Publications by authors named "Yasushi Yatabe"

504 Publications

Invasive Mucinous Adenocarcinoma of the Lung with a Mural Nodule-like Lesion.

Am J Surg Pathol 2022 Aug 2. Epub 2022 Aug 2.

Division of Molecular Pathology, National Cancer Center Research Institute.

Invasive mucinous adenocarcinoma (IMA) of the lung shares some clinicopathological features with mucinous carcinoma of other organs, such as the ovary. Sarcoma-like lesions, called mural nodules, have been reported in the cystic walls of ovarian mucinous tumors. In this study, we analyzed 213 surgically resected cases of IMA of the lung to determine whether similar mural nodule-like lesions were present. We considered abrupt discrete lesions composed of dedifferentiated tumor cells as mural nodule-like lesions. Of 213 IMAs, we identified 11 tumors with mural nodule-like lesions that were histologically categorized into three subtypes similar to those in the ovary. The sarcomatoid and anaplastic carcinoma-like nodules were composed of spindle cell proliferations and polygonal undifferentiated carcinoma, respectively. Sarcoma-like lesions mimicked sarcomatoid nodules, but the spindle cell proliferations were considered a fibroblastic reaction to the scattered, isolated clusters of tumor cells. Molecular analysis of the components of differentiated IMAs and mural nodule-like lesions revealed a clonal relationship, suggesting a spectrum of tumors with different histology. Clinicopathologically, an older age, the male sex, and smokers were significantly associated with IMAs with mural nodule-like lesions. Notably, patient outcomes were unaffected by the presence or absence of these lesions. Our findings demonstrated that IMA of the lung rarely develops mural nodule-like lesions (11 of 213, 5%). Despite a histological impression of clinical aggressiveness, there was no clear trend in patient outcomes, suggesting that pathologists should avoid overstating this mural nodule-like lesion.
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http://dx.doi.org/10.1097/PAS.0000000000001938DOI Listing
August 2022

Clinical application of a highly sensitive digital PCR assay to detect a small fraction of IDH1 R132H-mutant alleles in diffuse gliomas.

Brain Tumor Pathol 2022 Jul 29. Epub 2022 Jul 29.

Division of Brain Tumor Translational Research, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.

The current World Health Organization classification of diffuse astrocytic and oligodendroglial tumors requires the examination of isocitrate dehydrogenase 1 (IDH1) or IDH2 mutations. Conventional analysis tools, including Sanger DNA sequencing or pyrosequencing, fail in detecting these variants of low frequency owing to their limited sensitivity. Digital polymerase chain reaction (dPCR) is a recently developed, highly sensitive, and precise quantitative rare variant assay. This study aimed to establish a robust limit of quantitation of the dPCR assay to detect a small fraction of IDH1 R132H mutation. The dPCR assays with serially diluted IDH1 R132H constructs detected 0.05% or more of mutant IDH1 R132H in samples containing mutant DNA. The measured target/total value of the experiments was proportional to the dilution factors and was almost equal to the actual frequencies of the mutant alleles. Based on the average target/total values, together with a twofold standard deviation of the normal DNA, a limit of quantitation of 0.25% was set to secure a safe margin to judge the mutation status of the IDH1 R132H dPCR assay. In clinical settings, detecting IDH1 R132H using dPCR assays can validate ambiguous immunohistochemistry results even when conventional DNA sequencing cannot detect the mutation and assure diagnostic quality.
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http://dx.doi.org/10.1007/s10014-022-00442-5DOI Listing
July 2022

Single-Cell Transcriptome Profiling Reveals Intratumoral Heterogeneity and Molecular Features of Ductal Carcinoma In Situ.

Cancer Res 2022 Jul 19. Epub 2022 Jul 19.

National Cancer Center Research Institute, Tokyo, Japan.

Ductal carcinoma in situ (DCIS) is a precursor to invasive breast cancer. The frequency of DCIS is increasing because of routine mammography; however, the biological features and intratumoral heterogeneity of DCIS remain obscure. To address this deficiency, we performed single-cell transcriptomic profiling of DCIS and invasive ductal carcinoma (IDC). DCIS was found to be composed of several transcriptionally distinct subpopulations of cancer cells with specific functions. Several transcripts, including long noncoding RNAs, were highly expressed in IDC compared to DCIS and might be related to the invasive phenotype. Closeness centrality analysis revealed extensive heterogeneity in DCIS, and the prediction model for cell-to-cell interactions implied that the interaction network among luminal cells and immune cells in DCIS was comparable to that in IDC. Additionally, transcriptomic profiling of HER2+ luminal DCIS indicated HER2 genomic amplification at the DCIS stage. These data provide novel insight into the intratumoral heterogeneity and molecular features of DCIS, which exhibit properties similar to IDC.
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http://dx.doi.org/10.1158/0008-5472.CAN-22-0090DOI Listing
July 2022

Clinicopathological and molecular characteristics of RSPO fusion-positive colorectal cancer.

Br J Cancer 2022 Jun 17. Epub 2022 Jun 17.

Division of Diagnostic Pathology, National Cancer Center Hospital, Tokyo, Japan.

Background: RSPO fusions that lead to WNT pathway activation are potential therapeutic targets in colorectal cancer (CRC), but their clinicopathological significance remains unclear.

Methods: We screened 1019 CRCs for RSPO fusions using multiplex reverse transcription-PCR. The RSPO fusion-positive tumours were subjected to whole-exome sequencing (WES).

Results: Our analysis identified 29 CRCs with RSPO fusions (2.8%), consisting of five with an EIF3E-RSPO2 fusion and 24 with PTPRK-RSPO3 fusions. The patients were 17 women and 12 men. Thirteen tumours (45%) were right-sided. Histologically, approximately half of the tumours (13/29, 45%) had a focal or extensive mucinous component that was significantly more frequent than the RSPO fusion-negative tumours (13%; P = 8.1 × 10). Four tumours (14%) were mismatch repair-deficient. WES identified KRAS, BRAF, and NRAS mutations in a total of 27 tumours (93%). In contrast, pathogenic mutations in major WNT pathway genes, such as APC, CTNNB1 and RNF43, were absent. RSPO fusion status did not have a statistically significant influence on the overall or recurrence-free survival. These clinicopathological and genetic features were also confirmed in a pooled analysis of previous studies.

Conclusion: RSPO fusion-positive CRCs constitute a rare subgroup of CRCs with several characteristic clinicopathological and genetic features.
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http://dx.doi.org/10.1038/s41416-022-01880-wDOI Listing
June 2022

Low-grade tracheal adenocarcinoma with ETV6::NTRK3 fusion: unique morphology akin to subsets of sinonasal low-grade non-intestinal-type adenocarcinoma.

Virchows Arch 2022 Jun 7. Epub 2022 Jun 7.

Department of Human Pathology, Graduate School of Medicine, Juntendo University, 2-1-1, Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.

The prevalence of NTRK fusions in non-small cell carcinoma (NSCLC) is only approximately 0.2%, most of which harbor NTRK1 fusions. NSCLCs with NTRK3 fusions are extremely rare. Herein, we report a case of low-grade tracheal adenocarcinoma in a 64-year-old woman. Histologically, areas of complicated tubule-papillary or cribriform patterns constituted a major component of the tumor and comprised cuboidal to columnar epithelial tumor cells with pale eosinophilic cytoplasm and cytoplasmic mucin, similar to subsets of sinonasal low-grade non-intestinal-type adenocarcinomas. Immunohistochemically, the tumor was positive for MUC5AC and MUC4 and showed nuclear expression of the pan-Trk antibody. ETV6::NTRK3 was identified by reverse transcription-polymerase chain reaction using formalin-fixed paraffin-embedded tissues. To the best of our knowledge, this is the first case of low-grade tracheal adenocarcinoma with ETV6::NTRK3 fusion. Our case illustrates that low-grade adenocarcinomas with ETV6::NTRK3 fusion may exist throughout the respiratory tract.
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http://dx.doi.org/10.1007/s00428-022-03353-0DOI Listing
June 2022

Efficacy of Immune Checkpoint Inhibitors in SMARCA4-Deficient Thoracic Tumor.

Clin Lung Cancer 2022 Jul 29;23(5):386-392. Epub 2022 Apr 29.

Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan.

Background: SMARCA4-deficient thoracic tumor is a novel disease entity characterized by mutations in SMARCA4 resulting in loss of its expression. They could be divided according to their phenotypes; carcinoma or sarcomatoid. It remains unclear how many patients with these SMARCA4-deficient tumors could benefit from inhibitors of programmed death 1 (PD-1) or programmed death ligand 1 (PD-L1).

Methods: SMARCA4-deficient thoracic tumor cases were retrospectively identified from pathology and gene expression databases at the National Cancer Center Hospital in Japan. Clinical outcomes of patients treated with PD-1/PD-L1 inhibitors were reviewed.

Results: Eighteen patients with SMARCA4-deficient thoracic tumor [carcinoma (n = 10), sarcomatoid (n = 7), and ambiguous type (n = 1)] were identified. Of the twelve [carcinoma (n = 7), sarcomatoid (n = 5)] who had received immune checkpoint inhibitors (ICIs), 5 [carcinoma (n = 3), sarcomatoid (n = 2)] showed a partial response, all of whom had received an ICI as the first-line therapy. The overall response rate was The PD-L1 tumor proportion scores of the 5 responding patients were 100%, 80%, 5% (n = 2), and less than 1%. The median progression-free survival (PFS) of all the patients was 2.4 months [95% confidence interval (CI), 1.1 months-not achieved (NA)], while the median PFS of the 3 patients who received first-line ICIs was not reached (95% CI, 1.1 months-NA).

Conclusion: PD-1/PD-L1 inhibitors showed promising results in the treatment of SMARCA4-deficient tumor. Further studies, especially on patient selection and combination therapy, are needed.
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http://dx.doi.org/10.1016/j.cllc.2022.03.005DOI Listing
July 2022

Liposarcoma With Hibernoma-like Histology: A Clinicopathologic Study of 16 Cases.

Am J Surg Pathol 2022 Apr 27. Epub 2022 Apr 27.

Departments ofDiagnostic Pathology.

Hibernoma is an uncommon benign tumor of brown fat cells that consistently expresses uncoupling protein 1 (UCP1). Herein, we clinicopathologically characterized 16 liposarcomas, for which histology, at least focally, closely resembled that of hibernoma, including sheets of brown fat-like, finely multivacuolated-to-eosinophilic tumor cells with no or minimal nuclear atypia. The cohort consisted of 4 well-differentiated liposarcomas (WDLSs), 6 dedifferentiated liposarcomas with a concomitant WDLS component, and 6 myxoid liposarcomas (MLSs). For all dedifferentiated liposarcoma cases, hibernoma-like histology was present only in the WDLS component. All tumors presented as large, deep-seated masses. Hibernoma-like histology resembled the pale cell, mixed cell, eosinophilic cell, or spindle cell subtypes of hibernoma, and it was a focal observation, with conventional liposarcoma histology coexisting in all cases. However, a few biopsy samples were predominated by hibernoma-like patterns, and 1 case was initially interpreted as hibernoma. Hibernoma-like components in WDLS immunohistochemically coexpressed MDM2 and CDK4 in most cases and harboredMDM2amplification in tested cases, whereas half of the cases expressed UCP1. The hibernoma-like components of MLS expressed DDIT3, andDDIT3rearrangements were present in the tested cases, whereas only negative or equivocal UCP1 expression was observed. In summary, WDLS and MLS focally demonstrate hibernoma-like histology on rare occasions. These elements are neoplastic, and some such areas in WDLS likely represent true brown fat differentiation, as supported by UCP1 expression. This pattern requires recognition to avoid the misdiagnosis as hibernoma, especially in biopsies. A careful search for classic liposarcoma histology and additional work-ups for the MDM2/CDK4 or DDIT3 status will be helpful for an accurate diagnosis.
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http://dx.doi.org/10.1097/PAS.0000000000001911DOI Listing
April 2022

Co-expression of ERG and CD31 in a subset of CIC-rearranged sarcoma: a potential diagnostic pitfall.

Mod Pathol 2022 Apr 19. Epub 2022 Apr 19.

Department of Diagnostic Pathology, National Cancer Center Hospital, Tokyo, Japan.

CIC-rearranged sarcoma is characterized by round cell undifferentiated histology, frequent expression of ETV4 and WT1, and aggressive behavior. A clinical encounter of a case with CIC-DUX4 fusion and ERG/CD31 co-expression prompted us to systematically investigate ERG and CD31 expression status in 30 archival cases of CIC-rearranged sarcoma. Half (15) of them showed moderate or strong ERG expression in <5-100% of tumor cells, among which nine showed heterogeneous membranous CD31 reactivity, including four cases each showing diffuse or strong expression. None of them showed uniformly strong and diffuse ERG/CD31 co-expression; however, three cases were initially interpreted and treated as angiosarcoma without response. Except for smaller superficial tumor enrichment, the clinicopathological characteristics of these nine cases of ERG+/CD31+ CIC-rearranged sarcoma did not differ from those of remaining 21 cases. Five showed focal hemorrhagic clefts/cysts, mimicking vascular spaces. All tumors expressed ETV4 and/or nuclear WT1, and fusion to DUX4 was confirmed in seven cases. Four tumors examined by next-generation sequencing harbored no CIC missense mutations. Using DNA methylation profiling, one CD31+ CIC-rearranged sarcoma was clustered with CD31- CIC-rearranged sarcomas, but distant from angiosarcomas. When compared with epithelioid angiosarcomas lacking CIC rearrangements, ERG+/CD31+ CIC-rearranged sarcomas were distinguished by focal myxoid change and the entire lack of vasoformative architecture. The angiosarcomas were characterized by uniform strong expression of ERG and CD31, but none of them were found positive for ETV4 or nuclear WT1. Heterogeneous ERG/CD31 co-expression in a subset of CIC-rearranged sarcoma is a clinically relevant pitfall for angiosarcoma, as these two diseases are treated differently.
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http://dx.doi.org/10.1038/s41379-022-01078-8DOI Listing
April 2022

Role of Image-Guided Percutaneous Needle Biopsy in the Age of Precision Medicine.

Curr Oncol Rep 2022 Aug 1;24(8):1035-1044. Epub 2022 Apr 1.

Department of Diagnostic Pathology, National Cancer Center Hospital, Tokyo, Japan.

Purpose Of Review: With the remarkable progress in cancer precision medicine, the demand for biopsy has been increasing, and the role of biopsy has been changing. In this review, we discuss the current state and recent advances in the role of image-guided percutaneous needle biopsy (PNB) in facilitating precision medicine.

Recent Findings: Biopsies are useful not only in the diagnosis of cancer and histological sub-type but also in the analysis of its molecular characteristics for targeted treatments. PNB specimens have been shown to provide high DNA yields for genomic analysis. Liquid biopsy is an emerging technology but is under development; therefore, PNB is the current standard of practice and is performed complimentarily with liquid biopsy. In the age of precision medicine, interventional oncologists play a key role in optimal tissue collection for adequate genomic analysis. Effective PNB may improve its diagnostic utility and help optimize precision medicine.
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http://dx.doi.org/10.1007/s11912-022-01271-7DOI Listing
August 2022

NSCLC Subtyping in Conventional Cytology: Results of the International Association for the Study of Lung Cancer Cytology Working Group Survey to Determine Specific Cytomorphologic Criteria for Adenocarcinoma and Squamous Cell Carcinoma.

J Thorac Oncol 2022 06 22;17(6):793-805. Epub 2022 Mar 22.

Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland.

Introduction: Accurate subtyping of NSCLC into lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) is the cornerstone of NSCLC diagnosis. Cytology samples reveal higher rates of classification failures, that is, subtyping as non-small cell carcinoma-not otherwise specified (NSCC-NOS), as compared with histology specimens. This study aims to identify specific algorithms on the basis of known cytomorphologic features that aid accurate and successful subtyping of NSCLC on cytology.

Methods: A total of 13 expert cytopathologists participated anonymously in an online survey to subtype 119 NSCLC cytology cases (gold standard diagnoses being LUAD in 80 and LUSC in 39) enriched for nonkeratinizing LUSC. They selected from 23 predefined cytomorphologic features that they used in subtyping. Data were analyzed using machine learning algorithms on the basis of random forest method and regression trees.

Results: From 1474 responses recorded, concordant cytology typing was achieved in 53.7% (792 of 1474) responses. NSCC-NOS rates on cytology were similar among gold standard LUAD (36%) and LUSC (38%) cases. Misclassification rates were higher in gold standard LUSC (17.6%) than gold standard LUAD (5.5%; p < 0.0001). Keratinization, when present, recognized LUSC with high accuracy. In its absence, the machine learning algorithms developed on the basis of experts' choices were unable to reduce cytology NSCC-NOS rates without increasing misclassification rates.

Conclusions: Suboptimal recognition of LUSC in the absence of keratinization remains the major hurdle in improving cytology subtyping accuracy with such cases either failing classification (NSCC-NOS) or misclassifying as LUAD. NSCC-NOS seems to be an inevitable morphologic diagnosis emphasizing that ancillary immunochemistry is necessary to achieve accurate subtyping on cytology.
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http://dx.doi.org/10.1016/j.jtho.2022.02.013DOI Listing
June 2022

Rapidly progressing metastatic malignant melanoma mimicking primary pleural tumor: A case report.

Thorac Cancer 2022 05 21;13(9):1423-1426. Epub 2022 Mar 21.

Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan.

Malignant melanoma is the most aggressive skin cancer that originates from melanocytes. Primary or metastatic pleural melanoma shares clinical and imaging characteristics with primary pleural tumors, such as pleural mesothelioma. Identification of the primary site can be challenging to distinguish between primary and secondary melanomas. We report a case of a 46-year-old woman with metastatic, rapidly progressing pleural melanoma mimicking primary pleural tumor. The metastatic pleural tumor from a primary cutaneous melanoma was diagnosed by reevaluating a previous surgical specimen. When evaluating patients with pleural melanoma, the primary site should be reevaluated to distinguish between primary and secondary melanomas.
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http://dx.doi.org/10.1111/1759-7714.14392DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9058309PMC
May 2022

Clinicopathologic and Genotypic Features of Lung Adenocarcinoma Characterized by the International Association for the Study of Lung Cancer Grading System.

J Thorac Oncol 2022 05 25;17(5):700-707. Epub 2022 Feb 25.

Department of Diagnostic Pathology, National Cancer Center Hospital, Tokyo, Japan. Electronic address:

Introduction: The new grading system proposed by the Pathology Committee of the International Association for the Study of Lung Cancer in 2020 was based on the combination of the histologically predominant subtype and high-grade component. Because the predominant subtypes are associated with characteristic subsets, unique subsets can be identified by this grading system.

Methods: We analyzed the clinicopathologic, genotypic, and prognostic features of a cohort of 781 consecutive patients with invasive nonmucinous adenocarcinoma of the lung.

Results: Grade 3 tumors were associated with younger age, male sex, a higher smoking dose, and aggressive features (tumor size, lymph node metastasis, stage, lymphovascular invasion, and pleural invasion). Recurrence-free survival and 3-year overall survival were well-stratified according to tumor grade, and the differences were confirmed with multivariate analysis using the Cox proportional hazard model. Radiologically, most grade 3 tumors exhibit a solid nodular pattern on computed tomography images and a high maximum standardized uptake value with positron emission tomography. Genotypically, 43% of the grade 3 adenocarcinomas lacked any driver mutations, although one of the driver mutations was detected in 79% of grade 1 or 2 tumors. Patient age, positive smoking history, solid nodule on computed tomography image, and higher maximum standardized uptake value were identified as significant preoperative predictive factors of grade 3 tumors, with a prediction rate greater than 90%.

Conclusions: Besides stratifying the patient outcomes, the new grading system characterized unique clinicopathologic subsets and this study suggested that grade 3 tumors could be predicted using the preoperative variables.
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http://dx.doi.org/10.1016/j.jtho.2022.02.005DOI Listing
May 2022

Lung Cancer in Japan.

J Thorac Oncol 2022 03;17(3):353-361

Department of Radiology, Nagoya City University Graduate School of Medical Sciences, Aichi, Japan.

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http://dx.doi.org/10.1016/j.jtho.2021.11.020DOI Listing
March 2022

Activating KRAS and GNAS mutations in heterotopic submucosal glands of the stomach.

J Gastroenterol 2022 05 21;57(5):333-343. Epub 2022 Feb 21.

Department of Diagnostic Pathology, National Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.

Background: The heterotopic submucosal gland (HSG) is a common incidental finding in gastrectomy specimens. The majority of HSGs are small incidental lesions, which are also known as gastritis cystica profunda. However, larger lesions may appear as an inverted growth of well-organized mucosa referred to as gastric inverted polyps.

Methods: To determine whether genetic alterations are involved in HSG development, we analyzed 63 gastric HSG lesions using targeted next-generation sequencing and immunohistochemistry.

Results: Histologically, HSG lesions consistently had areas of pyloric gland differentiation with variable extent of foveolar differentiation. Although the background mucosa showed intestinal metaplasia in most cases (98%), intestinal-type epithelium was seen in only one HSG lesion (2%). Sequencing analysis identified activating KRAS, BRAF, CTNNB1, and GNAS mutations in 34 (54%), 1 (2%), 1 (2%), and 7 (11%) lesions, respectively. HSG lesions harboring a KRAS mutation were more likely to present extensive foveolar differentiation (P = 0.013) and absence of parietal cells (P = 0.0081). Five HSG lesions had a dysplastic component, and concordant genetic alterations were detected between the non-dysplastic and dysplastic areas of two lesions that were successfully analyzed. Immunohistochemical staining demonstrated diffuse expression of mutant KRAS protein in lesions with the most common genetic alteration, KRAS G12D.

Conclusions: Our study demonstrated that a major proportion of HSGs were proliferative lesions associated with oncogenic mutations, with more than half of lesions harboring activating KRAS mutations.
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http://dx.doi.org/10.1007/s00535-022-01863-xDOI Listing
May 2022

Somatostatin Receptor 2 Expression Profiles and Their Correlation with the Efficacy of Somatostatin Analogues in Gastrointestinal Neuroendocrine Tumors.

Cancers (Basel) 2022 Feb 2;14(3). Epub 2022 Feb 2.

Department of Pathology, Graduate School of Medicine, Tohoku University, Sendai 980-8575, Japan.

Somatostatin analogues (SSAs) are widely used to treat gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Somatostatin receptor 2 (SSTR2) immunoreactivity serves as a predictive marker of the therapeutic efficacy of SSAs in pancreatic NETs. However, SSTR2 expression profiles in tumor cells and their association with the therapeutic efficacy of SSAs remains virtually unknown in gastrointestinal NETs (GI-NETs). Therefore, we evaluated the association between SSTR2 immunoreactivity and embryological origin and proliferative activity in 132 resected surgical tissues of GI-NETs. The correlation between SSAs' therapeutic efficacy and SSTR2 immunoreactivity was evaluated in 14 GI-NETs treated with SSAs. SSTR2 immunoreactivity was evaluated using Volante scores, immunoreactive scores, and digital image analysis (DIA). SSTR2 immunoreactivity was significantly negatively and positively correlated with the Ki-67 labeling index in foregut and hindgut NETs, respectively. In the normal mucosa, neuroendocrine cells in the rectum had significantly lower positive rates of SSTR2 than those in the stomach and duodenum. SSTR2 expression profiles in GI-NETs could differ by primary sites, while the difference of those between foregut and hindgut NETs might be derived from the SSTR2 status of normal neuroendocrine cell counterparts. In addition, DIA could provide a good alternative for predicting response to SSAs in evaluating SSTR2 immunoreactivity of GI-NETs.
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http://dx.doi.org/10.3390/cancers14030775DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8834049PMC
February 2022

Multi-omic profiling of peritoneal metastases in gastric cancer identifies molecular subtypes and therapeutic vulnerabilities.

Nat Cancer 2021 09 16;2(9):962-977. Epub 2021 Aug 16.

Division of Cellular Signaling, National Cancer Center Research Institute, Tokyo, Japan.

Peritoneal metastasis, a hallmark of incurable advanced gastric cancer (GC), presently has no curative therapy and its molecular features have not been examined extensively. Here we present a comprehensive multi-omic analysis of malignant ascitic fluid samples and their corresponding tumor cell lines from 98 patients, including whole-genome sequencing, RNA sequencing, DNA methylation and enhancer landscape. We identify a higher frequency of receptor tyrosine kinase and mitogen-activated protein kinase pathway alterations compared to primary GC; moreover, approximately half of the gene alterations are potentially treatable with targeted therapy. Our analyses also stratify ascites-disseminated GC into two distinct molecular subtypes: one displaying active super enhancers (SEs) at the ELF3, KLF5 and EHF loci, and a second subtype bearing transforming growth factor-β (TGF-β) pathway activation through SMAD3 SE activation and high expression of transcriptional enhancer factor TEF-1 (TEAD1). In the TGF-β subtype, inhibition of the TEAD pathway circumvents therapy resistance, suggesting a potential molecular-guided therapeutic strategy for this subtype of intractable GC.
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http://dx.doi.org/10.1038/s43018-021-00240-6DOI Listing
September 2021

Lactic acid promotes PD-1 expression in regulatory T cells in highly glycolytic tumor microenvironments.

Cancer Cell 2022 02 28;40(2):201-218.e9. Epub 2022 Jan 28.

Department of Dermatologic Oncology, National Cancer Center Hospital, Tokyo 104-0045, Japan.

The balance of programmed death-1 (PD-1)-expressing CD8 T cells and regulatory T (Treg) cells in the tumor microenvironment (TME) determines the clinical efficacy of PD-1 blockade therapy through the competition of their reactivation. However, factors that determine this balance remain unknown. Here, we show that Treg cells gain higher PD-1 expression than effector T cells in highly glycolytic tumors, including MYC-amplified tumors and liver tumors. Under low-glucose environments via glucose consumption by tumor cells, Treg cells actively absorbed lactic acid (LA) through monocarboxylate transporter 1 (MCT1), promoting NFAT1 translocation into the nucleus, thereby enhancing the expression of PD-1, whereas PD-1 expression by effector T cells was dampened. PD-1 blockade invigorated the PD-1-expressing Treg cells, resulting in treatment failure. We propose that LA in the highly glycolytic TME is an active checkpoint for the function of Treg cells in the TME via upregulation of PD-1 expression.
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http://dx.doi.org/10.1016/j.ccell.2022.01.001DOI Listing
February 2022

Precision cancer genome testing needs proficiency testing involving all stakeholders.

Sci Rep 2022 01 27;12(1):1494. Epub 2022 Jan 27.

Department of Laboratory Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan.

To implement precision oncology, analytical validity as well as clinical validity and utility are important. However, proficiency testing (PT) to assess validity has not yet been systematically performed in Japan. To investigate the quality of next-generation sequencing (NGS) platforms and cancer genome testing prevalent in laboratories, we performed pilot PT using patient samples. We prepared genomic DNA from the cancer tissue and peripheral blood of 5 cancer patients and distributed these to 15 laboratories. Most participating laboratories successfully identified the pathogenic variants, except for two closely located KRAS variants and 25 bp delins in EGFR. Conversely, the EGFR L858R variant was successfully identified, and the allele frequency was similar for all the laboratories. A high DNA integrity number led to excellent depth and reliable NGS results. By conducting this pilot study using patient samples, we were able to obtain a glimpse of the current status of cancer genome testing at participating laboratories. To enhance domestic cancer genome testing, it is important to conduct local PT and to involve the parties concerned as organizers and participants.
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http://dx.doi.org/10.1038/s41598-022-05589-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8795413PMC
January 2022

PD-L1 immunohistochemistry comparison of 22C3 and 28-8 assays for gastric cancer.

J Gastrointest Oncol 2021 Dec;12(6):2696-2705

Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Japan.

Background: Nivolumab and pembrolizumab are promising therapies for gastric adenocarcinoma. The 22C3 and 28-8 pharmDx immunohistochemistry assays for programmed death ligand-1 scoring criteria have been developed. This study compared the programmed death ligand-1 staining patterns of gastric adenocarcinoma evaluated by the 22C3 and 28-8 pharmDx assays.

Methods: Tissue microarray analysis was performed for 226 patients with gastric adenocarcinoma who underwent curative surgery. Interobserver concordance between the 22C3 and 28-8 pharmDx assays was assessed to compare the dichotomized expression values. Programmed death ligand-1 positivity was assessed by combined positive score and tumor proportion score. Immunohistochemistry for deficient mismatch repair proteins and Epstein-Barr virus-encoded RNA hybridization was examined.

Results: Programmed death ligand-1 positivity with a combined positive score ≥5 was detected in 63 patients (28%) by the 22C3 pharmDx assay, and in 45 patients (20%) by the 28-8 pharmDx assay. A pairwise comparison of the 22C3 and 28-8 pharmDx assays showed 87% of pairs were concordant and 11% higher expressions for the 22C3 pharmDx assay, with strong concordance (kappa score =0.881 with a combined positive score cutoff of 5). The programmed death ligand-1 positivity rate (range, 3-5%) of the tumor proportion score was markedly lower than that of the combined positive score in the two assays. Programmed death ligand-1 positivity of the combined positive score in these two assays was associated with mismatch repair proteins and Epstein-Barr virus status. There was no significant difference in the overall survival between programmed death ligand-1, mismatch repair proteins, and Epstein-Barr virus status.

Conclusions: The study findings suggest the potential interchangeability of the 22C3 and 28-8 pharmDx assays to determine programmed death ligand-1 expression levels in gastric adenocarcinoma patients.
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http://dx.doi.org/10.21037/jgo-21-505DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8748031PMC
December 2021

Establishment and characterization of NCC-DMM1-C1, a novel patient-derived cell line of desmoplastic malignant pleural mesothelioma.

Oncol Lett 2022 Feb 27;23(2):64. Epub 2021 Dec 27.

Division of Rare Cancer Research, National Cancer Center Research Institute, Chuo-ku, Tokyo 104-0045, Japan.

Desmoplastic malignant pleural mesothelioma (DMM) is a rare histological variant of malignant pleural mesothelioma, which is a highly aggressive neoplasm of the mesothelium. DMM is associated with distant metastases and short survival. Effective treatments for DMM are not established and the development of histotype-tailored treatments is difficult due to the rarity of the disease. Although patient-derived cancer models are crucial tools for the development of novel therapeutics, they are difficult to obtain for DMM; no DMM cell lines or xenografts are available from public biobanks and only two cell lines have been reported. Thus, the present study aimed to establish a novel cell line of DMM as a resource for drug screening. A cell line of DMM was established, designated as NCC-DMM1-C1, using surgically resected tumor tissues from a 73-year-old male patient with DMM. Characteristics of NCC-DMM1-C1 cells were examined, such as growth, spheroid formation and invasion capability. Drug targets and anti-cancer drugs with anti-proliferative efficacy were examined using a comprehensive kinase activity assay and drug screening of 213 anti-cancer agents, respectively. NCC-DMM1-C1 exhibited fast growth, spheroid formation and invasion capability, suggesting that the NCC-DMM1-C1 cells retained the aggressive features of DMM. NCC-DMM1-C1 cells and the tumor tissue shared common activity profiles of kinases, which included FES, Wee1, platelet-derived growth factor receptor-β and Src. The drug screening revealed that bortezomib, fostamatinib, gemcitabine, homoharringtonine and vinorelbine had anti-proliferative effects, which have not been previously reported for DMM. It was concluded that NCC-DMM1-C1 cells may be a useful tool for the study of DMM.
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http://dx.doi.org/10.3892/ol.2021.13182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8756558PMC
February 2022

Assessment of Resectability of Mediastinal Germ Cell Tumor Using Preoperative Computed Tomography.

J Surg Res 2022 04 20;272:61-68. Epub 2021 Dec 20.

Department of Thoracic Surgery, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan.

Background And Objectives: Mediastinal germ cell tumor (MGCT) is a relatively rare tumor. Complete resection after chemotherapy is a standard treatment against this disease. However, the risk factors of incomplete resection are unclear. Therefore, we analyzed survival rates and risk factors for incomplete resection based on preoperative imaging.

Methods: We retrospectively reviewed the medical records of patients (n = 56) with MGCT operated at National Cancer Center Hospital, and analyzed preoperative computed tomography (CT) data in terms of relationship of the tumor and vessels, and investigated survival rate and risk factors for incomplete resection.

Results: A total of 56 patients underwent resection of MGCT. The 5-y progression-free survival (PFS) and overall survival (OS) were 79% and 83%. In multivariate analysis, complete resection was the only significant prognostic factor for better PFS (hazard ratio (HR) = 9.083, P= 0.00021) and OS (HR = 5.519, P= 0.0445). The preoperative CT finding of arteries (including the aorta, right brachiocephalic artery, left common carotid artery, and left subclavian artery) surrounded by the tumor was a predictor of incomplete resection (odds ratio = 10.089, P= 0.049).

Conclusions: Complete resection is essential for improving the survival of MGCT, and the risk stratification using preoperative CT imaging brings important information to achieve the complete resection.
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http://dx.doi.org/10.1016/j.jss.2021.11.002DOI Listing
April 2022

MicroSEC filters sequence errors for formalin-fixed and paraffin-embedded samples.

Commun Biol 2021 12 15;4(1):1396. Epub 2021 Dec 15.

Division of Cellular Signaling, National Cancer Center Research Institute, Tokyo, Japan.

The clinical sequencing of tumors is usually performed on formalin-fixed, paraffin-embedded samples and results in many sequencing errors. We identified that most of these errors are detected in chimeric reads caused by single-strand DNA molecules with microhomology. During the end-repair step of library preparation, mutations are introduced by the mis-annealing of two single-strand DNA molecules comprising homologous sequences. The mutated bases are distributed unevenly near the ends in the individual reads. Our filtering pipeline, MicroSEC, focuses on the uneven distribution of mutations in each read and removes the sequencing errors in formalin-fixed, paraffin-embedded samples without over-eliminating the mutations detected also in fresh frozen samples. Amplicon-based sequencing using 97 mutations confirmed that the sensitivity and specificity of MicroSEC were 97% (95% confidence interval: 82-100%) and 96% (95% confidence interval: 88-99%), respectively. Our pipeline will increase the reliability of the clinical sequencing and advance the cancer research using formalin-fixed, paraffin-embedded samples.
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http://dx.doi.org/10.1038/s42003-021-02930-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8674242PMC
December 2021

Comparative Study on the Efficacy and Exposure of Molecular Target Agents in Non-small Cell Lung Cancer PDX Models with Driver Genetic Alterations.

Mol Cancer Ther 2022 02 15;21(2):359-370. Epub 2021 Dec 15.

Division of Molecular Pharmacology, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan.

Patient-derived xenografts (PDX) can adequately reflect clinical drug efficacy. However, the methods for evaluating drug efficacy are not fully established. We selected five non-small cell lung cancer (NSCLC) PDXs with genetic alterations from established PDXs and the corresponding molecular targeted therapy was administered orally for 21 consecutive days. Genetic analysis, measurement of drug concentrations in blood and tumors using LC/MS-MS, and analysis of drug distribution in tumors using matrix-assisted laser desorption/ionization mass spectrometry were performed. Fifteen (20%) PDXs were established using samples collected from 76 patients with NSCLC with genetic alterations. The genetic alterations observed in original patients were largely maintained in PDXs. We compared the drug efficacy in original patients and PDX models; the efficacies against certain PDXs correlated with the clinical effects, while those against the others did not. We determined blood and intratumor concentrations in the PDX model, but both concentrations were low, and no evident correlation with the drug efficacy could be observed. The intratumoral spatial distribution of the drugs was both homogeneous and heterogeneous for each drug, and the distribution was independent of the expression of the target protein. The evaluation of drug efficacy in PDXs enabled partial reproduction of the therapeutic effect in original patients. A more detailed analysis of systemic and intratumoral pharmacokinetics may help clarify the mode of action of drugs. Further development of evaluation methods and indices to improve the prediction accuracy of clinical efficacy is warranted.
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http://dx.doi.org/10.1158/1535-7163.MCT-21-0371DOI Listing
February 2022

Clinical Utility of Circulating Tumor DNA in Advanced Rare Cancers.

Front Oncol 2021 24;11:732525. Epub 2021 Nov 24.

Department of Medical Oncology, National Cancer Center Hospital, Tokyo, Japan.

Purpose: Patients with advanced/relapsed rare cancers have few treatment options. Analysis of circulating tumor DNA in plasma may identify actionable genomic biomarkers using a non-invasive approach.

Patients And Methods: Rare cancer patients underwent prospective plasma-based NGS testing. Tissue NGS to test concordance was also conducted. Plasma DNA alterations were assessed for incidence, functional impact, therapeutic implications, correlation to survival, and comparison with tissue NGS.

Results: Ninety-eight patients were analyzed. Diseases included soft-tissue sarcoma, ovarian carcinoma, and others. Mean turn-around-time for results was 9.5 days. Seventy-six patients had detectable gene alterations in plasma, with a median of 2.8 alterations/patient. Sixty patients had a likely pathogenic alteration. Five received matched-therapy based on plasma NGS results. Two developed known resistance mutations while on targeted therapy. Patients with an alteration having VAF ≥5% had a significantly shorter survival compared to those of lower VAF. Tissue NGS results from eleven of 22 patients showed complete or partial concordance with plasma NGS.

Conclusion: Plasma NGS testing is less invasive and capable of identifying alterations in advanced rare cancers in a clinically meaningful timeframe. It should be further studied as a prospective enrollment assay in interventional studies for patients with rare advanced stage cancers.

Clinical Registration: [https://www.umin.ac.jp/ctr/index-j.htm], identifier UMIN000034394.
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http://dx.doi.org/10.3389/fonc.2021.732525DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8652216PMC
November 2021

Clinical usefulness of PET/MRI in differentiating anterior mediastinal masses.

Nucl Med Commun 2022 Jan;43(1):92-99

Department of Diagnostic Radiology, National Cancer Center Hospital.

Objectives: To investigate the clinical usefulness of 18F-fluorodeoxyglucose (FDG) PET/MRI in differentiating anterior mediastinal lesions, including small ones.

Material And Methods: Among 96 patients who underwent 18F-FDG PET/MRI screening for anterior mediastinal lesions, we retrospectively reviewed images of 42 patients with histologically or clinically diagnosed thymic carcinomas, thymomas or anterior mediastinal cysts. MRI findings and maximum standardized uptake value (SUVmax) were compared among the three categories. In addition, small lesions measuring <3.0 cm which did not show very high signal intensity (isointense to water) on T2 weighted images (T2WI) were sub-analyzed.

Results: Significant differences in SUVmax were observed among anterior mediastinal cysts (P < 0.001, vs. thymomas and thymic carcinomas), thymomas (P = 0.032, vs. thymic carcinomas) and thymic carcinomas. Regarding the MRI findings, anterior mediastinal cysts showed higher T2WI signal intensity (P = 0.004 vs. thymomas and P = 0.042 vs. thymic carcinomas) and thymic carcinomas tended to show ill-defined contours (P = 0.024 vs. anterior mediastinal cysts and P = 0.036 vs. thymomas). SUVmax was also significantly higher in small thymic tumors than small anterior mediastinal cysts without very high T2WI signal intensity (P = 0.003).

Conclusion: 18F-FDG PET/MRI is clinically useful in differentiating anterior mediastinal lesions, including those smaller than 3 cm.
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http://dx.doi.org/10.1097/MNM.0000000000001483DOI Listing
January 2022

A mimic of lung adenocarcinoma: a case report of histological conversion of metastatic thyroid papillary carcinoma.

Histopathology 2022 05 28;80(6):1004-1007. Epub 2022 Jan 28.

Department of Diagnostic Pathology, National Cancer Centre Hospital, Tokyo, Japan.

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http://dx.doi.org/10.1111/his.14607DOI Listing
May 2022

Cryobiopsy as a reliable technique for the preoperative identification of micropapillary/solid components in early-stage lung adenocarcinoma.

Lung Cancer 2021 12 13;162:147-153. Epub 2021 Nov 13.

Department of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo, Japan.

Objectives: Micropapillary (MIP) and solid (SOL) subtypes of early-stage lung adenocarcinomas are associated with lymph node metastasis and local recurrence after limited resection. Preoperative identification of these components may influence the decisions of treatment strategy, additional lymph node evaluation, indication for limited resection, and extent of lymph node dissection. However, conventional biopsy specimens are insufficient for identifying these subtypes, especially MIP components. Cryobiopsy can collect larger tissue samples with fewer crush artifacts than conventional forceps biopsy, which would be helpful for detecting MIP/SOL components. Thus, this study aimed to analyze the feasibility of using cryobiopsy for MIP/SOL subtype detection.

Material And Methods: Consecutive patients who underwent surgery for clinical IA lung cancer following a preoperative diagnosis of adenocarcinoma by cryobiopsy at our institution between October 2017 and July 2019 were retrospectively examined. The concordance rate of MIP/SOL subtypes between the specimens obtained by cryobiopsy and surgery was investigated.

Results: In total, 115 patients were evaluated. There were 26 (22.6%) and 14 (12.2%) patients with MIP and SOL subtypes, respectively. For concordance of MIP/SOL subtypes, the sensitivity was 65.7% (95% confidence interval [CI]: 57.7-65.7%). For the primary or secondary predominant patterns, a more satisfactory concordance rate of 72.2% (95% CI: 52.6-86.2%) was obtained. On assessing each subtype, high sensitivity was noted in SOL-predominant patterns (85.7%, 95% CI: 56.5%-96.0%) and MIP-secondary predominant patterns (83.3%, 95% CI: 45.8-97.0%). However, SOL-secondary predominant patterns revealed low sensitivity (0%, 95% CI, 0-38.2%). Overall, the MIP subtypes had higher sensitivity than the SOL subtypes (65.4% vs. 50.0%).

Conclusion: Cryobiopsy could be reliable for identifying MIP/SOL components, especially the MIP component, in clinical stage IA adenocarcinomas.
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http://dx.doi.org/10.1016/j.lungcan.2021.11.004DOI Listing
December 2021

The 2021 WHO Classification of Lung Tumors: Impact of Advances Since 2015.

J Thorac Oncol 2022 03 20;17(3):362-387. Epub 2021 Nov 20.

Memorial Sloan Kettering Cancer Center, New York, New York.

The 2021 WHO Classification of Thoracic Tumours was published earlier this year, with classification of lung tumors being one of the chapters. The principles remain those of using morphology first, supported by immunohistochemistry, and then molecular techniques. In 2015, there was particular emphasis on using immunohistochemistry to make classification more accurate. In 2021, there is greater emphasis throughout the book on advances in molecular pathology across all tumor types. Major features within this edition are (1) broader emphasis on genetic testing than in the 2015 WHO Classification; (2) a section entirely dedicated to the classification of small diagnostic samples; (3) continued recommendation to document percentages of histologic patterns in invasive nonmucinous adenocarcinomas, with utilization of these features to apply a formal grading system, and using only invasive size for T-factor size determination in part lepidic nonmucinous lung adenocarcinomas as recommended by the eighth edition TNM classification; (4) recognition of spread through airspaces as a histologic feature with prognostic significance; (5) moving lymphoepithelial carcinoma to squamous cell carcinomas; (6) update on evolving concepts in lung neuroendocrine neoplasm classification; (7) recognition of bronchiolar adenoma/ciliated muconodular papillary tumor as a new entity within the adenoma subgroup; (8) recognition of thoracic SMARCA4-deficient undifferentiated tumor; and (9) inclusion of essential and desirable diagnostic criteria for each tumor.
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http://dx.doi.org/10.1016/j.jtho.2021.11.003DOI Listing
March 2022

Adenocarcinoma in situ and minimally invasive adenocarcinoma in lungs of smokers: image feature differences from those in lungs of non-smokers.

BMC Med Imaging 2021 11 19;21(1):172. Epub 2021 Nov 19.

Department of Diagnostic Radiology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.

Purpose: We aimed to examine the characteristics of imaging findings of adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) in the lungs of smokers compared with those of non-smokers.

Materials And Methods: We included seven cases of AIS and 20 cases of MIA in lungs of smokers (pack-years ≥ 20) and the same number of cases of AIS and MIA in lungs of non-smokers (pack-years = 0). We compared the diameter of the entire lesion and solid component measured on computed tomography (CT) images, pathological size and invasive component diameter measured from pathological specimens, and CT values of the entire lesion and ground-glass opacity (GGO) portions between the smoker and non-smoker groups.

Results: The diameters of AIS and MIA on CT images and pathological specimens of the smoker group were significantly larger than those of the non-smoker group (p = 0.036 and 0.008, respectively), whereas there was no significant difference in the diameter of the solid component on CT images or invasive component of pathological specimens between the two groups. Additionally, mean CT values of the entire lesion and GGO component of the lesions in the smoker group were significantly lower than those in the non-smoker group (p = 0.036 and 0.040, respectively).

Conclusion: AIS and MIA in smoker's lung tended to have larger lesion diameter and lower internal CT values compared with lesions in non-smoker's lung. This study calls an attention on smoking status in CT-based diagnosis for early stage adenocarcinoma.
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http://dx.doi.org/10.1186/s12880-021-00705-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8603503PMC
November 2021

Molecular testing in stage I-III non-small cell lung cancer: Approaches and challenges.

Lung Cancer 2021 12 15;162:42-53. Epub 2021 Sep 15.

Department of Pathology, Aberdeen University, Medical School and Aberdeen Royal Infirmary, Foresterhill, Aberdeen, UK. Electronic address:

Precision medicine in non-small cell lung cancer (NSCLC) is a rapidly evolving area, with the development of targeted therapies for advanced disease and concomitant molecular testing to inform clinical decision-making. In contrast, routine molecular testing in stage I-III disease has not been required, where standard of care comprises surgery with or without adjuvant or neoadjuvant chemotherapy, or concurrent chemoradiotherapy for unresectable stage III disease, without the integration of targeted therapy. However, the phase 3 ADAURA trial has recently shown that the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), osimertinib, reduces the risk of disease recurrence by 80% versus placebo in the adjuvant setting for patients with stage IB-IIIA EGFR mutation-positive NSCLC following complete tumor resection with or without adjuvant chemotherapy, according to physician and patient choice. Treatment with adjuvant osimertinib requires selection of patients based on the presence of an EGFR-TKI sensitizing mutation. Other targeted agents are currently being evaluated in the adjuvant and neoadjuvant settings. Approval of at least some of these other agents is highly likely in the coming years, bringing with it in parallel, a requirement for comprehensive molecular testing for stage I-III disease. In this review, we consider the implications of integrating molecular testing into practice when managing patients with stage I-III non-squamous NSCLC. We discuss best practices, approaches and challenges from pathology, surgical and oncology perspectives.
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http://dx.doi.org/10.1016/j.lungcan.2021.09.003DOI Listing
December 2021
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