Evaluation of a novel medical device for pegfilgrastim administration.

Pegfilgrastim, a pegylated form of granulocyte colony-stimulating factor, has reduced the risk of developing febrile neutropenia, which is associated with an increase in severe infection and prolonged hospitalization. However, pegfilgrastim administration requires that patients visit hospital following cancer chemotherapy, thus imposing a burden on patients and those around them. An on-body injector (OBI), which automatically administers pegfilgrastim about 27 hours after chemotherapy, was used in this study. The OBI, which consists of a main pump unit and infusion set, is a drug delivery device designed to be attached to the patient's body, with a timer-controlled dosing function. This study was conducted in breast cancer patients to evaluate the safety of pegfilgrastim administered subcutaneously via the OBI. The study period consisted of screening and treatment observation periods involving four cycles of neoadjuvant or adjuvant chemotherapy with docetaxel plus cyclophosphamide. One 3.6-mg pegfilgrastim dose was administered subcutaneously via OBI during each cycle of chemotherapy. The study enrolled 35 patients, and no serious adverse events or febrile neutropenia occurred. Administration of pegfilgrastim was successfully completed at all times when the OBI was attached to the patient, and no safety concerns associated with OBI function arose. For outpatients requiring pegfilgrastim following cancer chemotherapy, the use of an OBI was considered to be a safe option to reduce the need for outpatient visits that restrict their activities of daily living.

A phase 3 safety study of fosnetupitant as an antiemetic in patients receiving anthracycline and cyclophosphamide: CONSOLE-BC.

BACKGROUND: Fosnetupitant (FosNTP), an intravenous neurokinin 1 receptor antagonist, demonstrated a favorable safety profile with a potentially low risk of injection site reactions (ISRs) and promising antiemetic efficacy in patients receiving cisplatin-based highly emetogenic chemotherapy in a previous phase 2 study. We conducted a randomized, double-blind safety study to evaluate the safety profile of FosNTP, including ISRs, in patients receiving doxorubicin-cyclophosphamide or epirubicin-cyclophosphamide (AC/EC) chemotherapy. METHODS: Patients scheduled to receive AC/EC were randomized 1:1 to receive 235 mg of FosNTP or 150 mg of fosaprepitant (FosAPR), both in combination with 0.75 mg of intravenous palonosetron and 9.9 mg of dexamethasone on day 1. The stratification factors were age category (<55 vs ≥55 years) and study site. The primary end point was the incidence of treatment-related adverse events (TRAEs) with FosNTP. RESULTS: Overall, 102 patients were randomized to FosNTP (n = 52) or FosAPR (n = 50), and all were treated with the study drug and evaluated for safety. The primary end point, the incidence of TRAEs, was similar with FosNTP (21.2%; 95% confidence interval [CI], 11.1%-34.7%) and FosAPR (22.0%; 95% CI, 11.5%-36.0%), with any-cause ISRs observed in 5.8% and 26.0% of patients, respectively, and treatment-related ISRs observed in 0% and 10.0%, respectively. The overall (0-120 hour) complete response (defined as no emetic event and no rescue medication) rate, standardized by age category in the full analysis set, was 45.9% (23 of 51 patients) with FosNTP and 51.3% (25 of 49 patients) with FosAPR. CONCLUSIONS: FosNTP demonstrated a favorable safety profile with a very low risk of ISRs in the AC/EC setting.

Osimertinib for patients with EGFR T790M mutation-positive non-small-cell lung cancer and a poor performance status.

BACKGROUND: Osimertinib is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that is effective against EGFR T790M mutation-positive non-small-cell lung cancer (NSCLC) in patients who have good performance status (PS). However, the efficacy and safety of osimertinib for patients with poor PS is unknown. METHODS: We retrospectively evaluated the efficacy and safety of osimertinib in patients with EGFR T790M mutation-positive NSCLC who had Eastern Cooperative Oncology Group PS scores of 2-4 and who were administered 80 mg of osimertinib once daily between March 2016 and February 2017. RESULTS: Thirty patients (8 men and 22 women) with EGFR T790M mutation-positive NSCLC were evaluated; their median age was 66 years (range: 39-89 years). Twenty-four and six patients had PS scores of 2 and 3, respectively; none had a PS score of 4. All patients had previously been treated with first- or second-generation EGFR-TKIs. T790M was detected in the tumor samples of 23 patients, the blood samples of two patients, and both the tumor and blood samples of five patients. The overall response rate was 53% (95% confidence interval: 36-70%), and the PS score improvement rate was 63%. The median progression-free survival was 8.2 months (95% confidence interval: 4.3-13.2 months), while the median overall survival time was not reached. No patient required treatment cessation owing to adverse events, and no treatment-related deaths occurred. CONCLUSIONS: Osimertinib therapy demonstrates promising efficacy and acceptable safety in patients with EGFR T790M mutation-positive NSCLC who have poor PS.

Isolation and molecular analysis of circulating tumor cells from lung cancer patients using a microfluidic chip type cell sorter.

Circulating tumor cells (CTCs) are a tumor-derived material utilized for liquid-based biopsy; however, capturing rare CTCs for further molecular analysis remains technically challenging, especially in non-small-cell lung cancer. Here, we report the results of a clinical evaluation of On-chip Sort, a disposable microfluidic chip-based cell sorter, for capture and molecular analysis of CTCs from patients with lung adenocarcinoma. Peripheral blood was collected from 30 metastatic lung adenocarcinoma patients to enumerate CTCs using both On-chip Sort and CellSearch in a blind manner. Captured cells by On-chip Sort were subjected to further molecular analysis. Peripheral blood samples were also used for detection of EGFR mutations in plasma using droplet digital PCR. Significantly more CTCs were detected by On-chip Sort (22/30; median 5; range, 0-18 cells/5 mL blood) than by CellSearch (9/30; median, 0; range, 0-12 cells/7.5 mL) (P < 0.01). Thirteen of 30 patients who had a negative CTC count by CellSearch had a positive CTC count by On-chip Sort. EGFR mutations in CTCs captured by On-chip Sort were observed in 40.0% (8/20) of patients with EGFR-mutated primary tumor. EGFR mutations were often observed in 53.3% (8/15) of patients detected in plasma DNA. Expressions of EGFR and vimentin protein on CTCs were also successfully assessed using On-chip Sort. These results suggest that On-chip Sort is an efficient method to detect and capture rare CTCs from patients with lung adenocarcinoma that are undetectable with CellSearch. Mutation detection using isolated CTCs remains to be further tackled (UMIN000012488).

Changes in programmed death ligand 1 expression in non-small cell lung cancer patients who received anticancer treatments.

BACKGROUND: The expression of programmed death ligand 1 (PD-L1) is considered a predictive biomarker of anti-programmed death 1 (PD-1)/PD-L1 cancer therapies. However, changes in PD-L1 expression of tumor cells during clinical courses have not been fully evaluated. We evaluated changes in PD-L1 expression for non-small cell lung cancer (NSCLC) patients who received anticancer treatments during clinical courses. METHODS: In 76 NSCLC patients, PD-L1 expression was evaluated before and after anticancer treatment by immunohistochemical (IHC) analysis using an anti-PD-L1 antibody. We defined two cut-off points of PD-L1 expression (1 and 50%) and three corresponding IHC groups (A: 0%, B: 1-49%, and C: ≥50%). IHC group B and C were considered to be positive expression, and we defined the difference of IHC group between pre- and post-treatment as 'major change' in PD-L1 expression. RESULTS: Before anticancer treatment, PD-L1 expression was observed in 38/76 (50%) patients, and was significantly less common in patients harboring mutations in the epidermal growth factor receptor gene (EGFR) than in those without (P = 0.039). After anticancer treatment, PD-L1 expression was observed in 36/76 (47%) patients. Major increases in PD-L1 expression were seen in 11 (14%), and major decreases in 18 (24%) patients. Among 13 patients harboring EGFR mutations treated with EGFR tyrosine-kinase inhibitor (EGFR-TKI), five (38%) showed major increases. CONCLUSION: Major changes of PD-L1 expression in tumor cells were observed in 38% of NSCLC patients who received anticancer treatments. And, treatments with EGFR-TKI may increase PD-L1 expression in NSCLC patients harboring EGFR mutations.

Skeletal muscle depletion during chemotherapy has a large impact on physical function in elderly Japanese patients with advanced non-small-cell lung cancer.

BACKGROUND: Elderly patient with advanced cancer is one of the most vulnerable populations. Skeletal muscle depletion during chemotherapy may have substantial impact on their physical function. However, there is little information about a direct relationship between quantity of muscle and physical function. We sought to explore the quantitative association between skeletal muscle depletion, and muscle strength and walking capacity in elderly patients with advanced non-small cell lung cancer (NSCLC). METHODS: Thirty patients aged ≥70 years with advanced NSCLC (stage III-IV) scheduled to initiate first-line chemotherapy were prospectively enrolled between January 2013 and November 2014. Lumbar skeletal muscle index (LSMI, cm2/m2), incremental shuttle walking distance (ISWD, m), and hand-grip strength (HGS, kg) were assessed at baseline, and 6 ± 2 weeks (T2) and 12 ± 4 weeks (T3) after study enrollment. Associations were analyzed using linear regression. RESULTS: Altogether, 11 women and 19 men with a median age of 74 (range, 70-82) years were included in the study; 24 received cytotoxic chemotherapy and 6, gefitinib. Mean ± standard deviation of LSMI, ISWD and HGS were 41.2 ± 7.8 cm2/m2, 326.0 ± 127.9 m, and 29.3 ± 8.5 kg, respectively. LSMI and ISWD significantly declined from baseline to T2 and T3. HGS significantly declined from baseline to T2 and T3 only in men. Change in LSMI was significantly associated with change in HGS (ß = 0.3 ± 0.1, p = 0.0127) and ISWD (ß = 8.8 ± 2.4, p = 0.0005). CONCLUSIONS: Skeletal muscle depletion accompanied with physical functional decline started in the early phase of the chemotherapy in elderly patients with advanced NSCLC. Our results suggest that there may be a need for early supportive care in these patients to prevent functional decline during chemotherapy. TRIAL REGISTRATION: Trial registration number: UMIN000009768 Name of registry: UMIN (University hospital Medical Information Network). URL of registry: Date of registration: 14 January 2013. Date of enrolment of the first participant to the trial: 23 January 2013.

Unfavorable impact of cancer cachexia on activity of daily living and need for inpatient care in elderly patients with advanced non-small-cell lung cancer in Japan: a prospective longitudinal observational study.

BACKGROUND: Cancer cachexia in elderly patients may substantially impact physical function and medical dependency. The aim of this study was to estimate the impact of cachexia on activity of daily living (ADL), length of hospital stay, and inpatient medical costs among elderly patients with advanced non-small-cell lung cancer (NSCLC) receiving chemotherapy. METHODS: Thirty patients aged ≥70 years with advanced NSCLC (stage III-IV) scheduled to receive first-line chemotherapy were prospectively enrolled between January 2013 and November 2014. ADL was assessed using the Barthel index. The disability-free survival time (DFS) was calculated as the time between the date of study entry and the date of onset of a disabling event, which was defined as a 10-point decrease in the Barthel index from that at baseline. The mean cumulative function of the length of hospital stay and inpatient medical costs (¥, Japanese yen) was calculated. RESULTS: The study patients comprised 11 women and 19 men, with a median age of 74 (range, 70-82) years. Cachexia was diagnosed in 19 (63%) patients. Cachectic patients had a shorter DFS (7.5 vs. 17.1 months, p < 0.05). During the first year from study entry, cachectic patients had longer cumulative lengths of hospital stay (80.7 vs. 38.5 days/person, p < 0.05), more frequent unplanned hospital visits or hospitalizations (4.2 vs. 1.7 times/person, p < 0.05), and higher inpatient medical costs (¥3.5 vs. ¥2.1 million/person, p < 0.05) than non-cachectic patients. CONCLUSIONS: Elderly NSCLC patients with cachexia showed higher risks for disability, prolonged hospitalizations, and higher inpatient medical costs while receiving chemotherapy than patients without cachexia. Our results might indicate that there is a potential need for an early intervention to minimize progression to or development of cachexia, improve functional prognosis, and reduce healthcare resource burden in this population. TRIAL REGISTRATION: Trial registration number: UMIN000009768 . Name of registry: UMIN (University hospital Medical Information Network). Date of registration: 14 January 2013. Date of enrolment of the first participant to the trial: 23 January 2013.

The effects of advanced age and serum α1 -acid glycoprotein on docetaxel unbound exposure and dose-limiting toxicity in cancer patients.

AIM: α1 -Acid glycoprotein (AAG), which is a major binding protein of docetaxel, is considered to be a determinant for docetaxel pharmacokinetics. However, there are no reports about the impact of serum AAG on pharmacokinetics and pharmacodynamics in elderly patients treated with docetaxel. The aim of this prospective study was to elucidate the effects of advanced age and serum AAG on docetaxel unbound exposure and neutropenia, dose-limiting toxicity, in cancer patients. METHODS: Docetaxel was administered at 60 mg m-2 to 51 patients with non-small cell lung cancer, 17 of whom were ≥75 years of age. Pharmacokinetics, unbound fraction (fu), neutropenia, serum protein levels of AAG and albumin, as well as baseline absolute neutrophil count (ANC) were assessed during the first course. Population pharmacokinetic and pharmacodynamic analyses were performed to evaluate the influence of clinically relevant factors on docetaxel pharmacokinetics and neutropenia. RESULTS: Clearance of docetaxel and degree of fu were significantly associated with serum AAG level, but not with age. Area under the concentration-time curve of unbound docetaxel (fu·AUC) was significantly higher in patients aged ≥75 years (0.389 µg·h ml-1 , 95% CI; 0.329-0.448 µg·h ml-1 ) compared with patients aged <75 years (0.310 µg·h ml-1 , 95% CI; 0.268-0.352 µg·h ml-1 ). Percent decrease in ANC at nadir related to fu·AUC, and was dependent on baseline ANC. CONCLUSION: Regardless of ageing, serum level of AAG determines docetaxel unbound exposure and related dose-limiting toxicity. Serum AAG level and ANC at baseline appear to be predictive of neutropenia for patients of all ages following the administration of docetaxel.

Rebiopsy for patients with non-small-cell lung cancer after epidermal growth factor receptor-tyrosine kinase inhibitor failure.

Although third-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKI) can overcome T790M-mediated resistance in non-small-cell lung cancer (NSCLC), rebiopsy to confirm T790M status is occasionally difficult. We aimed to investigate the current tendency and the limitations of rebiopsy in clinical practice. This study included 139 consecutive NSCLC patients with EGFR mutations, who had experienced progressive disease (PD) after EGFR-TKI treatment. We retrospectively reviewed patient characteristics, tumor progression sites and rebiopsy procedures. Of 120 patients (out of the original 139) who were eligible for clinical trials, 75 (63%) underwent rebiopsy for 30 pleural effusions, 32 thoracic lesions, four bone, two liver, and seven at other sites. Rebiopsy procedures included 30 thoracocentesis, 24 transbronchial biopsies, 13 computed tomography (CT)-guided needle biopsies and 8 other procedures. Of the 75 rebiopsied patients, 71 (95%) were pathologically diagnosed with malignancy; and 34 (45%) had available tissue samples for EGFR analyses. Of the 75 biopsied patients, 61 (81%) were analyzed for EGFR mutation, using tissue or cytology samples; T790M mutations were identified in 20 (33%) of the 61 patients. Of the 120 patients, 45 (38%) did not undergo rebiopsy, because of inaccessible tumor sites (n = 19), patient refusal (n = 6) or decision of physician (n = 10). In conclusion, among patients with EGFR mutations who had PD after EGFR-TKI treatment, 63% underwent rebiopsy. Most rebiopsy samples were diagnosed with malignancy. However, tissue samples were less available and T790M mutations were identified less frequently than in previous studies. Skill and experience with rebiopsy and noninvasive alternative methods will be increasingly important.

Frequency of EGFR T790M mutation and multimutational profiles of rebiopsy samples from non-small cell lung cancer developing acquired resistance to EGFR tyrosine kinase inhibitors in Japanese patients.

BACKGROUND: The majority of non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutation eventually develop resistance to EGFR tyrosine kinase inhibitors (TKIs). Minimal information exists regarding genetic alterations in rebiopsy samples from Asian NSCLC patients who develop acquired resistance to EGFR-TKIs. METHODS: We retrospectively reviewed the medical records of patients with NSCLC harboring EGFR mutations who had undergone rebiopsies after developing acquired resistance to EGFR-TKIs. We analyzed 27 practicable samples using a tumor genotyping panel to assess 23 hot-spot sites of genetic alterations in nine genes (EGFR, KRAS, BRAF, PIK3CA, NRAS, MEK1, AKT1, PTEN, and HER2), gene copy number of EGFR, MET, PIK3CA, FGFR1, and FGFR2, and ALK, ROS1, and RET fusions. Additionally, 34 samples were analyzed by commercially available EGFR mutation tests. RESULTS: Sixty-one patients underwent rebiopsy. Twenty-seven samples were analyzed using our tumor genotyping panel, and 34 samples were analyzed for EGFR mutations only by commercial clinical laboratories. Twenty-one patients (34 %) had EGFR T790M mutation. Using our tumor genotyping panel, MET gene copy number gain was observed in two of 27 (7 %) samples. Twenty patients received continuous treatment with EGFR-TKIs even after disease progression, and 11 of these patients had T790M mutation in rebiopsy samples. In contrast, only 10 of 41 patients who finished EGFR-TKI treatment at disease progression had T790M mutation. The frequency of T790M mutation in patients who received continuous treatment with EGFR-TKIs after disease progression was significantly higher than that in patients who finished EGFR-TKI treatment at disease progression (55 % versus 24 %, p = 0.018). CONCLUSIONS: The frequency of T790M mutation in this study was lower than that in previous reports examining western patients. These results suggest that continuous treatment with EGFR-TKI after disease progression may enhance the frequency of EGFR T790M mutation in rebiopsy samples.

Comparison of the efficacy of radiotherapy between postoperative mediastinal lymph node recurrence and stage III disease in non-small cell lung cancer patients.

PURPOSE: It is unknown if local treatment is equally effective in non-small cell lung cancer (NSCLC) patients with postoperative mediastinal lymph node recurrence or primary stage III disease. The purpose of this study was to investigate the effectiveness of radiotherapy, with or without chemotherapy, in patients with postoperative mediastinal lymph node recurrence. METHODS: Patient characteristics, treatment response and survival were compared between NSCLC patients with mediastinal lymph node metastases treated between 2002-2009 by radiotherapy alone or by chemoradiotherapy (group A, N=33) and those with primary stage III disease (group B, N = 157). RESULTS: Men accounted for 60.6% of group A and 78.9% of group B (p=0.04 patients). ECOG performance status 0 was detected in 78.7% of group A and 57.3% of group B (p=0.02). The response rates in groups A and B were 66.6 and 72.3%, respectively (p=0.64). Progression-free survival (PFS) was similar between groups A and B (median 15.0 vs 11.0 months; hazard ratio [HR] 0.78; 95% CI 0.51-1.20; p=0.26). However, overall survival (OS) was better in group A than in group B (median 67.0 vs 39.0 months; HR 0.56; 95% CI 0.29-0.97; p=0.03). Postoperative PFS (median 12.5 vs 19.0 months; HR 1.50; 95% CI 0.64-3.49; p=0.34) and OS (median, 67.0 vs 60.0 months; HR 1.22; 95% CI 0.36-4.14; p=0.74) were similar between the group A treatments (radiotherapy and chemoradiotherapy, respectively). CONCLUSION: Postoperative mediastinal lymph node recurrent NSCLC demonstrated distinctive features including better OS compared to patients with primary stage III disease, despite similar response rates and PFS.

Prognostic significance of diabetes mellitus in locally advanced non-small cell lung cancer.

BACKGROUND: To investigate the prognostic significance of patient characteristics and clinical laboratory test results in locally advanced non-small cell lung cancer (NSCLC), and in particular the impact of diabetes mellitus (DM) on the survival of patients who underwent chemoradiotherapy. METHODS: We retrospectively reviewed 159 patients with locally advanced NSCLC with a focus on DM and other potential prognostic factors, using the log-rank test, and univariate and multivariate analyses to assess their association with survival. RESULT: Five significant prognostic factors were identified in univariate analysis: stage (p < 0.001), DM (p = 0.04), hemoglobin levels (p = 0.003), serum albumin (p <0.001) and lactate dehydrogenase (LDH) levels (p = 0.01). Furthermore, among the factors tested using Fisher's exact test and the Wilcoxon rank sum test, gender (p = 0.019) and plasma glucose level (p <0.001) were found to have prognostic significance. Multivariate analysis showed that stage, DM, serum albumin and LDH levels were independent prognostic factors for survival (p = 0.007, p = 0.024, p = 0.007 and p = 0.005, respectively). CONCLUSIONS: The presence of DM at the time of diagnosis was identified as an independent and significant prognostic factor for predicting negative outcome in locally advanced NSCLC patients.

Prognostic impact of cancer cachexia in patients with advanced non-small cell lung cancer.

PURPOSE: Cancer cachexia (CC) is commonly seen in advanced lung cancer patients and associated with poor prognosis. However, little is known about CC that develops during chemotherapy. We evaluated the prognostic impact of CC and skeletal muscle wasting that develops during the course of chemotherapy in advanced non-small cell lung cancer (NSCLC) patients. METHODS: The clinical data of 134 newly diagnosed NSCLC patients were retrospectively reviewed. CC was defined as a body weight loss >5 or >2 % in patients with a body mass index of <20 kg/m(2). CC was assessed at baseline (T1) and 3 months (T2), 6 months (T3), and 12 months (T4) after chemotherapy initiation. Skeletal muscle mass was assessed using the lumber skeletal muscle index (LSMI). RESULTS: The proportion of patients with CC at T1, T2, T3, and T4 was 45.6, 46.1, 25.5, and 26.0 %, respectively. The frequency of grade 3 chemotherapy-induced anorexia was higher in patients with CC than those without CC at T2 (15.4 vs. 0.0 %, P = 0.0044). At all time points, patients with CC had shorter survival times than those without CC. Patients with low LSMIs (men, <41 cm(2)/m(2); women, <38 cm(2)/m(2)) tended to have poor prognosis. Adjusted Cox proportional hazard ratios and corresponding confidence intervals for CC at T1, T2, T3, and T4 were 2.53 (1.33-4.88), 1.97 (1.27-3.06), 3.86 (2.14-6.81), and 1.62 (0.80-3.16), respectively. CONCLUSION: CC presence and decreased skeletal muscle mass are associated with poor prognosis in advanced NSCLC patients receiving chemotherapy.

The effect of gefitinib in patients with postoperative recurrent non-small cell lung cancer harboring mutations of the epidermal growth factor receptor.

BACKGROUND: It is unclear whether there is a difference in the effect of gefitinib treatment between patients with postoperative recurrent non-small cell lung cancer (NSCLC) and those with stage IV NSCLC harboring mutations in the epidermal growth factor receptor (EGFR). METHODS: We retrospectively reviewed the medical records of consecutive patients with postoperative recurrent NSCLC (postoperative group) or stage IV NSCLC (stage IV group) harboring EGFR mutations who were treated with gefitinib at the Shizuoka Cancer Center between September 2002 and March 2012 to compare the effect of gefitinib on survival from treatment initiation. RESULTS: A total of 168 patients were treated with gefitinib (postoperative group, 49 patients; stage IV group, 119 patients). The response rate of gefitinib treatment in the postoperative group was similar to that in the stage IV group (58 vs. 61 %, p = 0.613). In contrast, median progression-free survival (PFS; 15.8 vs. 9.8 months, p < 0.001) and median overall survival (OS; 51.1 vs. 22.2 months, p < 0.001) were significantly longer in the postoperative group. In addition, postoperative recurrent disease, performance status (0-1), and a single metastatic organ were independent favorable prognostic factors in the multivariate analysis of survival. CONCLUSIONS: PFS and OS were superior in patients with postoperative recurrent NSCLC harboring EGFR mutations treated by gefitinib than in those with stage IV disease. These results suggest that postoperative recurrent disease may be considered a stratification factor in clinical trials for NSCLC with EGFR mutations.

Clinical impact of post-progression survival on overall survival in patients with limited-stage disease small cell lung cancer after first-line chemoradiotherapy.

BACKGROUND: The effects of first-line chemoradiotherapy on overall survival (OS) may be confounded by subsequent lines of therapy in patients with limited-stage disease small cell lung cancer (LD-SCLC). Therefore, we aimed to determine the relationships between progression-free survival (PFS), post-progression survival (PPS) and OS after first-line chemoradiotherapy in LD-SCLC patients. PATIENTS AND METHODS: We retrospectively analyzed 71 LD-SCLC patients with performance status (PS) 0-2 who received first-line chemoradiotherapy and had disease recurrence between September 2002 and March 2013 at Shizuoka Cancer Center (Shizuoka, Japan). We determined the correlation between PFS and OS and between PPS and OS at the individual level. In addition, we performed univariate and multivariate analyses to identify significant prognostic factors of PPS. RESULTS: OS is more strongly correlated with PPS (Spearman's r = 0.86, R (2) = 0.72, p < 0.05) than PFS (Spearman's r = 0.46, R (2) = 0.38, p < 0.05). In addition, the response to second-line treatments, the presence of distant metastases at recurrence and the number of additional regimens after first-line chemoradiotherapy were significant independent prognostic factors for PPS. CONCLUSIONS: PPS has more impact on OS than PFS in recurrent LD-SCLC patients with good PS at beginning of the treatment. Moreover, treatments administered after first-line chemoradiotherapy may affect their OS. However, larger multicenter studies are needed to validate these findings.

Assessment of mutational profile of Japanese lung adenocarcinoma patients by multitarget assays: a prospective, single-institute study.

BACKGROUND: Integration of mutational profiling to identify driver genetic alterations in a clinical setting is necessary to facilitate personalized lung cancer medicine. A tumor genotyping panel was developed and the Shizuoka Lung Cancer Mutation Study was initiated as a prospective tumor genotyping study. This study reports the frequency of driver genetic alterations in Japanese lung adenocarcinoma patients, and clinicopathologic correlations with each genotype. METHODS: Between July 2011 and January 2013, 411 lung adenocarcinoma patients admitted to the Shizuoka Cancer Center were included in this study with their written informed consent. Surgically resected tissues, tumor biopsies, and/or body cavity fluids were collected and tested for 23 hotspot sites of driver mutations in 9 genes (EGFR, KRAS, BRAF, PIK3CA, NRAS, MEK1, AKT1, PTEN, and HER2), gene amplifications in 5 genes (EGFR, MET, PIK3CA, FGFR1, and FGFR2), and ALK, ROS1, and RET fusions. RESULTS: Genetic alterations were detected in 54.3% (223 of 411) of all patients. The most common genetic alterations detected in this study were EGFR mutations (35.0%) followed by KRAS mutations (8.5%) and ALK fusions (5.0%). Concurrent genetic alterations were detected in 22 patients (5.4%), and EGFR mutations were observed in 16 patients as the most common partner for concurrent genetic alteration. Significantly more concurrent genetic alterations were observed in older patients. CONCLUSIONS: This is one of the largest reports of a prospective tumor genotyping study on Japanese patients with adenocarcinoma. These data suggest that mutational profiling data using a multimutational testing platform would be valuable for expanding the range of molecular-targeted therapeutics in lung cancer.

Prospective genetic profiling of squamous cell lung cancer and adenosquamous carcinoma in Japanese patients by multitarget assays.

BACKGROUND: Despite considerable recent progress in the treatment of lung adenocarcinoma, there has been little progress in the development of efficacious molecular targeted therapies for squamous cell lung cancer. In addition to the recent comprehensive genome-wide characterization of squamous cell lung cancer, it is also important to genotype this form of cancer. We therefore conducted the Shizuoka Lung Cancer Mutation Study to analyze driver mutations in patients with thoracic malignancies. Here we report the results of genotyping in patients with squamous cell lung cancer. METHODS: Based on the biobanking system, in conjunction with the clinic and pathology lab, we developed a genotyping panel designed to assess 24 mutations in 10 genes (EGFR, KRAS, BRAF, PIK3CA, NRAS, MEK1, AKT1, PTEN, HER2 and DDR2), EGFR, MET, PIK3CA, FGFR1 and FGFR2 copy numbers, and EML4-ALK and ROS1 translocations, using pyrosequencing plus capillary electrophoresis, quantitative polymerase chain reaction (PCR) and reverse-transcription PCR, respectively. RESULTS: A total of 129 patients with squamous cell lung cancer and adenosquamous carcinoma were enrolled in this study between July 2011 and November 2012. We detected genetic alterations in 40% of all cases. Gene alterations included: EGFR mutations, 6%; KRAS mutations, 4%; PIK3CA mutations, 13%; NRAS mutations, 1%; KIF5b-RET fusion gene, 1%; EGFR copy number gain, 5%; PIK3CA copy number gain, 15%; and FGFR1 copy number gain, 5%. Twelve patients (9%) harbored simultaneous genetic alterations. Genetic alterations were detected more frequently in surgically-resected, snap-frozen samples than in formalin-fixed, paraffin-embedded samples (50% vs. 29%). In addition, patients aged ≤70 years old and never-smokers showed high frequencies of genetic alterations. CONCLUSIONS: This study represents one of the largest prospective tumor-genotyping studies to be performed in Asian patients with squamous cell lung cancer. These results suggest that incorporation of genetic profiling into lung cancer clinical practice may facilitate the administration of personalized cancer treatments in patients with squamous cell lung cancer.

Progression-free survival at 2 years is a reliable surrogate marker for the 5-year survival rate in patients with locally advanced non-small cell lung cancer treated with chemoradiotherapy.

BACKGROUND: In locally advanced Non-Small-Cell Lung Cancer (LA-NSCLC) patients treated with chemoradiotherapy (CRT), optimal surrogate endpoint for cure has not been fully investigated. METHODS: The clinical records of LA-NSCLC patients treated with concurrent CRT at Shizuoka Cancer Center between Sep. 2002 and Dec. 2009 were reviewed. The primary outcome of this study was to evaluate the surrogacy of overall response rate (ORR) and progression-free survival (PFS) rate at 3-month intervals (from 9 to 30 months after the initiation of treatment) for the 5-year survival rate. Landmark analyses were performed to assess the association of these outcomes with the 5-year survival rate. RESULTS: One hundred and fifty-nine patients were eligible for this study. The median follow-up time for censored patients was 57 months. The ORR was 72%, median PFS was 12 months, and median survival time was 39 months.Kaplan-Meier curve of progression-free survival and hazard ratio of landmark analysis at each time point suggest that most progression occurred within 2 years. With regard to 5-year survival rate, patients with complete response, or partial response had a rate of 45%. Five-year survival rates of patients who were progression free at each time point (3-months intervals from 9 to 30 months) were 53%, 69%, 75%, 82%, 84%, 89%, 90%, and 90%, respectively. The rate gradually increased in accordance with progression-free interval extended, and finally reached a plateau at 24 months. CONCLUSIONS: Progression-free survival at 2 years could be a reliable surrogate marker for the 5-year survival rate in LA-NSCLC patients treated with concurrent CRT.

Long-term prognostic value of the GenesWell BCT score in Asian women with hormone receptor-positive/HER2-negative early breast cancer.

BACKGROUND: Accurate prediction of the risk of recurrence is crucial for optimal treatment decisions in hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative early breast cancer. The GenesWell BCT is a molecular assay to predict the 10-year risk of distant metastasis. In this study, we evaluated the long-term prognostic value of the GenesWell BCT assay. METHODS: The BCT score was assessed in patients with HR-positive/HER2-negative early breast cancer who did not receive chemotherapy. We compared the 15-year distant metastasis-free survival (DMFS) between risk groups classified based on the BCT score. The risk of early (0-5 years) and late (5-15 years) recurrence was evaluated based on the BCT score classification. RESULTS: According to the BCT score, 366 patients from Japan and Korea were categorized as BCT low risk (83.6%) and high risk (16.4%) for distant metastasis. Median follow-up time was 17.4 years. The 15-year DMFS rate was significantly lower in the BCT high-risk group (63.3%) than in the BCT low-risk group (93.6%) (P < 0.001). The BCT risk group was an independent prognostic factor for 15-year DMFS (hazard ratio, 4.59; 95% confidence interval 2.13-9.88; P < 0.001). Furthermore, the BCT score was a significant predictor of late recurrence (5-15 years) in patients aged ≤ 50 years and those aged > 50 years, and added prognostic information to traditional clinical prognostic factors. CONCLUSION: The BCT score can identify patients at low risk for recurrence who may not require adjuvant chemotherapy or extended endocrine therapy, regardless of age.

The Clinicopathological and Prognostic Significance of HER2-Low Breast Cancer: A Comparative Analysis Between HER2-Low and HER2-Zero Subtypes.

BACKGROUND: HER2-low breast cancer (BC) is a newly defined subset of HER2-negative BC. However, it is still uncertain whether HER2-low BC can be categorized as a distinct biological/clinical subgroup with any prognostic significance. METHODS: Invasive BC cases (n = 10,215) with Stage I-III were retrospectively analyzed to determine the HER2 status. The HER2 status was then divided into 3 groups: HER2-0, HER2-low, and HER2-positive. RESULTS: The HER2 status was classified as HER2-0 in 1,227 cases (12.0%), HER2-low in 7,209 cases (70.6%), and HER2-positive in 1779 cases (17.4%). HER2-low cases had more positive nodes and were significantly associated with positive ER/PgR, lower nuclear grade, and lower Ki-67 index. HER2-0 had the lowest OS rate in the primary cases and after recurrence. HER2-0 in the node positive group had the lowest OS and was significantly different from HER2-low in the same group. The pathological complete response (pCR) rate for NAC was lowest in the HER2-low group. The DFS after NAC was significantly better in all the pCR cases, regardless of the HER2 status. However, the DFS was significantly lower in the HER2-low non-pCR cases. CONCLUSION: HER2-low accounted for 70% of the cases and correlated with favorable biological markers. The HER2-low group had a significantly better OS than the HER2-0 group. However, the response to NAC was low in the HER2-low group, and this group had the poorest prognosis among all the non-pCR cases. These findings indicate that HER2-low may have a different biology and prognosis and therefore should be classified as a new entity.