Immunotherapy including immune checkpoint inhibitors (ICIs) has become the backbone of treatment for most lung cancers with advanced or metastatic disease. In addition, they have increasingly been ...used for early stage tumors in neoadjuvant and adjuvant settings. Unfortunately, however, only a subset of patients experiences meaningful response to ICIs. Although programmed death-ligand 1 (PD-L1) protein expression by immunohistochemistry (IHC) has played a role as the principal predictive biomarker for immunotherapy, its performance may not be optimal, and it suffers multiple practical issues with different companion diagnostic assays approved. Similarly, tumor mutational burden (TMB) has multiple technical issues as a predictive biomarker for ICIs. Now, ongoing research on tumor- and host immune-specific factors has identified immunotherapy biomarkers that may provide better response and prognosis prediction, in particular in a multimodal approach. This review by the International Association for the Study of Lung Cancer Pathology Committee provides an overview of various immunotherapy biomarkers, including updated data on PD-L1 IHC and TMB, and assessments of neoantigens, genetic and epigenetic signatures, immune microenvironment by IHC and transcriptomics, and microbiome and pathologic response to neoadjuvant immunotherapies. The aim of this review is to underline the efficacy of new individual or combined predictive biomarkers beyond PD-L1 IHC and TMB.
The use of patient‐derived xenografts (PDXs) has recently attracted attention as a drug discovery platform with a high predictive clinical efficacy and a preserved tumor heterogeneity. Given the ...racial differences in genetic variations, it would be desirable to establish a PDX library from Japanese cancer patients on a large scale. We thus tried to construct the Japanese PDX (J‐PDX) library with a detailed clinical information for further clinical utilization. Between August 2018 and May 2020, a total of 1126 cancer specimens from 1079 patients were obtained at the National Cancer Center Hospital and National Cancer Center Hospital East, Japan, and were immediately transplanted to immunodeficient mice at the National Cancer Center Research Institute. A total of 298 cross‐cancer PDXs were successfully established. The time to engraftment varied greatly by cancer subtypes, especially in the first passage. The engraftment rate was strongly affected by the clinical stage and survival time of the original patients. Approximately 1 year was needed from tumor collection to the time when coclinical trials were conducted to test the clinical utility. The 1‐year survival rates of the patients who were involved in establishing the PDX differed significantly, from 95.6% for colorectal cancer to 56.3% for lung cancer. The J‐PDX library consisting of a wide range of cancer subtypes has been successfully established as a platform for drug discovery and development in Japan. When conducting coclinical trials, it is necessary to consider the target cancer type, stage, and engraftment rate in light of this report.
We have successfully established a PDX library derived from Japanese cancer patients. In less than 2 years, we have registered more than 1000 specimens and established nearly 300 PDXs. We will further enrich the library and use it as a platform to accelerate drug discovery in Japan.
Background
There are limited studies on the results of comprehensive genomic profiling testing for pancreatic cancer tissue specimens by endoscopic ultrasound-guided tissue acquisition (EUS-TA). This ...study aimed to evaluate the proportion of specimens obtained by EUS-TA using a 19-gauge (G) fine-needle biopsy (FNB) needle for unresectable pancreatic cancer (UR-PC) that met the OncoGuide
™
NCC Oncopanel System (NOP) analysis suitability criteria.
Methods
In this single-arm, prospective, phase II study, EUS-TA was performed using a 19G FNB biopsy needle in patients with suspected UR-PC based on a contrast-enhanced computed tomography scan. The primary endpoint was the proportion of patients who met the NOP analysis suitability criteria, with a threshold, expected value, α-error, and power of 40%, 70%, 0.025, and 0.9, respectively, and the planned number of enrolled patients was 33. The NOP analysis suitability criteria were defined as tumor cell content ≥ 20% and tissue size ≥ 4 mm
2
.
Results
Thirty-three patients were enrolled. The procedural success rate was 100%, and the cytodiagnosis of class V was observed in all patients. The proportion of patients meeting the NOP analysis suitability criteria was 63.6% (95% CI 47.22–80.05), which satisfied the predefined criteria to be considered valid. Adverse events occurred in 9.0% of the patients.
Conclusions
The proportion of patients with UR-PC who met the NOP analysis suitability criteria for EUS-TA using a 19G FNB needle was effective for achieving the primary endpoint, making it a valid test method. Adverse events occurred at a higher rate than that previously reported.
Currently, lung cancer is treated by the highest number of therapeutic options and the benefits are based on multiple large‐scale sequencing studies, translational research and new drug development, ...which has promoted our understanding of the molecular pathology of lung cancer. According to the driver alterations, different characteristics have been revealed, such as differences in ethnic prevalence, median age and alteration patterns. Consequently, beyond traditional chemoradiotherapy, molecular‐targeted therapy and treatment with immune check‐point inhibitors (ICI) also became available major therapeutic options. Interestingly, clinical results suggest that the recently established therapies target distinct lung cancer proportions, particularly between the EGFR/ALK and PD‐1/PD‐L1‐positive subsets, e.g. the kinase inhibitors target driver mutation‐positive tumours, whereas driver mutation‐negative tumours respond to ICI treatment. These therapeutic efficacy‐related differences might be explained by the molecular pathogenesis of lung cancer. Addictive driver mutations promote tumour formation with powerful transformation performance, resulting in a low tumour mutation burden, reduced immune surveillance, and subsequent poor response to ICIs. In contrast, regular tobacco smoke exposure repeatedly injures the proximal airway epithelium, leading to accumulated genetic alterations. In the latter pathway, overgrowth due to alteration and immunological exclusion against neoantigens is initially balanced. However, tumours could be generated from certain clones that outcompete immunological exclusion and outgrow the others. Consequently, this cancer type responds to immune check‐point treatment. These pathogenic differences are explained well by the two‐compartment model, focusing upon the anatomical and functional composition of distinct cellular components between the terminal respiratory unit and the air‐conducting system.
Two‐compartment model in the putative molecular pathogenesis of lung cancer. The accumulation of genetic alterations with escaping immune surveillance is a key factor for tumours from the air‐conducting system under the strong influence of tobacco smoke, whereas oncogene‐addicted adenocarcinomas are driven by a single oncogenic mutation with powerful transformation activity.
Summary Background Patients with non-small-cell lung cancer harbouring mutations in the epidermal growth factor receptor ( EGFR ) gene respond well to the EGFR-specific tyrosine kinase inhibitor ...gefitinib. However, whether gefitinib is better than standard platinum doublet chemotherapy in patients selected by EGFR mutation is uncertain. Methods We did an open label, phase 3 study (WJTOG3405) with recruitment between March 31, 2006, and June 22, 2009, at 36 centres in Japan. 177 chemotherapy-naive patients aged 75 years or younger and diagnosed with stage IIIB/IV non-small-cell lung cancer or postoperative recurrence harbouring EGFR mutations (either the exon 19 deletion or L858R point mutation) were randomly assigned, using a minimisation technique, to receive either gefitinib (250 mg/day orally; n=88) or cisplatin (80 mg/m2 , intravenously) plus docetaxel (60 mg/m2 , intravenously; n=89), administered every 21 days for three to six cycles. The primary endpoint was progression-free survival. Survival analysis was done with the modified intention-to-treat population. This study is registered with UMIN (University Hospital Medical Information Network in Japan) , number 000000539. Findings Five patients were excluded (two patients were found to have thyroid and colon cancer after randomisation, one patient had an exon 18 mutation, one patient had insufficient consent, and one patient showed acute allergic reaction to docetaxel). Thus, 172 patients (86 in each group) were included in the survival analyses. The gefitinib group had significantly longer progression-free survival compared with the cisplatin plus docetaxel goup, with a median progression-free survival time of 9·2 months (95% CI 8·0–13·9) versus 6·3 months (5·8–7·8; HR 0·489, 95% CI 0·336–0·710, log-rank p<0·0001). Myelosuppression, alopecia, and fatigue were more frequent in the cisplatin plus docetaxel group, but skin toxicity, liver dysfunction, and diarrhoea were more frequent in the gefitinib group. Two patients in the gefitinib group developed interstitial lung disease (incidence 2·3%), one of whom died. Interpretation Patients with lung cancer who are selected by EGFR mutations have longer progression-free survival if they are treated with gefitinib than if they are treated with cisplatin plus docetaxel. Funding West Japan Oncology Group (WJOG): a non-profit organisation supported by unrestricted donations from several pharmaceutical companies.
Patients with pancreatic neuroendocrine neoplasm grade-3 (PanNEN-G3) show variable responses to platinum-based chemotherapy. Recent studies indicated that PanNEN-G3 includes well-differentiated ...neuroendocrine tumor with G3 (NET-G3). Here, we examined the clinicopathologic and molecular features of PanNEN-G3 and assessed the responsiveness to chemotherapy and survival.
A total of 100 patients with PanNEN-G3 were collected from 31 institutions, and after central review characteristics of each histologic subtype NET-G3 vs. pancreatic neuroendocrine carcinoma (NEC-G3) were analyzed, including clinical, radiological, and molecular features. Factors that correlate with response to chemotherapy and survival were assessed.
Seventy patients analyzed included 21 NETs-G3 (30%) and 49 NECs-G3 (70%). NET-G3 showed lower Ki67-labeling index (LI; median 28.5%), no abnormal Rb expression (0%), and no mutated
(0%), whereas NEC-G3 showed higher Ki67-LI (median 80.0%), Rb loss (54.5%), and
mutations (48.7%). Chemotherapy response rate (RR), platinum-based chemotherapy RR, and prognosis differed significantly between NET-G3 and NEC-G3. Chemotherapeutic outcomes were worse in NET-G3 (
< 0.001). When we stratified PanNEN-G3 with Rb and
, PanNENs-G3 with Rb loss and those with mutated
showed significantly higher RRs to platinum-based chemotherapy than those without (Rb loss, 80% vs. normal Rb, 24%,
= 0.006; mutated
, 77% versus wild type, 23%,
= 0.023). Rb was a predictive marker of response to platinum-based chemotherapy even in NEC-G3 (
= 0.035).
NET-G3 and NEC-G3 showed distinct clinicopathologic characteristics. Notably, NET-G3 does not respond to platinum-based chemotherapy. Rb and
are promising predictors of response to platinum-based chemotherapy for PanNEN-G3, and Rb for NEC-G3.
.
In epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy for lung cancer patients, acquired resistance develops almost inevitably and this limits the improvement in patient ...outcomes. EGFR T790M mutation and MET amplification are the two main mechanisms underlying this resistance, but the relationship between these two mechanisms is unclear. In this study, we explored their relationship using in vitro models and autopsy specimens.
Erlotinib-resistant HCC827 (HCC827ER) cells were developed by chronic exposure to erlotinib at increasing concentrations. HCC827EPR cells were also developed by chronic exposure to erlotinib in the presence of PHA-665,752 (a MET TKI). The erlotinib-resistant mechanisms of these cells were analyzed. In addition, 33 autopsy tumor samples from 6 lung adenocarcinoma patients harboring multiple gefitinib-refractory tumors were analyzed.
HCC827ER developed MET amplification, and clinically relevant resistance occurred at ≥4-fold MET gene copy number gain (CNG). By contrast, HCC827EPR developed T790M without MET CNG. Of six patients harboring gefitinib-refractory tumors, three exhibited T790M only, one exhibited MET amplification only, and the other two exhibited T790M and/or MET amplification depending on the lesion sites. In these gefitinib-refractory tumors, T790M developed in 93% (14 of 15) of tumors without MET gene CNGs, in 80% (4 of 5) of tumors with moderate MET gene CNGs (<4-fold), and in only 8% (1 of 13) of tumors with MET amplification (≥4-fold).
These results indicate a reciprocal and complementary relationship between T790M and MET amplification and the necessity of concurrent inhibition of both for further improving patient outcomes.
MicroRNAs (miRNAs) are small noncoding RNAs, thought to be involved in physiologic and developmental processes by negatively regulating expression of target genes. We have previously reported ...frequent down-regulation of the let-7 miRNA family in lung cancers and, in the present study, assessed alteration in a panel of 19 lung cancer cell lines. As a result, we found for the first time that the miR-17-92 cluster, which comprises seven miRNAs and resides in intron 3 of the C13orf25 gene at 13q31.3, is markedly overexpressed in lung cancers, especially with small-cell lung cancer histology. Southern blot analysis revealed the presence of increased gene copy numbers of the miRNA cluster in a fraction of lung cancer cell lines with overexpression. In addition, we were able to show predominant localization of C13orf25 transcripts within the nucleus and introduction of the expression construct of the miR-17-92 cluster, but not the putative open reading frame of C13orf25, enhancing lung cancer cell growth. These findings clearly suggest that marked overexpression of the miR-17-92 cluster with occasional gene amplification may play a role in the development of lung cancers, especially in their most aggressive form, small-cell lung cancer, and that the C13orf25 gene may well be serving as a vehicle in this regard.
Heterogeneous nuclear ribonucleoprotein L‐like (HNRNPLL), a suppressor of colorectal cancer (CRC) metastasis, is transcriptionally downregulated when CRC cells undergo epithelial‐mesenchymal ...transition (EMT). Here we show that decrease of MYB mediates the downregulation of HNRNPLL during EMT. The promoter activity was attributed to a region from −273 to −10 base pairs upstream of the transcription start site identified by 5'‐RACE analysis, and the region contained potential binding sites for MYB and SP1. Luciferase reporter gene assays and knockdown or knockout experiments for genes encoding the MYB family proteins, MYB, MYBL1, and MYBL2, revealed that MYB was responsible for approximately half of the promoter activity. On the other hand, treatment with mithramycin A, an inhibitor for SP1 and SP3, suppressed the promoter activity and their additive contribution was confirmed by knockout experiments. The expression level of MYB was reduced on EMT while that of SP1 and SP3 was unchanged, suggesting that the downregulation of HNRNPLL during EMT was mediated by the decrease of MYB expression while SP1 and SP3 determine the basal transcription level of HNRNPLL. Histopathological analysis confirmed the accumulation of MYB‐downregulated cancer cells at the invasion front of clinical CRC tissues. These results provide an insight into the molecular mechanism underlying CRC progression.
Heterogeneous nuclear ribonucleoprotein L‐like (HNRNPLL), a suppressor of colorectal cancer (CRC) metastasis, is transcriptionally downregulated when CRC cells undergo epithelial‐mesenchymal transition (EMT). Here we show that decrease of MYB mediates the downregulation of HNRNPLL during EMT.
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