Virtual Library

Background:
Comprehensive NGS panel based genetic testing is becoming more common to help clinicians select appropriate therapies. It has been recommended that matched tumor-normal sequencing analyses are essential for precise identification and interpretation of genetic somatic mutations. Though it has been reported germline EGFR T790M mutations result in a unique hereditary lung cancer syndrome, little is known about germline mutation of other common hereditary cancer syndrome genes in lung cancer patients.

Method:
We reviewed the germline variants of 1000 consecutive lung cancer patients who had paired tumor-normal NGS panel sequencing in our institute between 2016 and 2017. Hybridization capture-based NGS panel sequencing enables simultaneously assess single-nucleotide variants, insertions/deletions, rearrangements, and copy-number alterations at least 59 genes (range 59 – 1021 genes). Germline variants were interpreted following ACMG guidelines, and the variants were classified into pathogenic, likely pathogenic, variant of unknown significance, likely benign, and benign 5 classes.

Result:
Twenty-seven cases were identified to carry germline pathogenic or likely pathogenic mutations in 12 gene (2.7%): 5 with ATM ; 4 with BRCA1, BRCA2 or MSH2 respectively; 2 with CHEK2 or PMS2 respectively; 1 in ATR, CDKN2A, FANCC, MSH3, PTCH2 or RET respectively (details in table). Mean age at diagnosis was 58 (30 – 84 years) for the patients with germline mutations and 61 (29-93 years) for those without. Interestingly, none of the patients had been diagnosed with other tumors. The incidence of actionable somatic mutations of the 27 patients was similar to others: 10 patients with EGFR mutation, 3 patients with KRAS mutation, 1 patient with KIF5B-RET fusion, MET copy number gain or BRCA1 mutation respectively.

No.	Gene	cHGVS	pHGVS	Mutation type
1	ATM	c.1402_1403delAA	p.K468Efs*18	frameshift
2	ATM	c.1898+1G>C	.	splice
3	ATM	c.2143_2144delCT	p.L715Cfs*22	frameshift
4	ATM	c.6019dupG	p.E2007Gfs*11	frameshift
5	ATM	c.903dupT	p.A302Cfs*3	frameshift
6	ATR	c.80_81insA	p.N27Kfs*16	frameshift
7	BRCA1	c.4185+1G>A	.	splice
8	BRCA1	c.962G>A	p.W321*	nonsense
9	BRCA1	c.3340delG	p.E1114Kfs*3	frameshift
10	BRCA1	c.81-2A>G	.	splice
11	BRCA2	c.3968_3971delAATA	p.K1323Ifs*11	frameshift
12	BRCA2	c.5054C>G	p.S1685*	nonsense
13	BRCA2	c.6132_6135delCTTT	p.F2045Hfs*5	frameshift
14	BRCA2	c.6485_6486delAA	p.K2162Tfs*13	frameshift
15	CDKN2A	c.73delG	p.V25*	frameshift
16	CHEK2	c.1010delC	p.A337Efs*10	frameshift
17	CHEK2	c.1684C>T	p.R562*	nonsense
18	FANCC	c.1257_1258insC	p.T420Hfs*15	frameshift
19	MSH2	c.1165C>T	p.R389*	nonsense
20	MSH2	c.1A>T	p.0?	init-loss
21	MSH2	c.2785C>T	p.R929*	nonsense
22	MSH2	c.340delG	p.E114Rfs*60	frameshift
23	MSH3	c.802C>T	p.R268*	nonsense
24	PMS2	c.1053delG	p.L351Ffs*5	frameshift
25	PMS2	c.943C>T	p.R315*	nonsense
26	PTCH2	c.2441_2442delCT	p.S814*	frameshift
27	RET	c.2410G>A	p.V804M	missense

Conclusion:
Germline mutations in common hereditary cancer syndrome genes is not rare in lung cancer patients, and it can be identified on routine matched tumor-normal NGS sequencing. Retrospective family history analysis and genetic counseling for those patients are underway.

Background:
A key hallmark of cancer cells is the ability to proliferate despite remarkable levels of DNA damage. Non-small cell lung cancers (NSCLC) tend to have high mutation rates, frequently related to smoking. While many genes have been functionally implicated in maintaining the integrity of the genome, for the majority of these genes there remains a lack of evidence of a direct relationship between loss-of-function and increased tumor mutation burden (TMB). Recent studies suggested an association between high TMB and cancer response to immunotherapies. The aim of this study was to comprehensively analyze the relationship between DNA integrity-related genes and TMB in NSCLC.

Method:
Whole exome DNA sequencing and copy number array data were downloaded from TCGA lung adenocarcinoma (LAC) and squamous cell carcinoma (LSCC) datasets, and mutation burdens were calculated for each of 974 tumors. We identified 150 genes across 7 pathways and 9 groups known to be involved in repairing or compensating for DNA damage. To test each gene, tumors were placed into one of three groups according to the gene’s mutation status; wild-type, homozygous deleted or mutated with loss-of-function, and non-synonymous missense mutated. We then compared the average mutation burden in each of these groups. This workflow was then repeated with pathways instead of genes.

Result:
Our comprehensive analysis demonstrates a landscape of significant alterations to genes and pathways responsible for maintaining DNA integrity in NSCLC. A loss of function mutation or homozygous deletion in at least one signature gene occurred in 49% of LAC and 59% of LSCC. We searched for genes in this signature associated with significantly higher tumor mutation burdens (one sided t-test, p < 0.05) and found 4 in LAC (RRM1 1%, TP53 17%, FANCE 1%, and MLH1 2%) and 8 in LSCC (NEIL1 0.5%, POLE 4%, POLG 0.5%, FANCE 3%, GEN1 1%, MLH1 4%, MSH6 1%, and RPA1 2%) datasets. Of note, tumors with nonsense mutations, indels, or homozygous deletions in the FANCE or MLH1 genes have significantly higher TMB in both LAC and LSCC. We repeat this process to find pathways significantly associated with increased TMB.

Conclusion:
We present a comprehensive study of the association between genes responsible for maintaining DNA integrity and TMB in NSCLC. These findings are important to the search for potential predictive biomarkers for immunotherapy.

Background:
The objective response rate of squamous cell carcinoma of the lung (SCCL) to checkpoint inhibitors, as well as the frequency of known NSCLC oncogenic drivers, is low. We performed comprehensive genomic profiling (CGP) on a large set of SCCL cases to identify new opportunities for potential benefit from targeted or immunotherapies.

Method:
Hybrid-capture based CGP of up to 315 genes was performed prospectively on DNA isolated from tissue-based FFPE samples of SCCL, and tumor mutational burden (TMB) was assessed as described previously (PMID: 28420421).

Result:
From a dataset of 958 unique SCCL cases, we identify 2.6% of cases harboring alterations in PTCH1, 0.3% in SMO1, and 01.2% in SUFU, which were primarily mutually exclusive Genes known to be oncogenic drivers in NSCLC were altered at the following frequencies in SCCL 8.0% KRAS, 6.8% EGFR, 3.4% MET, 1.9% BRAF, and less than 1% each for ALK, ROS, and RET. In PTCH1-mutated cases 96% did not harbor alterations in these driver genes (1/23 positive for co-occurrence).. The overall SCCL population has a median TMB of 9.0, with 11.3%) cases higher than 20 mutations/Mb (m/Mb). Two index cases with PTCH1 mutations and no alterations in established NSCLC driver genes were identified. A year 77-year-old male with a 40 pack-year smoking history was diagnosed with metastatic SCCL, basaloid variant, harboring PTCH1 s799fs*29 with TMB of 3.7 m/Mb, and he had a year-long complete response to vismodegib. A 69-year-old male with poorly differentiated SCCL harboring PTCH1 W197* and W460* had a 7 month response to vismodegib. On progression, biopsy of recurrent disease after vismodegib failure demonstrated the same PTCH1 alterations as well as acquisition of the 11q13 (CCND1/FGF3/FGF4/FGF19) amplicon. Both biopsies had TMB > 45 m/mb. Nine additional cases not in this series identified as the basaloid variant of SCCL by expert thoracic pathology review were assayed by CGP and 11% (1/9) harbored PTCH1 mutation, but no other alterations of the hedgehog pathway were identified.

Conclusion:
The index cases presented here suggest a subset of PTCH1-mutated SCCL may see clinical benefit from hedgehog inhibitors, regardless of TMB. In a small series of expert diagnosed basaloid histology in SCCL cases, this histology may enrich for hedgehog pathway alterations. Further investigation of underlying PTCH1 LOH and TMB will be undertaken to assess which SCCL cases can respond to respond to hedgehog pathway inhibitors.

Background:
Matched tumor-normal sequencing analyses are essential for precise identification and interpretation of somatic and germline alterations. A 2015 study of 815 paired tumor and normal genomes showed that both genomes are required for precise identification and interpretation of both somatic and germline variation. In this study, we further demonstrate the critical importance of both tumor and germline sequencing using a selected panel of genes that are relevant to cancer prognosis and treatment.

Method:
Tumor and normal (germline) genomes were sequenced using the Illumina HiSeqX platform. Data was aligned to GRCh37 using methods described previously. Tumor versus matched-normal variant analysis was performed using the NantOmics Contraster analysis pipeline to determine somatic and germline genomic variants. RNA-Seq libraries were prepared from tumor samples using KAPA stranded RNA-Seq with RiboErase kit and sequencing on the Illumina platform. RNA sequencing reads were aligned and variants were identified using methods that have been previously described.

Result:
44 patients with NSCLC with tumor-normal sequencing were analyzed. 29 patients also had RNA-Seq whole transcriptome data available for analysis. Focusing on somatic SNVs in ALK, BRAF, CDKN2A, CEBPA, DNMT3A, EGFR, ERBB2, EZH2, FLT3, IDH1, IDH2, JAK2, KIT, KRAS, KMT2A (MLL), NPM1, NRAS, MET, NOTCH1, PDGFRA, PDGFRB, PGR, PIK3CA, PTEN, RET; 427 germline plus somatic variants were detected in these 25 genes in 44 patients; 386 out of 427 (90%) variants detected in somatic tissue were also present in germline (true positive germline variant, false positive somatic variant). 5 out of 29 patients (17%) did not have detectable expression in at least one somatic variant. Focusing on germline SNVs in APC, MYH, MLH1, MSH2, MSH6, PMS2, EPCAM, POLE, POLD1, BMPR1A, PTEN, STK11; 350 germline plus somatic variants were detected in these 12 genes in 44 patients, 10 out of 44 patients (23%) had at least one variant detected in their tumor DNA in these 12 genes that was not detected in the patient’s germline DNA (false positive germline variant, true positive somatic variant).

Conclusion:
Somatic-only sequencing may lead to false positive variant calls which has important clinical implications for highly actionable targets and for the veracity of mutational load algorithms. Calling germline variants from somatic DNA has a false positive risk---called variants may truly be somatic mutations. This is further complicated by the presence of circulating tumor DNA which may also lead to a false positive “germline” result in the absence of a true normal comparator.

Abstract not provided

Background:
Tumor spread through air space (STAS) is a newly recognized form of invasion in lung adenocarcinoma and squamous cell carcinoma and growing evidence shows it is associated with recurrence and survival. The observation that tumor STAS clusters/nests or single cells within air spaces on two-dimensional H&E slides raised the question of how these cells could survive within air spaces without a vascular supply and this has led some to speculate STAS is an artifact. Herein, we perform the high resolution-high quality 3D reconstruction and visualization of normal lung and tumor in a lung adenocarcinoma to investigate the invasive pattern of STAS.

Method:
A formalin-fixed paraffin embedded block of invasive adenocarcinoma with micropapillary pattern and extensive STAS was studied. Following our histology 3D reconstruction standard procedure, 3D reconstruction was performed for analysis from 200 serial sections of H&E stained 20x (0.5um/pixel resolution) whole slide images. The relationship to alveolar walls between micropapillary structures within the tumor and STAS clusters in lung parenchyma distant from the tumor was evaluated.

Result:
3D reconstruction and analysis demonstrated the following novel features – a) in the main tumor area, micropapillary structures within airspaces were connected to alveolar walls, b) unlike in 2D evaluation where STAS appeared as ‘free-floating’ micropapillary clusters, in 3D evaluation many STAS clusters within air spaces are attached to alveolar walls, and c) STAS clusters that appear ring-like in 2D by 3D evaluation they are actually balls of tumor cells surrounding a central space.

Conclusion:
Our 3D reconstructed image analysis for the first-time demonstrates that most STAS cells are not ‘free-floating’, rather attached to the alveolar walls. In addition within the main tumor micropapillary clusters are attached to alveolar walls. These findings raise an intriguing hypothesis that STAS cells are clusters of tumor cells spread within alveolar spaces in a non-contiguous fashion to reattach to the alveolar walls at a distance possibly by co-option of alveolar wall capillaries to support their growth. This form of spread is analogous to the phenomenon of vascular spread where tumor cells spread freely within blood vessels to distant sites where they attach to endothelium and extravasate through the vessel walls to form metastases. It is possible the ball-like configuration of STAS clusters may facilitate movement through alveolar spaces distant from the main tumor. The frequent alveolar wall attachment of STAS observed on serial 3D imaging disputes the concept this is an artifact.

Background:
Cancer cells “floating” in stroma, air space, or lymphovascular channels are often found in aggressive lung adenocarcinomas. Recently, the concept of STAS (spread through alveolar space) has been proposed, and studies have shown that STAS predicts early recurrence and poor patient prognosis. However, the biologic basis for the aggressive phenotype of the tumor with these histologic features remains elusive. In this study, we tested whether 3D (three-dimensional) low-attachment culture could be an in vitro model for STAS and “floating” cancer cells.

Method:
Lung adenocarcinoma cell lines harboring diverse driver mutations (EGFR, KRAS, BRAF, HER2, RET) were used. Cells were subjected to detached condition by using low-attachment culture dishes to generate “floating” cancer cells in vitro. Cell growth assay, immunohistochemistry and Western blotting were used to characterize the biologic properties of “floating” cancer cells. Cancer cells were inoculated in pleural cavity or left ventricle of the heart of NOD/SCID mice to test their metastatic potential in vivo.

Result:
Upon detachment, cancer cells formed solid, micropapillary, or hollow ring-like structures, admixed with single cells, recapitulating a histologic spectrum of STAS in primary tumors. Outlining with MUC1, a feature of micropapillary lung adenocarcinoma, was also demonstrated in the in-vitro-generated micropapillary clusters as well. Detached cells initially showed retarded cell growth, but some cell lines regained growth potential with time in culture. Expression analysis of various biomarkers revealed that detached cells showed features of cell stress and altered metabolism, as indicated by increased expression of phospho-p38 (a stress-activated MAP kinase) and GLUT-1 (glucose transporter-1), respectively, and these findings were confirmed by analysis of primary tumors. Finally, cancer cells that adapted to detached conditions exhibited increased metastasis in vivo. Figure 1



Conclusion:
3D low-attachment culture may be a convenient model to study the biology of aggressive lung cancer with STAS and “floating” cancer cells.

Background:
Small cell lung cancer (SCLC) is regarded as the most devastative type of human lung malignancies, with their rapid growth and we have discovered that there are FLI1 circular RNAs (circFLI1s) aberrantly expressed in SCLC tissues, such as circFLI1E2-4 and circFLI1E2-5 which are derived from exon 2-exon 4 and exon 2-exon 5 of FLI1, respectively. This study investigated the role of circFLI1s in the biological processes of SCLC.

Method:
The expression level of circFLI1s was evaluated by fluorescence in situ hybridization(FISH) in 54 primary SCLC and 50 non-small cell lung cancer (NSCLC) patients with known follow-up data. Correlation between circFLI1s expression and clinical characteristics was assessed with logistic regression. Cellular proliferation, apoptosis, cell cycle, migration and ability of colony formation were used to investigate the function of circFLI1s in SCLC. Ulteriorly, we explored the possible mechanism of circFLI1s via luciferase reporter assay, RT-PCR and FISH.

Result:
The expression of circFLI1E2-4 and circFLI1E2-5 were up-regulated in SCLC tissues compared with NSCLC tissues . The high expression of these circFLI1s was significantly associated with positive lymph nodal involvement (p < 0.05). The silencing of circFLI1E2-4 and circFLI1E2-5 but not FLI1 mRNA significantly inhibited migration of highly aggressive SCLC cell lines in vitro and vivo, while did not affect their proliferation, cell cycle, apoptosis and colony formation. Via bioinformatic analysis and luciferase screening assay, circFLI1s were observed to sponge to 2 miRNAs with 6 potential binding sites. Specifically, we showed that these circFLI1s directly binded to miR-584-3p and inhibited miR-584-3p activity, further to regulate the transcriptional activity of its target gene ROCK1 and the RhoA/ROCK1 signal pathway.

Conclusion:
This study uncovers that circFLI1s is an important driving factor that promotes tumor metastasis in SCLC through , and may serve as an attractive target for therapeutic intervention of SCLC.

Abstract not provided

Abstract:
Stage 4 NSCLC 1[st] line Rx: In addition to complete staging, all patients with any histology should have PD-L1 testing of their tumor. In addition patients with an adenocarcinoma histology and never smokers should have molecular testing that would include at least EGFR, ALK, ROS1 and BRAF. If NGS testing is selected that additional genes can be tested including MET,RET, HER2,and NTRK. Patients with a PD-L1 tumor proportion score (TPS) >49% who do not have a molecular driver can be treated with pembrolizumab as their first therapy. This therapy is continued for 2 years or until progression or unacceptable toxicity. For those with a TPS score of 1-49, concurrent chemotherapy plus pembrolizumab may be considered based on the results of a small phase II trial. However, larger phase III trials are in progress and may alter this choice. Patients with a molecular alteration in EGFR, ALK, ROS1, or BRAF are treated with the appropriate TKI or TKI combination in the case of v600E BRAF. Although all of the randomized trials comparing these new therapies to chemotherapy included only PS 0-1 patients, there is clear evidence that patients with PS 2 and even PS 3 and elderly patients may benefit from these therapies and should thus be tested. For patients with a lower TPS score or no molecular abnormality and PS0-1, the standard therapy is a platinum doublet chemotherapy with or without bevacizumab. For patients with adenocarcinoma, the most frequently used regimen is pemetrexed with platinum. In North America the platinum is most often carboplatin because of its preferred toxicity profile. PS 0-1 adenocarcinoma patients may also receive bevacizumab if there are no comorbid conditions that would increase toxicity. A taxane doublet with or without bevacizumab is also acceptable. For patients with squamous carcinoma the platinum doublet usually contains gemcitabine or a taxane with carboplatin with or without bevacizumab. Patients receiving chemotherapy are restaged after 2 cycles. Those with progressive disease are offered second line therapy. Patients with stable disease or response receive 2 additional cycles and are then restaged again. Those with acceptable toxicity and continued response are offered 2 additional cycles for a total of 6. Those without further response or additional toxicity are offered maintenance therapy after the 4 cycles. Patients receiving 6 cycles are also offered maintenance therapy. Maintenance therapy may consist of continued pemetrexed or continued bevacizumab for those responding to these. Switch therapy to pemetrexed or to erlotinib or gemcitabine may be considered. 2[nd] Line Rx. For patients receiving 1[st] line pembrolizumab, 2[nd] line rx is first line chemotherapy as discussed above. For patients progressing on a 1[st] line TKI, the 2[nd] line therapy is most often a 2[nd] or 3[rd] generation TKI. When therapy with a TKI is exhausted, the next line of therapy is standard first line chemotherapy as described above. For patients who receive 1[st] line chemotherapy, the second line therapy is most often immunotherapy which can be any of the 3 approved agents for patients with a TPS score of >1 or nivolumab or atezolizumab for patients with a TPS score of 0. 3[rd] Line Rx: Patients who receive 1[st] line I/O followed by chemo or who receive gene specific TKIs followed by 1[st] line chemotherapy, the 3[rd] line treatment would be what was previously considered 2nl line chemo such as docetaxel +/- ramicirumab. Other chemotherapy agents can also be considered such as gemcitabline, other taxanes or irinotecan. Clinical trials may be substituted for any of these treatments in any lines of therapy. Unresectable Stage III. The standard approach is currently concurrent chemotherapy with chest radiotherapy. This is likely to change as positive results of a trial comparing CT/RT alone to CT/RT followed by immunotherapy with durvalumab were announced in mid-2017. The chest RT is generally about 60 Gy given over 6 weeks. The chemotherapy is generally a platinum doublet with etoposide, paclitaxel or pemetrexed. At the time of progression the algorhythm described for stage 4 above can be instituted. Resectable stage I-IIIA. For stage 1A standard therapy is lobectomy alone or stereotactic body radiotherapy (SBRT) for those who are medically inoperable. Patients with stage IB, especially with poor prognostic features such as large size or vascular invasion may receive neoadjuvant or adjuvant chemotherapy with a cisplatin doublet and surgery is standard while other smaller stage IB tumors are treated with lobectomy alone. Stage II and IIIA patients may be treated with neoadjuvant chemotherapy or neoadjuvant CT/RT followed by surgery. They may also receive surgical resection first followed by adjuvant CT or CT/RT. The future: It is highly likely that immunotherapy combinations will prove to be superior to single checkpoint inhibitors so that the majority of sage IV patients without a molecular driver are likely to receive an immunotherapy combination, likely irrespective of TPS score. For stage IV patients with a molecular driver, it is likely that initial therapy will consist of the TKI plus another agent that can affect the cells that persist after initial TKI therapy. It is likely that immunotherapy combinations and molecular combinations will be used in unresectable stage III disease before, after or during CT/RT and will improve cure rates. I believe that a large change in approach to early stage patients will occur with the development of neoadjuvant immunotherapy and molecular therapy. In these approaches we have the opportunity to improve cure rates as well as to more rapidly develop new therapies based on pathologic complete response rates as we now do in breast cancer. The future is also likely to see new ways to define risk in both smokers and non-smokers so that we can detect patients early and so that we can develop new prevention strategies for those at high risk. Figure 1

Abstract:
Where we are now, and where we will be in 10 years:　From Asian Perspective Nagahiro Saijo, MD, PHD, Tokyo Medical University, Kinki University School Medicine Compared with 30 years ago non-small cell carcinoma(NSCLC) became a vast dominant type of lung cancer and majority of clinical trials focus on it. At the end of 20[th] century, effect of platinum doublet containing third generation cytotoxic drugs reached a plateau and thoracic oncologists felt skepticism to achieve the goal in lung cancer treatment. Development of EGFR-TKIs (Gefitinib and Erlotinib) was one of the biggest breakthroughs for rollback of chemotherapy in lung cancer. The EGFR mutation was discovered in 2004 but it took 5 years until there was general agreement that it was an important driver mutation which could predict for response to EGFR-TKI. Evolution of EGFR-TKI proceeds to irreversible 2[nd] (Afatinib and Dacomitinib) and mutation specific 3[rd] generation (Osimertinib) TKIs which can combat the issues of resistance. In Asia more than 50% of adenocarcinoma are EGFR-Mt+ and physicians experienced many long term survivors like surgical treatment in early stage lung cancer. In addition CTONG trial demonstrated that adjuvant EGFR-TKI (Gefitinib) delays recurrence in EGFR-positive surgically resected EGFR-Mt+ NSCLC. WJOG in Japan is conducting exactly the same schedules of trial. There will be a possibility to conduct study of EGFR-TKI combined with chemoradiotherapy in EGFR-Mｔ+ stage III NSCLC in Asian countries although this strategy was not successful in unselected population. Many driver mutations have been identified and its molecular classification made rapid progress in lung cancer, especially adenocarcinoma. The identification ALK and ROS rearrangement quickly followed by the development of active drugs (Crizotinib, Alectinib, Brigotinib, Lorlatinib ). J-ALEX and ALEX trials clearly showed that Alectinib was extremely active drug against ALK rearranged NSCLC. The Nation Wide Genomic Screening Project (LC-Scrum-Japan) leaded by K Goto has been started on February 2013 in Japan. Under this project many driver mutations have been identified not only in non-squamous cell carcinoma but also in squamous and small cell lung cancer. Many clinical trials are ongoing targeting genomic alterations screened in LC-SCRUM-Japan. Among them LURET trial demonstrated that Vandetanib could show 53% response rate (9/17) in RET+ lung cancer and Crizotinib produced 69% response rate (89/129) in ROS-1+ patients in OxOnc12-01 Asian Global trial. Driver mutation targeted drugs showed dramatic effect compared with standard cytotoxic chemotherapy, however, there is so far no positive data of their combination in spite of clear preclinical synergistic or additive effect. Human RAS oncogenes are the most commonly mutated gene family in Caucasian. About 35% (15% in Asian) of lung cancer are driven by activating mutations of KRAS. RAS is really an oncogenic driver and numerous preclinical studies suggest that KRAS is an excellent and well validated target. However, unlike EGFR, ALK, ROS, there is no effective drugs against KRAS. It will be extremely an important issue to develop KRAS targeting drugs. Robust negative data accumulate in immunotherapy for lung cancer including peptide vaccine therapy. Based on unique idea of Allison J. first immune checkpoint inhibitor, anti-CTLA4 antibody (ipillimumab) produced survival benefit in melanoma. PD-1 was cloned by Honjo T　(Japan) on 1992 and antitumor activity of anti-PD-1 antibody was reported on 2002. During past 7 years, immune checkpoint inhibitors have been an exciting new addition to the armamentarium fort lung cancer. Two anti-PD-1 antibodies such as Nivolumab and Pemblolizumab has become a standard for second line treatment of lung cancer based on durable response and marked increase in overall survival. In first line treatment Pemblolizumab prolonged OS and PFS compared with standard chemotherapy in NSCLC with high PD-L1 expression >50% (Keynote024). On the other hand, Nivolumab failed to show PFS benefit compared with cytotoxic agents because of poor patient selection. The most important issue will be how to concentrate responsive population and how to eliminate ineffective patients. Although there is a tendency of correlation between PD-L1 expression and objective response/PFS/OS, responders are experienced even in PD-L1 negative patients. Microsatellite instability has related with response to anti-PD-1 antibody in colorectal cancer. Mutation burden may influence on antigenicity of tumor cells. Infiltration of CD8+ lymphocytes is also considered to be a predictive biomarker but it is too objective for precise quantification. The successful patient selection for immune checkpoint inhibitors may depend on the development of methods for quantitative measurement of tumor specific cytotoxic activity of CD8+ lymphocytes. Can cytotoxic drugs survive as one of the modalities for lung cancer treatment? Combination of cytotoxic drugs and immune checkpoint inhibitors shows promising antitumor activity in lung cancer and gastric cancer. Antibody-drug conjugate (ADC) is a very interesting strategy for effective chemotherapy. DS-8201 targeting HER2, developed by Daiichi-Sankyo showed high response rate and favorable toxicity profile in previously treated HER2 positive gastric and breast cancer. ADC will be a potent strategy in future cytotoxic chemotherapy for lung cancer. Progress in the treatment of small cell lung cancer is very behind because of decrease in absolute number of SCLC patients and no discovery of driver mutations. JCOG conducted serial randomized clinical trials in SCLC. However, treatment result reached a plateau in both of limited and extensive diseases. Discovery of druggable targets in near future may have a significant impact in small cell lung cancer.

Abstract not provided

Abstract not provided