Polymorphisms of the PD-L1 gene 3'-untranslated region are associated with the expression of PD-L1 in non-small cell lung cancer.

Recent results show that polymorphisms of programmed death ligand 1 (PD-L1, also known as CD274 or B7-H1) might be used as a possible marker for effectiveness of chemotherapy and cancer risk. However, the effect of PD-L1 gene variations on PD-L1 expression remain unclear. Given the post-transcriptional machinery in tumor PD-L1 expression, we investigated single nucleotide polymorphisms (SNPs) in the 3'-untranslated region (3'-UTR) of the PD-L1 gene, rs4143815 and rs4742098, using formalin-fixed paraffin-embedded sections of 154 patients with non-small cell lung cancers (NSCLCs). In rs4143815, the GG genotype showed significant association with PD-L1 expression (P = 0.032). In rs4742098, the AA genotype was significantly associated with histology and PD-L1 expression (P = 0.022 and P = 0.008, respectively). In multivariate logistic regression analysis, the AA genotype in rs4742098 was correlated with PD-L1 expression (odds ratio 0.408, P = 0.048). Interestingly, approximately 10% of the NSCLC cases showed somatic mutation when we compared genotypes of these SNPs between NSCLC tissues and non-tumor tissues from the same patients. In addition, cases with somatic mutation showed higher levels of PD-L1 expression than cases with germline mutation in rs4143815 GG. In conclusion, we demonstrated that the rs4143815 and rs4742098 SNPs in the 3'-UTR of PD-L1 were associated with tumor PD-L1 expression in NSCLCs.

Early prediction of treatment outcome for lenvatinib using 18F-FDG PET/CT in patients with unresectable or advanced thyroid carcinoma refractory to radioiodine treatment: a prospective, multicentre, non-randomised study.

BACKGROUND: Lenvatinib is widely used to treat unresectable and advanced thyroid carcinomas. We aimed to determine whether 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) performed 1 week after lenvatinib treatment initiation could predict treatment outcomes. RESULTS: This was a prospective, nonrandomised, multicentre study. Patients with pathologically confirmed differentiated thyroid carcinoma (DTC) and lesions refractory to radioiodine treatment were eligible for inclusion. Patients were treated with 24 mg lenvatinib as the initial dose and underwent PET/CT examination 1 week after treatment initiation. Contrast-enhanced CT was scheduled at least 4 weeks later as the gold standard for evaluation. The primary endpoint was to evaluate the discrimination power of maximum standardised uptake value (SUVmax) obtained by PET/CT compared to that obtained by contrast-enhanced CT. Evaluation was performed using the area under the receiver operating characteristic (ROC-AUC) curve. Twenty-one patients were included in this analysis. Receiver operating characteristic (ROC) curve analysis yielded an AUC of 0.714 for SUVmax after 1 week of lenvatinib treatment. The best cut-off value for the treatment response for SUVmax was 15.211. The sensitivity and specificity of this cut-off value were 0.583 and 0.857, respectively. The median progression-free survival was 26.3 months in patients with an under-cut-off value and 19.7 months in patients with an over-cut-off value (P = 0.078). CONCLUSIONS: The therapeutic effects of lenvatinib were detected earlier than those of CT because of decreased FDG uptake on PET/CT. PET/CT examination 1 week after the initiation of lenvatinib treatment may predict treatment outcomes in patients with DTC. TRIAL REGISTRATION: This trial was registered in the University Hospital Medical Information Network (UMIN) Clinical Trials Registry (number UMIN000022592) on 6 June, 2016.

Crystalline silica-exposed human lung epithelial cells presented enhanced anchorage-independent growth with upregulated expression of BRD4 and EZH2 in autocrine and paracrine manners.

Crystalline silica-induced inflammation possibly facilitates carcinogenesis. Here, we investigated its effect on lung epithelium damage. We prepared conditioned media of immortalized human bronchial epithelial cell lines (hereinafter bronchial cell lines) NL20, BEAS-2B, and 16HBE14o- pre-exposed to crystalline silica (autocrine crystalline silica conditioned medium), a phorbol myristate acetate-differentiated THP-1 macrophage line, and VA13 fibroblast line pre-exposed to crystalline silica (paracrine crystalline silica conditioned medium). As cigarette smoking imposes a combined effect on crystalline silica-induced carcinogenesis, a conditioned medium was also prepared using the tobacco carcinogen benzo[a]pyrene diol epoxide. Crystalline silica-exposed and growth-suppressed bronchial cell lines exhibited enhanced anchorage-independent growth in autocrine crystalline silica and benzo[a]pyrene diol epoxide conditioned medium compared with that in unexposed control conditioned medium. Crystalline silica-exposed nonadherent bronchial cell lines in autocrine crystalline silica and benzo[a]pyrene diol epoxide conditioned medium showed increased expression of cyclin A2, cdc2, and c-Myc, and of epigenetic regulators and enhancers, BRD4 and EZH2. Paracrine crystalline silica and benzo[a]pyrene diol epoxide conditioned medium also accelerated the growth of crystalline silica-exposed nonadherent bronchial cell lines. Culture supernatants of nonadherent NL20 and BEAS-2B in crystalline silica and benzo[a]pyrene diol epoxide conditioned medium had higher EGF concentrations, whereas those of nonadherent 16HBE14o- had higher TNF-α levels. Recombinant human EGF and TNF-α promoted anchorage-independent growth in all lines. Treatment with EGF and TNF-α neutralizing antibodies inhibited cell growth in crystalline silica conditioned medium. Recombinant human TNF-α induced BRD4 and EZH2 expression in nonadherent 16HBE14o-. The expression of γH2AX occasionally increased despite PARP1 upregulation in crystalline silica-exposed nonadherent lines with crystalline silica and benzo[a]pyrene diol epoxide conditioned medium. Collectively, crystalline silica- and benzo[a]pyrene diol epoxide-induced inflammatory microenvironments comprising upregulated EGF or TNF-α expression may promote crystalline silica-damaged nonadherent bronchial cell proliferation and oncogenic protein expression despite occasional γH2AX upregulation. Thus, carcinogenesis may be cooperatively aggravated by crystalline silica-induced inflammation and genotoxicity.

Assessment for the timing of comprehensive genomic profiling tests in patients with advanced solid cancers.

Comprehensive genomic profiling (CGP) tests have been covered by public insurance in Japan for patients with advanced solid tumors who have completed or are completing standard treatments or do not have them. Therefore, genotype-matched drug candidates are often unapproved or off-label, and improving clinical trial access is critical, involving the appropriate timing of CGP tests. To address this issue, we analyzed the previous treatment data for 441 patients from an observational study on CGP tests discussed by the expert panel at Hokkaido University Hospital between August 2019 and May 2021. The median number of previous treatment lines was two; three or more lines accounted for 49%. Information on genotype-matched therapies was provided to 277 (63%). Genotype-matched clinical trials were ineligible because of an excess number of previous treatment lines or use of specific agents were found in 66 (15%) patients, with the highest proportion in breast and prostate cancers. Many patients met the exclusion criteria of one to two or more treatment lines across cancer types. In addition, previous use of specific agents was a frequent exclusion criterion for breast, prostate, colorectal, and ovarian cancers. The patients with tumor types with a low median number (two or fewer) of previous treatment lines, including most rare cancers, primary unknown cancers, and pancreatic cancers, had significantly fewer ineligible clinical trials. The earlier timing of CGP tests may improve access to genotype-matched clinical trials, with their proportion varying by cancer type. Each relevant society needs to advocate the desirable timing of CGP testing nationwide.

Real-world data on the efficacy and safety of immune-checkpoint inhibitors in elderly patients with non-small cell lung cancer.

PURPOSE: Immune-checkpoint inhibitors (ICIs) are effective against advanced non-small cell lung cancer (NSCLC). However, whether the efficacy and safety of ICI treatment in elderly patients are similar to those in younger patients is unclear. This study was designed to address this question. METHODS: We enrolled patients who received ICI monotherapy in Japan between December 2015 and December 2017; those ≥75 years of age comprised the elderly group. We compared the efficacy and safety of ICI monotherapy in elderly patients with those in younger patients and explored prognostic factors in elderly patients. RESULTS: We enrolled 676 patients; 137 (20.3%) were assigned to the elderly group. The median age of the elderly and younger groups was 78 (range, 75-85) and 66 (range, 34-74) years. The median progression-free survival (4.8 months vs. 3.3 months, p = 0.1589) and median overall survival (12.3 months vs. 13.0 months, p = 0.5587) were similar between the elderly and younger groups. Multivariate analysis revealed that a significantly better OS in the elderly group was associated with better responses to first- or second-line ICI treatment (p = 0.011) and more immune-related adverse events (irAEs) (p = 0.02). IrAEs that led to ICI discontinuation occurred in 34 of 137 patients (24.8%) in the elderly group, and their survival was significantly higher than that in those who did not have irAEs. CONCLUSION: ICI is also effective in elderly NSCLC patients, and treatment discontinuation due to irAEs may be a good prognostic marker.

Efficacy of antacids for cisplatin-induced gastrointestinal symptoms in the treatment of lung cancer.

OBJECTIVE: Chemotherapy-induced nausea and vomiting (CINV) and chemotherapy-associated dyspepsia syndrome (CADS) are frequently appearing adverse effects of cisplatin (CDDP)-containing chemotherapy. Antiemetic guidelines suggest that the administration of antacids such as proton pump inhibitors (PPIs) or histamine type-2 receptor antagonists be considered for CADS, although their efficacy for treating these symptoms remains unknown. This study aimed to reveal whether antacids attenuate gastrointestinal symptoms in CDDP-containing chemotherapy. MATERIALS AND METHODS: In total, 138 patients with lung cancer who received ≥ 75 mg/m2 CDDP-containing regimens were enrolled in this retrospective study. Patients were divided into an antacid group including patients administered PPIs or vonoprazan during all chemotherapy periods and controls without antacid administration. The primary endpoint was the comparison of anorexia incidence during the first cycle of chemotherapy. Secondary endpoints were CINV evaluation and risk factor analysis for the incidence of anorexia using logistic regression analysis. RESULTS: The incidence of anorexia during the first cycle was 54.4% in the control group and 60.3% in the antacid group, without significant differences (p = 0.60). The incidence of nausea was also similar between the groups (p = 1.00). Multivariate analysis suggested that antacid administration was not associated with anorexia. CONCLUSION: Baseline antacid administration does not affect gastrointestinal symptoms associated with CDDP-containing treatment in lung cancer.

EGFR inhibition in EGFR-mutant lung cancer cells perturbs innate immune signaling pathways in the tumor microenvironment.

Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) elicit potent cell cycle arrest in EGFR-mutant non-small-cell lung cancer (NSCLC) cells. However, little is known about the mechanisms through which these drugs alter the tumor phenotype that contributes to the immune escape of EGFR-mutant cells. Using EGFR-mutant NSCLC cell lines and tissue samples from patients, we investigated the changes in immune checkpoints expressed in tumor cells following EGFR inhibition. Subsequently, we also analyzed the role of soluble factors from the dying tumor cells in the activation of immune signaling pathways involved in therapy resistance. Upon EGFR-TKI treatment, we found that EGFR-mutant cells upregulated the expression of innate immune checkpoint CD24 in vitro. We then analyzed biopsy samples from six patients who developed resistance to a first-generation EGFR-TKI without the acquired T790M mutation. Immunohistochemistry revealed that levels of tumor CD24 expression were increased upon treatment compared with those from pre-treatment samples. Monocyte-derived macrophages facilitated antibody-dependent cellular phagocytosis when EGFR-TKI-treated EGFR-mutant cells were incubated with anti-CD24 antibodies in vitro, suggesting that CD24 may be a therapeutical target for EGFR-mutant lung cancer. Moreover, EGFR inhibition accelerated the release of cell-free DNA (cfDNA) from dying tumor cells, which activated the type I interferon signaling pathways in human THP-1 monocytes in a stimulator of interferon genes-dependent manner. Our study indicates that EGFR inhibition in EGFR-mutant NSCLC cells fosters a tumor microenvironment associated with immune escape. Thus, CD24 targeted therapy and cfDNA monitoring may contribute to improved treatment outcomes in patients with EGFR-mutant NSCLC.

Association between skin immune-related adverse events (irAEs) and multisystem irAEs during PD-1/PD-L1 inhibitor monotherapy.

PURPOSE: Patients treated with immune checkpoint inhibitors (ICIs) often develop immune-related adverse events (irAEs) in various organs of the body. However, the patient factors associated with the development of multisystem irAEs are not well known. Skin irAEs most frequently occur and appear early after ICI treatment initiation. They may be a predictive marker for the development of multisystem irAEs, and their occurrence should be evaluated. METHODS: Data of patients receiving ICI monotherapy for lung cancer, melanoma, and head and neck cancer treatment were retrospectively evaluated (n = 207); the single irAE development group (n = 69) was compared with the multisystem irAE development group (n = 37). The primary endpoint was the comparison of the incidence of skin irAEs between the two groups. RESULTS: Skin, thyroid, and hepatic irAEs were associated with the development of multisystem irAEs (odds ratio: 3.30, 95% confidence interval: 1.27-8.52, p = 0.01 for skin; 5.07, 2.09-12.3, p = 0.0003 for thyroid; 10.63, 1.19-94.7, p = 0.03 for hepatic). Skin irAEs were the most common type (65.0% of total participants) and appeared earlier than other irAEs, except for gastrointestinal and ocular irAEs (median time to onset of skin irAEs: 7.5 weeks). Skin irAEs occurred more frequently in the multisystem irAE group (81.0%) than in the single irAE group (56.5%, p = 0.02). CONCLUSION: Skin irAEs can be a useful predictive marker for multisystem irAE development due to ICI treatment. Consequently, patients with skin irAEs should be treated and monitored for other types of irAEs.

Expression of Karyopherin Alpha 2 and Karyopherin Beta 1 Correlate with Poor Prognosis in Gastric Cancer.

INTRODUCTION: Karyopherin alpha 2 (KPNA2) and karyopherin beta 1 (KPNB1) constitute nuclear transport protein complexes involved in nuclear import and are significant in tumor progression. Although high KPNA2 expression was associated with poor prognosis in solid tumors, the relationship between KPNA2 and KPNB1 expression and their prognostic role in gastric cancer (GC) remains unclear. METHODS: Immunohistochemistry was used to correlate the expression of KPNA2 and KPNB1 with various features, including clinicopathological characteristics in 130 patients with GC and survival in 94 patients with invasive lesions extending to the submucosa or deeper. RESULTS: High expression of KPNA2 and KPNB1 was found in 25% and 36% of the patients, respectively. Both were significantly related to tumor depth, lymph node metastasis, lymphatic invasion, venous invasion, and Ki-67 expression. KPNA2 expression was significantly related to that of KPNB1 (p < 0.001). Patients with high KPNB1 expression had poorer prognosis than those with low expression (p = 0.027), as was also observed in case of KPNA2 (p < 0.001). Patients with high expression of both KPNA2 and KPNB1 accounted for 18% and had a poorer prognosis than those with high expression of either and those with low expression of both (p = 0.001). Multivariate analysis revealed that high expression of both KPNA2 and KPNB1 was an independent prognostic factor in patients with GC (hazard ratio, 3.46; 95% confidence interval, 1.64-2.73, p = 0.001). CONCLUSION: KPNA2 expression was correlated with KPNB1 expression, and high co-expression of KPNA2 and KPNB1 may represent a strong prognostic biomarker in GC.

Risk Factor Analysis for the Occurrence of Severe Adverse Effects in Eribulin Treatment.

BACKGROUND/AIM: Eribulin is an effective chemotherapeutic agent for the treatment of metastatic breast cancer and advanced or metastatic soft-tissue sarcomas. However, severe adverse effects (SAEs) occur in 30-40% of the patients, and significantly reduce the patients' quality of life and disturb the recommended treatment schedules. Neutropenia is the main cause of treatment suspension, delay, and/or dose reductions, also leading to relative dose intensity reduction. This study aimed to examine the risk factors for SAE occurrence after eribulin treatment. PATIENTS AND METHODS: Eighty patients with metastatic breast cancer or advanced or metastatic soft tissue sarcoma who received eribulin were retrospectively evaluated. Risk factors for SAE occurrence in the first cycle were primarily assessed. In addition, factors associated with SAE occurrence during all treatment cycles were evaluated. RESULTS: SAEs in the first cycle occurred in 45% of patients. The primary SAE was neutropenia (91.7%). The incidence of SAEs during all treatment cycles was 61.3%. Multivariate analyses suggested that lower baseline neutrophil and hemoglobin levels were risk factors for SAE occurrence and severe neutropenia incidence in the first cycle. An independent factor associated with SAE occurrence during all cycles was age ≥65 years and a tendency was confirmed for baseline anemia. CONCLUSION: Baseline neutropenia and anemia were risk factors for SAE occurrence during the first eribulin treatment cycle. Age ≥65 years was also associated with SAE occurrence during all treatment cycles. Patients with these risk factors should be carefully monitored for assessment and prophylaxis.

Suitability of Oral Rehydration Solution (ORS) for Use in the Cisplatin Short Hydration Method.

BACKGROUND/AIM: Short hydration is a method to change partial intravenous hydration to oral to administer cisplatin (CDDP); however, the most suitable form of oral hydration is unknown. This study aimed to determine whether oral rehydration solution (ORS) affects CDDP-induced nephrotoxicity (CIN) and electrolyte imbalance. PATIENTS AND METHODS: Lung cancer patients (n=200) who had received CDDP-including regimens (CDDP dosage ≥75 mg/m2) were retrospectively evaluated. We used logistic analysis to evaluate whether ORS intake could be a preventive factor for CIN (≥grade 2 serum creatinine elevation). Moreover, incidence of CIN and electrolyte imbalance and the variation in serum creatinine and electrolyte levels were compared between ORS and non-ORS (control) patients. RESULTS: CIN occurred in 9.8% of ORS patients, and 7.5% of non-ORS patients (p=0.79). The variation in serum creatinine level was also similar in both groups. Multivariate analysis suggested that ORS intake does not affect CIN, although CIN was associated with the coadministration of non-steroidal anti-inflammatory drugs and the presence of diabetes mellitus. The variations in serum electrolyte levels did not differ, and incidence of hyponatremia, hypokalemia, and hypochloremia was also similar between the groups. Moreover, patients in ORS group experienced significantly more anorexia compared to controls, and approximately 40% of the patients were unable to continue ORS intake. CONCLUSION: ORS intake in CDDP short hydration regimens does not affect CIN and CDDP-induced electrolyte imbalance; however, its intake is associated with the incidence of anorexia suggesting that ORS should not be used for oral hydration.

Phase II study of carboplatin-paclitaxel alone or with bevacizumab in advanced sarcomatoid carcinoma of the lung: HOT1201/NEJ024.

OBJECTIVES: Only a few prospective studies have been conducted to examine the efficacy and safety of systemic chemotherapy for patients with pulmonary sarcomatoid carcinomas (PSCs). There is, thus, a crucial need to develop novel treatment strategies for this rare tumor. PATIENTS AND METHODS: Chemotherapy-naïve patients with histologically confirmed PSCs were assigned to receive either carboplatin/paclitaxel alone (CP) or with bevacizumab (CPB) followed by bevacizumab maintenance. The primary endpoint was overall response rate (ORR). Secondary endpoints included overall survival (OS), progression-free survival (PFS), and safety. RESULTS: This study was closed before accumulating the expected number of cases due to slow patient accrual. Eventually, 16 patients were enrolled. The ORR was 25.0% and disease control rate was 56.3%. CPB was administered in all four patients with an objective response [partial response (PR)]; among the four PR cases, two patients had pleomorphic carcinoma, and two had carcinosarcoma. Median PFS and median survival time (MST) in all the enrolled patients were 2.6 months and 8.8 months, respectively. Median PFS was 1.2 months in the CP group and 4.2 months in the CPB group. In addition, MST was 7.9 months in the CP group and 11.2 months in the CPB group. Hematological and non-hematological adverse events were common and reversible, although ileus (grade 4) and nasal bleeding (grade 3) occurred in one case each in the CPB group. CONCLUSIONS: CPB might be effective as first-line treatment for PSCs. Further study is warranted to clarify the role of cytotoxic chemotherapy for this rare and aggressive tumor. CLINICAL TRIALS REGISTRATION: University Hospital Medical Information Network (UMIN) Clinical Trial Registry (UMIN000008707).

First-line osimertinib in elderly patients with epidermal growth factor receptor-mutated advanced non-small cell lung cancer: a retrospective multicenter study (HOT2002).

Osimertinib is a standard of care therapy for previously untreated epidermal growth factor receptor mutation-positive non-small cell lung cancer. However, limited data exist regarding the efficacy and safety of osimertinib as a first-line therapy for elderly patients aged 75 years or older. To assess the potential clinical benefits of osimertinib in this population, this retrospective multi-institutional observational study included 132 patients with non-small cell lung cancer (age ≥ 75 years), who received osimertinib as first-line treatment. The proportion of patients with 1-year progression-free survival was 65.8% (95% confidence interval 57.1-73.5). The median progression-free survival was 19.4 (95% confidence interval 15.9-23.9) months. The median overall survival was not reached (95% confidence interval 24.6-not reached). The frequency of pneumonitis was 17.4%, with a grade 3 or higher rate of 9.1%. More than two-thirds of treatment discontinuations due to pneumonitis occurred within 3 months of starting osimertinib, and the prognosis of patients with pneumonitis was unsatisfactory. Osimertinib is one of the effective first-line therapeutic options for patients aged 75 years or older; however, special caution should be exercised due to the potential development of pneumonitis.

Hepatectomy and immune checkpoint inhibitor treatment for liver metastasis originating from non-cutaneous melanoma: a report of three cases.

The outcomes of hepatectomy alone for liver metastasis derived from non-cutaneous melanoma are insufficient, and the outcomes of systemic therapy alone are also insufficient, even since the development of immune checkpoint inhibitors (ICIs). We report the cases of three patients, in whom liver metastasis derived from non-cutaneous melanoma was treated with hepatectomy combined with ICI therapy, which was administered in various settings. One patient received ICI treatment for recurrent melanoma and survived 107 months after the first hepatectomy, one patient received both preoperative and adjuvant ICI treatment and has been disease-free for 27 months, and another patient received postoperative ICI treatment after reduction hepatectomy and has been alive with disease for 47 months. Since long-term survival is possible, hepatectomy combined with ICI therapy should be considered for the treatment of liver metastasis derived from non-cutaneous melanoma.

Prognostic significance of OX40+ lymphocytes in tumor stroma of surgically resected small-cell lung cancer.

OX40 (CD134) is a co-stimulatory molecule mostly expressed on activated T lymphocytes. Previous reports have shown that OX40 can be an immuno-oncology target and a clinical biomarker for cancers of various organs. In this study, we collected formalin-fixed paraffin-embedded tumor samples from 124 patients with small-cell lung cancer (SCLC) who had undergone surgery. We analyzed the expression profiles of OX40 and other relevant molecules, such as CD4, CD8, and Foxp3, in tumor stroma and cancer nest using immunohistochemistry and investigated their association with survival. High infiltration of OX40+ lymphocytes (OX40high) in tumor stroma was positively associated with relapse-free survival (RFS) and overall survival (OS) compared with low infiltration of OX40+ lymphocytes (OX40low) (RFS, median, 26.0 months [95% confidence interval (CI), not reached (NR)-NR] vs 13.2 months [9.1-17.2], p = .024; OS, NR [95% CI, NR-NR] vs 29.8 months [21.3-38.2], p = .049). Multivariate analysis revealed that OX40high in tumor stroma was an independent indicator of prolonged RFS. Moreover, RFS of patients with OX40high/CD4high in tumor stroma was significantly longer than that of patients with OX40low/CD4low. The RFS of patients with tumor stroma with OX40high/CD8high was significantly longer than that of patients with tumor stroma with OX40low/CD8high, OX40high/CD8low, or OX40low/CD8low. These findings suggest that OX40+ lymphocytes in tumor stroma play a complementary role in regulating the relapse of early-stage SCLC. Reinforcing immunity by coordinating the recruitment of OX40+ lymphocytes with CD4+ and CD8+ T cells in tumor stroma may constitute a potential immunotherapeutic strategy for patients with SCLC.

[Development of a System for Providing Cancer Genomic Medicine in Hokkaido-From the Standpoint of a Designated Core Hospital for Cancer Genomic Medicine].

Hokkaido University Hospital has been designated as a Core Hospital for Cancer Genomic Medicine and developed a system to provide cancer genomic medicine in Hokkaido with its liaison hospitals. Since being reimbursed in June 2019, comprehensive cancer genome profiling (CGP) testing showed certain therapeutic efficacy in patients with no standard treatment options, but it also revealed some problems such as the small number of patients who can receive therapeutic drugs matched with gene abnormalities. Since candidate drugs are often unapproved or off-label, it is necessary to smoothly introduce clinical trials, advanced medical treatment system, and patient-proposed health care service. At our hospital, we are focusing on sharing information on clinical trials being conducted in Hokkaido, launching investigator-initiated clinical trials, promoting patient-proposed health care service, promoting a registry study of genetic profiling and targeted therapies in patients with rare cancers and accompanying clinical trials, and incorporating pediatric cancer patients. This paper describes Hokkaido's cancer genomic medicine provision system, including its exit strategy, and the human resource development that serve as its foundation.

Prognostic factors in patients with advanced non-small cell lung cancer after long-term Anti-PD-1 therapy (HOT1902).

OBJECTIVES: Limited information is available on the appropriate treatment duration of immune checkpoint inhibitors (ICIs). We aimed to identify candidates who would benefit from ICI discontinuation after one year of treatment for metastatic non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: This retrospective multi-institutional observational study examined medical records of all consecutive patients with advanced or recurrent NSCLC, who started ICI monotherapy at 15 institutions in Japan between December 2015 and December 2017. Patients who received initial ICI therapy for >1 year without progressive disease were defined as the long-term treatment (LT) group; others were defined as the non-long-term treatment (NLT) group. Primary outcomes included the prognostic factors in the LT group, whereas secondary outcomes included efficacy of ICI rechallenge, safety, and survival outcomes in the overall population. RESULTS: In total, 676 patients were enrolled, and 114 (16.9 %) were assigned to the LT group. The median time interval from the start of initial ICI administration to data cutoff was 34.3 months (range, 24.1-47.8); thus, all surviving patients were followed-up for at least 2 years from the start of initial ICI. Median progression-free survival (PFS) was longer in the LT than in the NLT group (33.6 months vs. 2.7 months; p < 0.001). On multivariate analysis, significantly better PFS was associated with smoking (hazard ratio [HR]=0.36, p = 0.04), and complete response (CR; HR=uncomputable, p < 0.001) in the LT group. Thirty-seven patients (5.5 %) received ICI rechallenge, including 10 in the LT group. Among patients receiving rechallenge treatment, the median PFS was 2.2 months, with no difference between the LT and NLT groups. CONCLUSIONS: In the LT group, smoking and achieving CR were significantly associated with better PFS. Since rechallenge treatment was not effective, careful consideration is required for discontinuing ICI. However, these prognostic factors are helpful in considering candidates for ICI discontinuation. TRIAL REGISTRATION: UMIN ID, UMIN000041403.

Clinical significance of comprehensive genomic profiling tests covered by public insurance in patients with advanced solid cancers in Hokkaido, Japan.

BACKGROUND: Comprehensive cancer genomic profiling has been used recently for patients with advanced solid cancers. Two cancer genomic profiling tests for patients with no standard treatment are covered by Japanese public health insurance since June 2019. METHODS: We prospectively analyzed data of 189 patients with solid cancers who underwent either of the two-cancer genomic profiling tests at Hokkaido University Hospital and its liaison hospitals and whose results were discussed in molecular tumor board at Hokkaido University Hospital between August 2019 and July 2020. RESULTS: All 189 patients had appropriate results. Actionable gene alterations were identified in 93 patients (49%). Frequent mutations included PIK3CA (12%) mutation, BRCA1/2 alteration (7%), ERBB2 amplification (6%) and tumor mutation burden-High (4%). The median turnaround time from sample shipping to acquisition by the expert panel was 26 days. Although 115 patients (61%) were provided with information for genotype-matched therapies, only 21 (11%) received them. Notably, four of eight patients below the age of 20 years were provided information for genotype-matched therapies, and three received them. Their response rates and disease control rates were 29% and 67%, respectively. Most patients who did not undergo the genotype-matched therapies were provided information for only investigational drugs in phases I and II at distant clinical trial sites in central Japan. Twenty-six patients were informed of suspected germline findings, while 11 patients (42%) received genetic counseling. CONCLUSIONS: The publicly reimbursed cancer genomic profilings may lead to the modest but favorable therapeutic efficacy of genotype-matched therapy for solid cancer patients with no standard therapy. However, poor access to genotype-matched therapy needs to be resolved.

Delta-like 1 homolog (DLK1) as a possible therapeutic target and its application to radioimmunotherapy using 125I-labelled anti-DLK1 antibody in lung cancer models (HOT1801 and FIGHT004).

OBJECTIVES: Delta-like 1 homolog (DLK1) is a non-canonical Notch ligand known to be expressed in several cancers but whose role in lung cancer is not yet fully understood. We sought to confirm DLK1 expression in small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC), and to examine DLK1's clinical significance. Furthermore, we examined the possible utility of DLK1 as a novel target in radioimmunotherapy (RIT). METHODS: We retrospectively assessed the correlation between clinical features and DLK1 expression by immunohistochemistry in resected specimens from 112 patients with SCLC and 101 patients with NSCLC. Moreover, we performed cell and animal experiments, and examined the possibility of RIT targeting DLK1 in SCLC using iodine-125 (125I) -labeled anti-DLK1 antibody, knowing that 125I can be replaced with the alpha-particle-emitter astatine-211 (211At). RESULTS: In SCLC and NSCLC, 20.5 % (23/112) and 16.8 % (17/101) of patients (respectively) had DLK1-positive tumors. In NSCLC, DLK1 expression was associated with recurrence-free survival (P < 0.01) but not with overall survival. In SCLC, there was no association between DLK1 expression and survival. In addition, 125I-labeled anti-DLK1 antibody specifically targeted DLK1 on human SCLC tumor cell lines. Furthermore, 125I-labeled anti-DLK1 antibody was incorporated into tumor tissue in a mouse model. CONCLUSION: A proportion of SCLC and NSCLC exhibits DLK1 expression. As a clinical feature, DLK1 expression could be a promising prognostic factor for recurrence in patients with resected NSCLC. In addition, DLK1 could serve as a new therapeutic target, including RIT, as suggested by our pilot study using a radiolabeled anti-DLK1 antibody in SCLC.

Expression of the immunoproteasome subunit ß5i in non-small cell lung carcinomas.

AIM: The immunoproteasome is a specific proteasome isoform whose proteolytic activity enhances the generation of antigenic peptides to be presented by major histocompatibility complex class I molecules to CD8+ T cells. Physiologically, it is expressed abundantly in immune cells and is induced in somatic cells by cytokines, especially interferon-γ. Recently, variable expression of immunoproteasomes has been demonstrated in different types of cancers. However, the clinical significance of immunoproteasome expression in malignant tumours is poorly understood. In this study, we performed clinicopathological evaluation of immunoproteasome subunit ß5i in non-small cell lung carcinomas (NSCLCs). METHODS: Tumour tissues were collected from 155 patients with NSCLCs, and immunohistochemical analysis for ß5i was performed in relation to the prognosis of patients. RESULTS: High expression of ß5i was found in about 20% of all NSCLCs and was found significantly more frequently (40%) in the adenocarcinoma subset. High expression of ß5i was associated with a better 5-year relative survival rate in patients with pStage I to II adenocarcinoma and was also a significant and independent favourable prognostic factor in adenocarcinoma patients. In addition, when we performed in vitro analysis using NSCLC cell lines, combined treatment with the immunoproteasome-specific inhibitor ONX0914 and the proteasome inhibitor MG132 enhanced cell death in ß5i-expressing NSCLC cell lines. CONCLUSION: The expression of immunoproteasome can be explored as both a prognostic factor and a potential therapeutic target in NSCLCs. Since immunoproteasomes have crucial role in the antigen presentation, further studies may help to provide essential knowledge for therapeutic strategies in anticancer immunotherapy.