomography (CT). We retrospectively reviewed 26 consecutive, previously untreated, ES/PNET patients. We compare the results of bone marrow aspiration and biopsy (BMAB) and those of 18F-FDG PET/CT in ES/PNET patients. All of the 21 patients without metastases on 18F-FDG PET/CT had negative BMAB. The sensitivity of bone marrow involvement in bone metastases positive patients on 18F-FDG PET/CT was 75% (3/4), and the specificity was 100% (22/22). In addition to the metastatic findings on 18F-FDG PET/CT, tumor diameter, lactate dehydrogenase level at diagnosis, and the presence or absence of bone metastasis were factors related to bone marrow involvement. It may be a reasonable option to omit BMAB in ES/PNET patients with no distant metastasis based on 18F-FDG PET/CT findings.

Weekly dose-dense paclitaxel (PTX) in combination with carboplatin (CBDCA) every 3 weeks (ddTC therapy) is a standard treatment for patients with advanced ovarian cancer. However, there is no detailed analysis of the feasibility of ddTC therapy in elderly patients with ovarian cancer. We identified patients diagnosed with ovarian, fallopian tube, or peritoneal cancer who received ddTC therapy at the National Cancer Center Hospital from April 2003 to April 2013. We assessed the feasibility of ddTC therapy in elderly patients aged 70 years or older (elderly group), comparing relative dose intensity (RDI) for PTX, CBDCA, and ddTC; adverse events; and rate of chemotherapy discontinuation to those in patients below 70 years of age (younger group). A total of 143 patients (elderly group, 22; younger group, 121) was analyzed. A comparison of RDI between these two groups showed no significant differences for PTX, CBDCA, and ddTC. Nonhematological and hematological toxicity profiles of the elderly and younger groups were similar, except that severe peripheral neuropathy (Grade 2 or higher) was more common in the elderly group. There was no significant difference in the rate of chemotherapy discontinuation (elderly group, 13.6 % vs. younger group, 7.4 %, p = 0.397). Our study showed that ddTC therapy was feasible for elderly patients. However, to prevent severe neuropathy, PTX dose reduction deserves consideration.

This phase I study in Japanese patients evaluated the safety, pharmacokinetics, and preliminary efficacy of palbociclib, a highly selective and reversible oral cyclin-dependent kinase 4/6 inhibitor, as monotherapy for solid tumors (part 1) and combined with letrozole as first-line treatment of postmenopausal patients with estrogen receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer (part 2). Part 1 evaluated palbociclib 100 and 125 mg once daily (3 weeks on/1 week off; n = 6 each group) to determine the maximum tolerated dose. Part 2 evaluated palbociclib maximum tolerated dose (125 mg) plus letrozole 2.5 mg (n = 6). The most common treatment-related adverse event was neutropenia (all grades/grade 3/4): 100 mg, 83%/67%; 125 mg, 67%/33%; and palbociclib plus letrozole, 100%/83%. Heavier pretreatment with chemotherapy may have resulted in higher neutropenia rates observed with the 100-mg dose. Palbociclib exposure was higher with 125 vs 100 mg (mean area under the plasma concentration-time curve over dosing interval [τ]: 1322 vs 547.5 ng·h/mL [single dose], 2838 vs 1276 ng·h/mL [multiple dose]; mean maximum plasma concentration: 104.1 vs 41.4 ng/mL [single dose], 185.5 vs 77.4 ng/mL [multiple dose]). Half-life was 23-26 h. No drug-drug interactions between palbociclib and letrozole occurred. Four patients had stable disease (≥24 weeks in one patient with rectal cancer [100 mg] and one with esophageal cancer [125 mg]) in part 1; two patients had partial response and two had stable disease (both ≥24 weeks) in part 2. Palbociclib at the 125-mg dose (schedule 3/1) was tolerated and is the recommended dose for monotherapy and letrozole combination therapy in Japanese patients. The trials are registered with www.ClinicalTrials.gov: A5481010 and NCT01684215.

BACKGROUND Bone-modifying agents (BMAs) reduce the incidence of skeletal-related events (SREs) and are thus recommended for breast cancer patients with bone metastases. However, the risk factors for SREs during BMA treatment are not well-understood. This study evaluated the number and timing of SREs from case studies to identify these factors. METHODS The medical records of 534 women with breast cancer who developed bone metastases between 1999 and 2011 were reviewed. SREs were defined as a pathologic fracture, spinal cord compression, or the need for bone irradiation or surgery. Multiple variables were assessed and were analyzed by using the Cox proportional hazard analyses and the Andersen and Gill method. RESULTS Multivariate analyses for both the time to the first SRE and the primary and subsequent SRE frequency demonstrated that significant baseline risk factors included luminal B type disease, a history of palliative radiation therapy, BMA treatment within 2 years, and elevated serum calcium levels at the time of the initial BMA dose. Additionally, for the time to the first SRE and for the primary and subsequent SRE frequency, the presence of extraskeletal metastases and BMA administration initiation ≥6 months after the detection of bone metastases were also significant risk factors, respectively. CONCLUSION In breast cancer patients with bone metastases, more vigilant observation should be considered for patients with the identified risk factors. To reduce the risk for SRE, BMAs should be administered within 6 months of bone metastases diagnosis and before palliative radiation therapy. IMPLICATIONS FOR PRACTICE Retrospectively, risk factors were identified for skeletal-related events (SREs) in breast cancer patients with bone metastasis who were treated with bone-modifying agents (BMAs). For the time to the first SRE and for the SRE frequency, presence of extraskeletal metastases and BMA initiation ≥6 months after the detection of bone metastases were risk factors, respectively. Luminal B type disease, a history of palliative radiation therapy, BMA treatment within 2 years, and elevated serum calcium levels at initial BMA dose were risk factors for both first SRE and SRE frequency. More vigilant observation should be considered for patients with these risk factors.

The CIC gene rearrangement exists in a subset of small round cell sarcomas. As the nosologic relationship of these sarcomas to Ewing sarcomas remains undetermined, we examined 20 CIC-rearranged sarcomas to compare their clinicopathologic features with those of Ewing sarcomas. The CIC-rearranged sarcomas were from a group of 14 men and 6 women with a median age of 24.5 years. The primary tumor sites included the limbs, trunk wall, internal trunk, lung, cerebrum, and pharynx. A comparison of the demographic and clinical characteristics of the 20 patients with CIC-rearranged sarcomas with those of the 53 near-consecutive patients with EWSR1-rarranged Ewing sarcomas showed that there were no differences with respect to their ages and sexes. Although none of the CIC-rearranged sarcomas arose in the bone, 40% of the Ewing sarcomas primarily affected the skeleton. The overall survival of patients with Ewing sarcomas was significantly better than that for patients with CIC-rearranged sarcomas. A histologic comparison of the CIC-rearranged sarcomas with 20 EWSR1-rearranged Ewing sarcomas showed significantly higher degrees of lobulation, nuclear pleomorphism, the prominence of the nucleoli, spindle cell elements, and myxoid changes in the CIC-rearranged sarcomas. Distinguishing immunohistochemical features included heterogenous CD99 reactivity, nuclear WT1 expression, and calretinin expression in the CIC-rearranged sarcomas and NKX2.2 expression in the Ewing sarcomas. CIC-rearranged sarcomas are distinct from Ewing sarcomas clinically, morphologically, and immunohistochemically, and they should be considered a separate entity rather than being grouped within the same family of tumors.

Purpose Investigate the safety and tolerability of AZD5363 and define a recommended dose for evaluation in Japanese patients with advanced solid malignancies. Methods AZD5363 was administered orally as a single dose, and then the dose was escalated to twice daily (bid) in separate continuous (every day) and intermittent (4 days on, 3 days off [4/3] or 2 days on, 5 days off [2/5]) dosing schedules to reach recommended doses defined by dose-limiting toxicity (DLT). Doses for continuous, 4/3, and 2/5 intermittent dosing schedules were 80–400, 360–480, and 640 mg, respectively, and were informed by results from an equivalent study in Caucasian patients. Results Forty-one patients received AZD5363. DLTs were only experienced with continuous dosing. 97.6 % of patients reported at least one adverse event (AE); most common were diarrhea (78.0 %), hyperglycemia (68.3 %), nausea (56.1 %), and maculopapular rash (56.1 %). Grade ≥3 AEs were reported by 63.4 % of patients. Exposure of AZD5363 was generally dose proportional for both single and multiple doses. Single-dose pharmacokinetics of AZD5363 was generally predictive of multiple-dose pharmacokinetics. Confirmed partial responses were reported by two patients, both of whom were Akt1 (E17K) mutation positive. One patient in the 480 mg bid 4/3 dosing cohort maintained partial response for >2 years. Conclusions Intermittent dosing of AZD5363 was more tolerable than continuous dosing. 480 mg bid intermittent 4/3 dosing for AZD5363 monotherapy was selected for further investigation. Preliminary evidence of antitumor activity was observed. Akt1 (E17K) is a potent driver mutation that may predict clinical response to AZD5363.

Background: Taselisib (GDC-0032) is an orally bioavailable, potent and selective phosphoinositide 3-kinase (PI3K) inhibitor. Preclinical data showed that taselisib had increased antitumor activity against PIK3CA (gene encoding the PI3Kα isoform) mutant tumors. This study aimed to investigate the safety, tolerability and pharmacokinetics (PK) of taselisib as monotherapy and in combination with fulvestrant in Japanese patients (pts). Materials and methods: A 3+3 design was used. In Phase Ia, pts with advanced solid tumors received taselisib tablet monotherapy (2, 4 or 6 mg once daily [QD]), and safety and PK were evaluated. In Phase Ib, pts with hormone receptor-positive locally advanced or metastatic breast cancer received taselisib (2 or 4 mg QD) in combination with fulvestrant (500 mg at a time), and safety and PK were evaluated. Maximal administered doses of 6 mg QD as a single agent and 4 mg QD in combination with fulvestrant were based upon prior clinical trial experience with taselisib (Juric D. et al. AACR 2013, Abstract LB-64; Juric D. et al. SABCS 2013, Abstract PD1-3). Results: As of 15 Mar 2015, 9 pts (PIK3CA mutant: 2 pts) were enrolled in Phase Ia and 3 pts in Phase Ib. Phase Ia dose-escalation study has been completed and Phase Ib is ongoing. In Phase Ia, no dose-limiting toxicity (DLT) was observed at any dose level tested (maximum administered dose of 6 mg QD). Common (≥3 pts) adverse reactions (ARs) were stomatitis (4 pts), rash (3 pts) and diarrhea (3 pts); the only Grade ≥3 AR was neutropenia (1 pt). Partial response was observed in 1 pt who received taselisib 4 mg and had a PIK3CA mutant breast tumor. Stable disease was observed in 4 pts. Cmax and AUC indicated a dose-proportional PK profile of taselisib within the dose range tested. Moreover, taselisib PK in Japanese pts was consistent with the PK reported from North American and European pts (Juric D. et al. AACR 2013, Abstract LB-64). In Phase Ib, 3 pts received taselisib 2 mg in combination with fulvestrant and no DLT was observed. Preliminary ARs were similar to those with monotherapy and no Grade ≥3 AR was reported. Confirmation of tolerability of taselisib 4 mg in combination with fulvestrant is under evaluation. Conclusion: Taselisib monotherapy was well tolerated in Japanese pts up to a dose of 6 mg, which is the recommended dose in non-Japanese pts. Promising preliminary activity of monotherapy was observed in advanced solid tumors, especially in a pt with PIK3CA mutant tumor. The combination of taselisib 2 mg with fulvestrant is well tolerated. Investigation of tolerability of taselisib 4 mg in combination with fulvestrant is ongoing. Final results of this study will be presented here at the Symposium this year. Citation Format: Kobayashi T, Nakano K, Tomomatsu J, Nara E, Ito Y, Kobayashi K, Fukada I, Araki K, Shimomura A, Shimoi T, Kodaira M, Yunokawa M, Yonemori K, Shimizu C, Nakamura K, Kotani N, Inatani M, Tamura K, Takahashi S. Phase Ia/Ib study of taselisib (GDC-0032), a potent and selective phosphoinositide 3-kinase inhibitor, in Japanese patients with advanced solid tumors or hormone receptor-positive locally advanced or metastatic breast cancer (JO29196 study). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-14-10.

Background The clinical utility and prognostic impact of presumed primary breast or ovarian cancer among patients with an unfavorable subset of cancer of unknown primary site (CUP) remains unclear. We aimed to evaluate the clinical relevance of the presumed primary site of CUP and the clinical outcome of site-specific therapy based on such presumptions. Methods Patients referred to our center who were diagnosed with unfavorable-subset CUP and treated between April 2007 and March 2015 were enrolled in this study. Data were collected retrospectively from the hospital database and electronic medical records. Presumptive primary breast or ovarian cancer was based on histological and immunohistochemical analyses and metastatic patterns. The outcomes of patients with unfavorable-subset CUP with a putative primary site in the breast or ovary (P-CUP) and of patients with unfavorable-subset CUP, but without P-CUP (U-CUP), were assessed. Results A total of 780 patients were referred to our hospital with malignancy of unknown origin. Of these, 409 patients were diagnosed with CUP and 344 patients with unfavorable-subset CUP. Following clinicopathological examination, 40 (11.6%) of the 344 patients had P-CUP and the remaining 303 (88.3%) patients had U-CUP. In total, 136 patients received chemotherapy (22 with P-CUP and 114 with U-CUP). Among the 22 patients with P-CUP, three received hormonal therapy for breast cancer, and 19 received chemotherapy based on the presumed primary organ (breast, 4; ovaries, 15). Conventional platinum-based chemotherapy was administered to 105 patients with U-CUP and non-platinum drug treatment to nine patients. The objective response rates were 61.1% (95% confidence interval [CI]: 38.6–83.6) and 41.1% (95% CI: 31.8–50.4) for patients with P-CUP and U-CUP, respectively. The median overall survival durations were 50.0 months and 16.9 months (log-rank: P = 0.002) for patients with P-CUP and U-CUP, respectively. P-CUP was identified as an independent predictor of good prognosis according to multivariate analysis. Conclusions Patients with P-CUP had higher response rates and a better prognosis compared with patients with U-CUP. It might thus be reasonable to classify this subset as a new category of CUP with a favorable prognosis. Electronic supplementary material The online version of this article (10.1186/s12885-018-4092-4) contains supplementary material, which is available to authorized users.

Molecular imaging can visualize the biological processes at the molecular and cellular levels in vivo using certain tracers for specific molecular targets. Molecular imaging of breast cancer can be performed with various imaging modalities, however, positron emission tomography (PET) is a sensitive and non-invasive molecular imaging technology and this review will focus on PET molecular imaging of breast cancer, such as FDG-PET, FLT-PET, hormone receptor PET, and anti-HER2 PET.

Eribulin mesylate (eribulin) is a nontaxane microtubule inhibitor approved in Japan for treating soft tissue sarcoma irrespective of histological subtypes. Thus, our department routinely uses eribulin to treat any histological subtype of sarcoma for patients who have experienced disease progression during standard therapy. However, evidence on the efficacy of eribulin in treating sarcomas that are neither liposarcoma nor leiomyosarcoma is limited. Recently, we encountered a case of a heavily pretreated cardiac angiosarcoma that responded well to eribulin treatment. The patient was a 34-year-old Japanese woman with advanced angiosarcoma, who had been pretreated heavily using several lines of chemotherapy. Eribulin was administered as the eighth line of treatment and the dose was adjusted because of grade 4 neutropenia. After three cycles of treatment, contrast-enhanced computed tomography showed a partial tumor response, which was sustained for ~4 months. This case suggests that eribulin may be a potential therapeutic option for angiosarcoma. Further studies are needed to confirm the benefit of eribulin for patients with angiosarcoma and to establish predictive markers for eribulin sensitivity.

Hand-foot syndrome (HFS) is a major side effect of pegylated liposomal doxorubicin (PLD). Regional cooling during PLD infusion was shown to improve severe HFS. We investigated the utility of frozen gloves and socks (FGS) as a simpler cooling method. To evaluate the utility and safety of regional cooling with FGS for PLD-induced HFS, we retrospectively analyzed patients with advanced ovarian cancer who used FGS during PLD-containing regimens. Ninety-six patients were analyzed. The incidence of HFS was 51% (≥ grade 2, 32%) in the PLD group and 38% (≥ grade 2, 6%) in the PLD + CBDCA group. The respective percentages of patients who underwent PLD dose modification/discontinuation were 41%/75% in the PLD group and 9%/30% in the PLD + CBDCA group. The reasons for discontinuation of PLD and PLD + CBDCA therapy were progressive disease, HFS, allergy, oral mucositis, and others. HFS was the only reason for PLD dose modification in both the PLD and PLD + CBDCA groups. The completion rate of FGS was 96%, with discontinuation in three cases due to pain from cooling. Our study indicates that FGS is a safe, simple method with good tolerability. A prospective study is needed for further assessment.

Background There are limited colonoscopy-based cohort data concerning the effectiveness of colonoscopy in reducing colorectal cancer deaths. The aim of this study was to clarify whether colonoscopy reduces colorectal cancer mortality. Methods A cohort of 18,816 patients who underwent colonoscopy without a diagnosis of colorectal cancer between 2001 and 2010 at high colonoscopy procedure volume centers was selected. Patient characteristics and colonoscopy findings were assessed. The main endpoint was colorectal cancer death (all, right-sided, and left-sided cancers), and data were censored at the time of the final visit or the final colonoscopy. The standardized all colorectal, colon, and rectal cancer mortality rates were estimated with reference to those of the general Japanese population. Additional outcome was all- cause death and the standardized all-cause mortality rate was also estimated. Results The total observed person-year mortality for colorectal cancer was 67,119. Of these, 4, 3, and 1 patients died from colorectal, colon, and rectal cancers, respectively; these values were significantly lower than the number of expected deaths in the general population, estimated to be 53.1, 34.0, and 19.1, respectively. The standardized mortalities for all colorectal, colon, and rectal cancers were 0.08 (95% confidence interval (CI), 0.02–0.17), 0.09 (95% CI, 0.02–0.22), and 0.05 (95% CI, 0.0002–0.21), respectively. There were 586 all-cause deaths (3.11%) during the observation period. The standardized all-cause mortality ratios were 0.22 (95% CI, 0.206–0.23). Conclusions The colorectal cancer mortality of patients who received colonoscopy without colorectal cancer diagnosis decreased significantly compared with that of individuals in the general population. These results were compatible even in patients with right-sided colon cancer.

Background Triple-negative breast cancer (TNBC) patients are a poor prognostic subgroup, and currently, there is no biomarker for targeted therapy. Patients and methods Tissue samples were obtained from 75 TNBC patients with lymph-node metastases who had received adjuvant chemotherapy. We examined 11 biomarkers, including PIK3CA and AKT1mutation, with regard to event-free survival (EFS) and overall survival (OS) of patients. Results In the tumor tissues, phospho-AKT (pAKT) expression was significantly related to HER4 expression. Expression of each of these biomarkers was significantly related to longer EFS (P = 0.024 and 0.03, respectively). pERK expression was also a good prognostic factor regarding EFS and OS in TNBC (P = 0.002 and 0.006, respectively). We also identified a correlation between epidermal growth factor receptor positivity and insulin-like growth factor receptor type 1 positivity (P = 0.001). pERK and T-stage (1–3 versus >3) were independent good prognostic factors by multivariate analysis. Conclusions We determined that tumors expressing pAKT or pERK are a good prognostic subtype in node-positive TNBC. Different targeted therapies may be necessary for TNBC that involves activation of PI3K/AKT or MAPK pathways.

Background: Clinical progressive disease (cPD) occurs during neoadjuvant therapy (NAC) in 3 to 5% of breast cancer patients. By gene expression profiling analyses using DNA microarray, the expression of epithelial-to-mesenchymal transition (EMT)-associated genes were shown to be correlated with chemoresistant phenotype of breast cancer cell lines. In order to reveal clinical implication of EMT-associated molecules on the acquisition of cPD property, we designed a retrospective histopathilogical and immunohistochemical case-control study. Patients and Methods: From pathology database of patients who received surgical resection, 86 patients with early triple-negative breast cancer (TNBC) were identified: 23 patients suffered cPD during NAC (PD group) and 63 control group patients did not receive NAC (C group), in whom >95% of patients was estimated to be non-PD group if NAC was performed. For these 86 cases, histopathological classification was performed and negativity of hormone receptors and HER2 was confirmed. As EMT markers, we immunohistochemically examined the expressions of vimentin, Twist, Twist NB and Snail. The chi-square test was used to assess statistically significant differences between the groups.Results: Histologically, PD group comprised 12 invasive ductal carcinomas (IDCs) (52%) and 11 metaplastic carcinomas (MPCs) (48%), and they all were nuclear grade 3. In C group, 52 (83%) were IDCs and 10 (16%) were histological types other than IDC or MPC, and there was only 1 MPC (1%) (p = 4.31E-08). Nuclear grade was 1, 2, and 3 in 1, 9, and 53, respectively. Vimentin was positive in cytoplasm of 74% of PD group and the incidence was higher than that in C group (49%) (p = 0.016). Cytoplasmic twist-2 and cytoplasmic and nuclear Snail expressions were detected almost equally between PD group and C group. Cytoplasmic Twist NB expression was more frequent in PD group (26%) than in C group (1.6%) (p = 0.0002). In PD group, a total of 17 cases comprising 9 MPCs and 8 IDCs, were positive for vimentin. In these 17 vimentin-positive cases, 14 were stable disease or partial response with an anthracyclin-containing regimen while all 16 patients receiving a taxane-containing regimen became cPD during the taxane-containing regimen. Patient characteristics PD group (N = 23)Control group(N = 63)Age median (range)42(25-62)55(25-77)Clinical stage:I/II/III0/11/127/44/12Diagnosi at operation:IDC/MPC or MPC containing/others12/11/052/1/10Nuclear grade:1/2/30/0/231/9/53Tumor size at diagnosis4.8(2-14)2.8(1.2-12.0)Neoadjuvant chemoterapy regimen Anthracyclin containing:AC/CEF11/12-Taxane: paclitaxel/docetaxel20/2- Conclusion: EMT features detected by metaplastic phenotype and cytoplasmic vimentin expression could be predictors for cPD during NAC for TNBC. The tumors of these phenotypes were likely to be resistant to a taxane-containing regimen. Immunohistochemical profilingantibodyPD group (N = 23)Control group (N = 63)p-valueVimentin(cytoplasm)17 (74%)31 (49%)0.0411Twist-2(cytoplasm)21(91%)59 (94%)0.7849Snail-2(cytoplasm)12 (52%)38 (60%)0.5548Snail-2(nucleus)14 (61%)34 (54%)0.4677Twist NB(cyroplasm)6 (26%)1 (1.6%)0.0002 Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-08-12.

The purpose of this study was to determine the safety, distribution, internal dosimetry, and initial human epidermal growth factor receptor 2 (HER2)–positive tumor images of 64Cu-DOTA-trastuzumab in humans. Methods: PET was performed on 6 patients with primary or metastatic HER2-positive breast cancer at 1, 24, and 48 h after injection of approximately 130 MBq of the probe 64Cu-DOTA-trastuzumab. Radioactivity data were collected from the blood, urine, and normal-tissue samples of these 6 patients, and the multiorgan biodistribution and internal dosimetry of the probe were evaluated. Safety data were collected for all the patients after the administration of 64Cu-DOTA-trastuzumab and during the 1-wk follow-up period. Results: According to our results, the best timing for the assessment of 64Cu-DOTA-trastuzumab uptake by the tumor was 48 h after injection. Radiation exposure during 64Cu-DOTA-trastuzumab PET was equivalent to that during conventional 18F-FDG PET. The radioactivity in the blood was high, but uptake of 64Cu-DOTA-trastuzumab in normal tissues was low. In 2 patients, 64Cu-DOTA-trastuzumab PET showed brain metastases, indicative of blood–brain barrier disruptions. In 3 patients, 64Cu-DOTA-trastuzumab PET imaging also revealed primary breast tumors at the lesion sites initially identified by CT. Conclusion: The findings of this study indicated that 64Cu-DOTA-trastuzumab PET is feasible for the identification of HER2-positive lesions in patients with primary and metastatic breast cancer. The dosimetry and pharmacologic safety results were acceptable at the dose required for adequate PET imaging.

This report describes two cases with obstructive jaundice caused by poorly differentiated gastric adenocarcinoma. Computed tomography scans showed circumferential stenosis in the hilar bile ducts. Endoscopic retrograde cholangiopancreatography showed dilatation of the bilateral hepatic ducts and stenosis of the common hepatic ducts from the bifurcation of the bilateral hepatic ducts. The first diagnoses were hilar cholangiocarcinoma and biliary drainage decreased serum bilirubin; however, both patients died of cancer within a short period of time. Autopsies revealed lymphatic vessel invasion and possible subepithelial invasion by gastric adenocarcinoma into the hilar bile ducts. A differential diagnosis should thus be required in suspected cases of hilar cholangiocarcinoma.

Weekly dose-dense paclitaxel with carboplatin every 3 weeks (dose-dense TC) provides good efficacy, and neoadjuvant chemotherapy is common for advanced-stage disease. However, it is unclear the efficacy and safety of dose-dense TC as neoadjuvant chemotherapy. Therefore, we evaluated neoadjuvant dose-dense TC chemotherapy for advanced-stage ovarian carcinoma. We retrospectively reviewed cases of ovarian carcinoma that were not suited for primary debulking surgery (2003–2014). The patients received neoadjuvant dose-dense TC chemotherapy, followed by interval debulking surgery and adjuvant chemotherapy. We identified 74 patients (mean age 60 years, range 39–85 years). The FIGO stages were IIIC (39/74, 52.7%) and IV (34/74, 45.9%). Fifty-six patients (75.6%) had a performance status of 0–1. The adverse events were grade 3/4 neutropenia (55.4%), anemia (44.6%), thrombocytopenia (21.6%), and peripheral neuropathy (8.1%); no treatment-related deaths were observed. Among the 66 patients who underwent debulking (89.2%), 55 patients (74.3%) achieved optimal debulking and 47 patients (63.5%) achieved complete resection. The median progression-free and overall survivals were 19.0 months (95% CI 16.2–23.7 months) and 55.1 months (95% CI 44.6 months to not estimable), respectively. A performance status of 2–3 was independently associated with poor prognosis (hazard ratio 3.84; p = 0.001). Neoadjuvant dose-dense TC chemotherapy was effective (complete resection in >60% of cases) and tolerable for advanced-stage ovarian carcinoma.

Adult rhabdomyosarcoma (RMS) is a highly aggressive tumor. Multidisciplinary treatment is important. However, the role of surgery is controversial. The purpose of this study was to reveal the role of a delayed primary excision (DPE) after induction chemotherapy (IC) in localized nonmetastatic adult head and neck RMS. We retrospectively reviewed 24 adult head and neck RMS. Treatment was classified into the following two groups: the DPE group, who received IC followed by surgery, postoperative radiotherapy, and adjuvant chemotherapy (17 patients); the chemoradiotherapy (CRT) group, who received IC followed by chemoradiotherapy (seven patients). We analyzed the efficacy of IC, local control rate (LCR), and overall survival (OS). In the DPE group, 10 patients (59%) underwent complete surgical resection. In the evaluation of the surgical specimens, 14 patients (82%) had residual viable tumors after IC. The response to IC was significantly associated with the 3‐year LCR (CR/PR vs. SD/PD: 100% vs. 33%, P = 0.0014). In patients with good response to chemotherapy, the DPE group had a significantly better 3‐year LCR compared with that of the CRT group (DPE group vs. CRT group, 100% vs. 44%, P = 0.018). However, the treatment modalities were not associated with OS (DPE group vs. CRT group, 65% vs. 57%: P = 0.98). The recurrence patterns differed according to treatments, and distant metastases were more frequent in the DPE group. DPE may impact local control of localized nonmetastatic adult head and neck RMS. Poor response to IC is a risk factor for local recurrence.

No standard chemotherapy for adults with recurrent/refractory rhabdomyosarcoma (RMS) has yet been established. The present study aimed to assess the effect of ifosfamide and etoposide (IE) chemotherapy on previously treated RMS.Adults with recurrent/refractory RMS were treated with ifosfamide (1,800 g/m(2)/day), etoposide (100 mg/m(2)/day) and mesna (1,080 mg/m(2)/day) for 5 days. The effect and toxicity were evaluated by chart review.Fifteen patients, with a median age of 33 years (range=25-67 years), were treated with IE chemotherapy. A median of six cycles of chemotherapy were administered and an objective response was obtained in eight patients. The median progression-free survival was 5.2 months (95% confidence interval=2.3-6.7 months) and overall survival was 14.4 months (95% confidence interval=4.6-28.3 months). Toxicity greater than grade 3 was as follows: neutropenia in all patients, anemia in seven, thrombocytopenia in seven and febrile neutropenia in eight.IE chemotherapy could be an alternative optional treatment method in adults with recurrent/refractory RMS.

The prognosis of adult rhabdomyosarcoma (RMS) has been considered dismal. The question is raised that vincristine, d-actinomycin, and cyclophosphamide (VAC) chemotherapy may not be administered as per schedule for adult RMS; consequently, low dose intensity (DI) leads to poor prognosis. Herein, we examined whether the administration of VAC chemotherapy for adults and children with RMS is feasible with regard to the DIs of VAC. Chart review was retrospectively performed for all identified patients. The percentage of relative DI (RDI) was calculated according to the Children’s Oncology Group D9803 protocol. Further, we examined the RDI in the first 6 cycles of VAC (induction phase) and the DI after the first 6 cycles of VAC (maintenance phase). We identified a total of 27 adults and 18 children with RMS, respectively. The mean RDIs of vincristine in total phase were significantly lower in adults than that in children (P = 0.04). In induction phase, the mean RDIs of vincristine and cyclophosphamide were similar for both groups; however, they were dropped significantly in adults during maintenance phase (P

Pharmaceutical companies in Japan often provide a unique document called the Guidance for Proper Usage (GPU) to medical oncologists, in order to promote the proper use of an approved drug. The aim of the study was to examine the content of and current trends in the efficacy and safety data provided in GPU documents, in order to understand what pharmaceutical companies regard as important information for an oncologist to ensure proper usage of oncology drugs in Japan. Furthermore, this study analysed the influence of route of administration (oral or injection), drug class (cytotoxic or other), type of malignancy (haematological or solid malignancy) and the period of GPU publication (before and after April 2004) on the content of the GPU document. For the 103 oncology drugs approved for use in Japan, 59 GPU documents, covering 50 drugs, were distributed to medical oncologists and were compared by multivariate analysis over two consecutive time periods, from October 1994 to March 2004 and April 2004 to December 2010. For each document, we determined the total number of pages and the proportion of pages that provided drug and toxicity information and the results of registration trials, including postmarketing surveillance. The median number of pages in the GPUs was 48 (range, 11–98). The proportion of pages providing toxicity information, drug information (e.g. warnings, contraindications, instructions, and directions for indications and usage, dosage and administration) and the results of registration trials were 30%, 26% and 11%, respectively. After April 2004, the publication of GPU documents doubled, and the proportion of pages discussing the results of registration trials significantly increased (p = 0.002). The proportions of pages discussing toxicity information and the results of registration trials in molecular-targeted drugs were significantly greater than those for other types of drugs (p < 0.001 and p = 0.008, respectively), while the proportion of pages discussing drug information was significantly lower (p = 0.001). The number and length of GPU publications distributed by pharmaceutical companies in Japan has increased since 2004. Significant changes in content have included a reduction in the amount of information about drug administration and an increase in information on the results of pharmaceutical company-sponsored registrational trials. A further study is warranted to evaluate how often oncologists actually access GPU documents and what type of information could be most useful in medical practice in Japan.

Outcomes in adult patients with rhabdomyosarcoma are poor, with a 5-year survival rate of approximately 30 %. The current study aimed to compare the clinical outcomes of adult and childhood rhabdomyosarcoma patients with local and metastatic disease and to examine the impact and timing of local therapy on metastasis.Clinicopathological features and patient outcomes were reviewed retrospectively for rhabdomyosarcoma patients receiving chemotherapy between 1981 and 2010 at our institution. Adults were defined as those aged 21 years or older.Of the 98 patients identified, 36 were adults (median age, 29; range, 21-72) and 62 were children (median age, 11; range, 0.6-20). Median progression-free survival of localized and metastatic disease for children and adults was as follows: localized disease, 166.9 versus 22.4 months (p = 0.005), and metastatic disease, 13.3 versus 13.3 months (p = 0.949), respectively. Multivariate regression analysis revealed that older age (≥ 21 vs.21) was a significant poor prognostic factor in localized disease. Conversely, age was not related to survival in metastatic disease. Receiving radiotherapy to the primary site was an independent factor indicating a better prognosis. An analysis of the optimal timing of local therapy was performed for 53 patients; however, its significance on survival could not be determined.Age was a negative prognostic factor in rhabdomyosarcoma patients with localized disease, but it did not affect the survival in metastatic disease. For metastatic disease, although local therapies may be effective for survival, the timing of such therapies should be determined individually.

The human IgG2 monoclonal antibody tremelimumab is an immune checkpoint inhibitor that blocks cytotoxic T lymphocyte-associated antigen-4 (CTLA-4). The therapeutic response of anti-CTLA-4 monoclonal antibodies possess unique kinetics, in that antitumor responses are often observed after initial short-term disease progression, in some cases as long as 6–12 months after anti-CTLA-4 treatment initiation. Here, we report two cases: one of bile duct cancer and the other of squamous cell carcinoma of unknown primary, both of which demonstrated initial rapid disease progression followed by dramatic tumor shrinkage after one or two doses of tremelimumab, without any immune-related adverse events. This delayed, yet dramatic antitumor response suggests that tremelimumab may hold promise in the treatment of solid tumors.

Cancer stem cells (CSCs) have been identified in various types of cancer; however, the mechanisms by which cells acquire CSC properties such as drug resistance and tumour seeding ability are not fully understood. Here, we identified microRNA-27b (miR-27b) as a key regulator for the generation of a side-population in breast cancer cells that showed CSC properties, and also found that the anti-type II diabetes (T2D) drug metformin reduced this side-population via miR-27b-mediated repression of ectonucleotide pyrophosphatase/phosphodiesterase family member 1 (ENPP1), which is involved in T2D development. ENPP1 induced the generation of the side-population via upregulation of the ABCG2 transporter. ENPP1 was also identified as a substrate of the 26S proteasome, the activity of which is downregulated in CSCs. Overall, these results demonstrate that a T2D-associated gene plays an important role in tumour development and that its expression is strictly controlled at the mRNA and protein levels., MicroRNAs have a role in the acquisition of stem cell-like properties of cancer cells. Here the authors show that microRNA-27b mediates generation of a side-population of breast cancer stem cells, in part by regulating the protein ENPP1, which has been previously linked to the development of diabetes.

MK-2206 is an oral, highly selective inhibitor of AKT. The safety, tolerability, pharmacokinetics (PK), and anti-tumor activity of MK-2206 was evaluated in Japanese patients with advanced solid tumors. Patients received a single oral dose of MK-2206 according to an every other day (QOD) dosing schedule or a once weekly (QW) dosing schedule in repeating 28-day treatment cycles, with a 7-day rest after only the first cycle. The dose-limiting toxicities (DLTs) were evaluated during Cycle 1. Full PK sampling was performed during Cycle 1. Twenty-four patients were treated at 45 mg (n = 3) or 60 mg (n = 9) QOD or at 135 mg (n = 3) or 200 mg (n = 9) QW. One patient experienced a DLT at 60 mg QOD, and three patients experienced DLTs at 200 mg QW. No DLTs were observed at 45 mg QOD or at 135 mg QW. The DLTs included mucosal inflammation, hyponatremia, face edema, erythema multiforme, and hyperglycemia. Common adverse events related to MK-2206 included rash, an elevated insulin c-peptide level, stomatitis, pyrexia, eosinophilia, leukopenia, and hyperglycemia. PK differences in MK-2206 exposure were observed between Japanese patients and non-Japanese patients. The higher exposure in Japanese patients was likely caused by the relatively lower weight of Japanese patients versus non-Japanese patients. No tumor responses were observed, but six patients exhibited stable disease lasting longer than 4 months. MK-2206 has an acceptable safety profile in Japanese patients with advanced solid tumors and warrants further investigation.

AKT1E17K mutations occur at low frequency in a variety of solid tumors, including those of the breast and urinary bladder. Although this mutation has been shown to transform rodent cells in culture, it was found to be less oncogenic than PIK3CA mutations in breast epithelial cells. Moreover, the therapeutic potential of AKT inhibitors in human tumors with an endogenous AKT1E17K mutation is not known. Expression of exogenous copies of AKT1E17K in MCF10A breast epithelial cells increased phosphorylation of AKT and its substrates, induced colony formation in soft agar, and formation of lesions in the mammary fat pad of immunodeficient mice. These effects were inhibited by the allosteric and catalytic AKT inhibitors MK-2206 and AZD5363, respectively. Both AKT inhibitors caused highly significant growth inhibition of breast cancer explant models with AKT1E17K mutation. Furthermore, in a phase I clinical study, the catalytic Akt inhibitor AZD5363 induced partial responses in patients with breast and ovarian cancer with tumors containing AKT1E17K mutations. In MGH-U3 bladder cancer xenografts, which contain both AKT1E17K and FGFR3Y373C mutations, AZD5363 monotherapy did not significantly reduce tumor growth, but tumor regression was observed in combination with the FGFR inhibitor AZD4547. The data show that tumors with AKT1E17K mutations are rational therapeutic targets for AKT inhibitors, although combinations with other targeted agents may be required where activating oncogenic mutations of other proteins are present in the same tumor. Mol Cancer Ther; 14(11); 2441–51. ©2015 AACR.

Background The purpose of this study was to determine whether brain metastases from HER2-positive breast cancer could be detected noninvasively using positron emission tomography (PET) with 64Cu-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-trastuzumab. Methods PET was performed on five patients with brain metastases from HER2-positive breast cancer, at 24 or 48 h after the injection of approximately 130 MBq of the probe 64Cu-DOTA-trastuzumab. Radioactivity in metastatic brain tumors was evaluated based on PET images in five patients. Autoradiography, immunohistochemistry (IHC), and liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis were performed in one surgical case to confirm HER2 specificity of 64Cu-DOTA-trastuzumab. Results Metastatic brain lesions could be visualized by 64Cu-DOTA-trastuzumab PET in all of five cases, which might indicated that trastuzumab passes through the blood-brain barrier (BBB). The HER2 specificity of 64Cu-DOTA-trastuzumab was demonstrated in one patient by autoradiography, immunohistochemistry, and LC-MS/MS. Conclusions Cu-DOTA-trastuzumab PET could be a potential noninvasive procedure for serial identification of metastatic brain lesions in patients with HER2-positive breast cancer. Trial registration UMIN000004170

Background & Aims: The relationship between single nucleotide polymorphisms (SNPs) and clinical outcomes has been intensively studied. We intended to determine SNPs of CYP2C19 and 23S rRNA of Helicobacter pylori by using rapid urease test (RUT)-positive gastric mucosal samples. Methods: One hundred thirty-nine patients with H pylori-positive results based on RUT completed 1-week treatment with lansoprazole 30 mg twice a day, clarithromycin 200 mg 3 times daily, and amoxicillin 500 mg 3 times daily. SNPs from adenine to guanine at positions 2142 and 2143 of 23S rRNA of H pylori (A2142G and A2143G) and SNPs from guanine to adenine at positions 681 in exon 5 (*2) and 636 in exon 4 (*3) of CYP2C19 were determined by the serial invasive signal amplification reaction assay by using DNAs extracted from gastric tissue samples already used for RUT. Minimum inhibitory concentrations of clarithromycin for H pylori were determined by culture test. CYP2C19 genotypes were classified into the rapid metabolizer (*1/*1), intermediate metabolizer (*1/*2 or *1/*3), and poor metabolizer (*2/*2, *2/*3, or *3/*3) groups. Results: H pylori strains with A2142G or A2143G mutation had higher minimum inhibitory concentrations for clarithromycin. Cure rates in rapid, intermediate, and poor metabolizer groups were 57.8% (95% confidence interval, 42.1%–72.4%), 88.2% (78.1%–94.8%), and 92.3% (74.9%–99.1%), respectively (P

Congenital absence of the portal vein (CAPV) is a rare malformation that is often accompanied by other anomalies such as cardiac and skeletal malformations and/or hepatic tumors. We describe here a case of CAPV complicating hepatic tumors in a 16-year-old Japanese girl. Abdominal ultrasonography revealed a hyperechoic tumor in the liver and dilatation of the portal vein that appeared to be connected directly with the inferior vena cava. Subsequent abdominal computed tomography (CT) revealed tumors and magnetic resonance angiography confirmed that the portal vein entered directly into the inferior vena cava just above the liver. In addition, there was absence of the right portal vein and the left intrahepatic branch except for the presence of left portal vein only within the porta hepatis. These findings led to a diagnosis of CAPV complicated hepatic tumors. Careful monitoring of these hepatic tumors is ongoing due to the possibility of malignant transformation.

Background The presence of tumour-infiltrating lymphocytes (TILs) is a favourable prognostic factor in patients with early breast cancer. Programmed cell death-1 (PD-1) and its ligand PD-L1 are associated with a variety of adverse features. The purpose of this study was to clarify the relationships between TILs, PD-1 and PD-L1 as well as their prognostic implications in early breast cancer. Methods We investigated 180 patients with breast cancer who received neoadjuvant chemotherapy and underwent subsequent surgery for stage II–III invasive breast carcinoma between 1999 and 2007. TIL expression was classified as low or high using a previously reported scoring model. PD-1 and PD-L1 expression levels were determined by immunohistochemistry. The correlation between PD-1 expression in TILs and PD-L1 expression in cancer cells was also investigated. Results Higher tumour grade was significantly correlated with PD-L1 expression in tumours (p

This descriptive study used the Japanese spontaneous reporting data to investigate the time taken (TTILD) to development of interstitial lung disease (ILD) after initiation of chemotherapy and the death rates attributed in part to post-chemotherapy ILD (i.e., DR) for anticancer drugs. We evaluated TTILD and DR endpoints for 36 anticancer drugs, which are widely used for treating 11 solid and 3 hematological cancers, and are suspected of causing ILD, by using 8- year spontaneous reporting data recording for 2,553 patients in the reporting system of the relevant Japanese regulatory agency. The median TTILD and overall DR attributable to post-chemotherapy ILD for the drugs were 1.8 months and 29%, respectively. For most drugs, the median TTILDs were between 1 to 4 months, and the DRs attributable to postchemotherapy ILD were