Invasive Mucinous Adenocarcinoma Of Lung Research Articles

Prognostic impact of mucin spread, tumor cell spread, and invasive size in invasive mucinous adenocarcinoma of the lung

ObjectivesThe pathological T descriptor of lung invasive mucinous adenocarcinoma (IMA) is currently defined according to mucin spread, whereas that of lung non-mucinous adenocarcinoma is defined according to invasive lesion. This study aimed to evaluate and compare the prognostic impact of mucin spread, tumor cell spread, and invasive lesion in patients with lung IMA. Materials and MethodsTwenty-seven patients with completely resected pT1-4N0M0 IMA were evaluated. The radiological size (RS), mucin spread size (MS), tumor cell spread size (TS), and invasive size (IS) of the primary tumors were determined. Cox proportional hazards models were used to estimate recurrence-free survival (RFS). Because the MS, TS, and IS may be mutually confounding factors, they were evaluated using separate multivariate models including potential prognostic factors identified as significant on univariate analyses. ResultsThe median postoperative follow-up time was 4.9 years. TS and IS were significantly smaller than RS by a median of 0.3 cm (p = 0.027) and 1.4 cm (p < 0.0001), whereas MS and RS were not significantly different (p > 0.999). Univariate analyses identified T descriptors defined by MS, TS, and IS as potentially negative prognostic factors, in addition to age >75 years and carcinoembryonic antigen >5 ng/mL. Multivariate analyses revealed that T factors defined by MS, TS, and IS were significant predictors of RFS (p < 0.0001, p = 0.0002, and p = 0.0067, respectively). ConclusionMS is a reasonable determinant of the pathological T descriptor of lung IMA. TS and IS are potential candidates, although they remain discordant with RS. If the TS or IS is to be considered a candidate for the pathological T descriptor of lung IMA, the discordance with RS should first be resolved. If IS is used to define pathological T factor, clear criteria for mucinous AIS/MIA with IMA features should be developed.

Optimal method for measuring invasive size that predicts survival in invasive mucinous adenocarcinoma of the lung.

The purpose of this study was to determine the optimal method for measuring pathological invasive size that predicts prognosis in invasive mucinous adenocarcinoma (IMA). We analyzed patients who underwent complete surgical resection for lung IMA. The invasive size of IMA was measured using two methods: (1) excluding lepidic method (ELM), that is, lepidic component was excluded from the invasive area regardless of alveolar mucin and (2) including lepidic method (ILM), that is, lepidic component was included as invasive area if alveolar space was filled with mucin. The prognostic predictability of ELM and ILM on survival was assessed using univariable and multivariable Cox regression models. The discriminative power was assessed using concordance probability estimate (CPE) and Akaike's information criteria (AIC), and the prognostic impact of the newly redefined pathological stage according to ELM or ILM was also assessed. A total of 101 patients were included. The median invasive size via ELM and ILM was 1.4cm (range, 0.0-7.7cm) and 2.1cm (range, 0.0-14.2cm), respectively. ELM had better discriminative power than ILM (ELM, HR = 1.38, AIC = 110.19, CPE = 0.671; ILM, HR = 1.19, AIC = 111.52, CPE = 0.655). Although the survival curves based on ILM crossed between T3 and T4, the overall survival (OS) curves based on ELM were sufficiently distinct from one another. ELM has higher discriminative power for OS, and thus the optimal method for measuring the pathological invasive size of IMA should exclude the lepidic component regardless of alveolar mucin.

1969P - Targeting NRG1-fusions in multiple tumour types: Afatinib as a novel potential treatment option

1969P - Targeting NRG1-fusions in multiple tumour types: Afatinib as a novel potential treatment option

Comparing clinicopathological features and prognosis of primary pulmonary invasive mucinous adenocarcinoma based on computed tomography findings

ObjectiveTo evaluate the relationship between clinicopathologic characteristics and prognosis in patients with invasive mucinous adenocarcinoma (IMA) of the lung.MethodsA total of 68 patients who underwent surgical resection for primary lung IMA were reviewed during the period of 2009 and 2017. Tumors were classified as solitary-type or pneumonic-type according to the computed tomography (CT) findings. Cox proportional hazards model was used to assess the effects of clinicopathological characteristics on univariate and multivariable analyses of disease-free survival (DFS).ResultsSolitary-type was found in 54 patients, while pneumonic-type was found in 14 patients. The patients’ age varied between 56 and 68 years (patients’ median age was 61 years). Besides, 50 patients had T1/T2 tumor stage (73.5%). Compared with solitary-type, higher T stage, N stage, and pathological stage (P < 0.001) were found in pneumonic-type. Moreover, the survival analysis showed that the pneumonic-type had a significantly poorer DFS compared with solitary-type (P = 0.004). Univariate analysis showed that pneumonic pattern on CT scan, T stage, pathologic stage, and thyroid transcription factor-1 (TTF-1) were significant predictive factors of survival (P = 0.011, 0.014, 0.013, 0.029, respectively). Multivariate analysis further indicated that pneumonic-type was the only independent prognostic factor for poor survival [hazard ratio (HR) = 6.764, 95% confidence interval (CI): 1.563–29.269, P = 0.011].ConclusionsBased on CT findings, the solitary-type IMA is associated with a lower stage and better prognosis compared with the pneumonic-type IMA.

Pro-tumoural CXCL10/CXCR3-A autocrine loop in invasive mucinous lung adenocarcinoma.

Invasive mucinous adenocarcinoma (IMA) is a mucinous variant of lepidic predominant lung adenocarcinoma (LPA) and associated with a worse prognosis. We postulated that cytokine expression would enable us to differentiate IMA from LPA in terms of prognosis and acquisition of pro-tumoural capacities.A 30-cytokine panel was assessed in bronchoalveolar lavage fluids (BALF) from IMA (n=38), LPA (n=25) and control samples (n=7). We investigated the expression of differentially expressed cytokines and splice variants of their receptors in surgical samples. The presence of EGFR and KRAS mutations were determined. We also examined the expression of cytokines and splice variants of their receptors in different cell lines, exploring their functional impact on signalling pathways, proliferation and migration.Only C-X-C motif chemokine 10 (CXCL10) was differentially expressed, namely overexpressed in IMA BALF compared with LPA. CXCL10 overexpression in BALF was linked to a worse prognosis. In surgical samples, CXCL10 and its receptor C-X-C motif chemokine receptor 3 (CXCR3) were overexpressed in IMA compared to LPA. A pro-tumoural CXCR3-A splice variant was overexpressed in IMA, suggesting a CXCL10/CXCR3-A autocrine loop in IMA. CXCL10 and CXCR3 expression were not correlated with EGFR or KRAS status. CXCL10 up-regulated CXCR3-A expression, Erk1/2 phosphorylation and enhanced migration in the mucinous H2228 cell line.CXCL10/CXCR3-A may play a pro-tumoural role in IMA via an autocrine mechanism.

P3.01-008 Clinicopathological and Immunohistochemical Features in Lung Invasive Mucinous Adenocarcinoma According to Computed Tomography Findings: Topic: Morphology

We performed the analysis to clarify the differences of lung invasive mucinous adenocarcinoma (IMA) based on computed tomography (CT) finding, in clinicopathological and molecular features, as well as prognosis. On the basis of CT findings, we divided lung IMA into three subtypes; solid, bubbling, and pneumonic type. We investigated differences in clinicopathological characteristics, prognosis, and expressions of well-identified biomarkers, including Cox-2, ERCC1, RRM1, Class III beta-tubulin, TS, SPARC, PD-L1and EGFR mutation, among the three subtypes. A total of 29 patients of resected lung IMA were analyzed. Compared with the solid or bubbling type, the pneumonic type had a higher proportion of a symptom, large tumor size, a higher pathological stage, and a significantly worse prognosis. Immunohistochemical findings tended to be high expression in RRM1, Class III beta tubulin, Cox-2 in tumor and SPARC in stroma, but not ERCC1, TS, and PDL-1 in tumor. All biomarkers in tumor were not prognostic biomarker, however, only SPARC expression in stroma was worse prognostic biomarker. Clinical and pathological features in conjunction with molecular data indicate that IMA should be divided into different subgroups. In our results, pneumonic type had significantly worse prognosis, and could guess to be effective to cisplatin, pemetrexed, or nab-paclitaxel, and/or Cox-2 inhibitor. Further studies should be performed to confirm our conclusion and explore its molecular functions.

Clinicopathological and immunohistochemical features of lung invasive mucinous adenocarcinoma based on computed tomography findings.

BackgroundWe performed an analysis to clarify differences in clinicopathological and molecular features of lung invasive mucinous adenocarcinoma (IMA) based on computed tomography (CT) findings and their impact on prognosis.Patients and methodsOn the basis of CT findings, we divided lung IMA into three subtypes: solid, bubbling, and pneumonic. We then investigated differences in clinicopathological characteristics, prognosis, and the expressions of well-identified biomarkers, including cyclooxygenase-2 (Cox-2), excision repair cross-complementation group 1 (ERCC1), ribonucleotide reductase M1 (RRM1), class III beta-tubulin, thymidylate synthase (TS), secreted protein acidic and rich in cysteine (SPARC), programmed cell death-1 ligand-1 (PD-L1), and epidermal growth factor receptor mutation, among the three subtypes.ResultsA total of 29 patients with resected lung IMA were analyzed. Compared with the solid or bubbling type, the pneumonic type had a higher proportion of symptoms, a larger tumor size, a higher pathological stage, and a significantly worse prognosis. The immunohistochemical findings tended to show high expression of RRM1, class III beta-tubulin, and Cox-2 in the tumor and of SPARC in the stroma, but not of ERCC1, TS, and PD-L1 in the tumor. None of the biomarkers with high expression levels in the tumor were prognostic biomarkers, but the expression of SPARC in the stroma was correlated with a poor outcome.ConclusionClinical and pathological features, in conjunction with molecular data, indicate that IMA should be divided into different subgroups. In our results, the pneumonic type was correlated with a significantly worse outcome. Further studies should be performed to confirm our conclusion and to explore its molecular implications.

NRG1 fusion in a French cohort of invasive mucinous lung adenocarcinoma.

Invasive mucinous lung adenocarcinoma (IMA) is a rare subtype of lung adenocarcinoma with no effective treatment option in advanced disease. KRAS mutations occur in 28–87% of the cases. NRG1 fusions were recently discovered in KRAS‐negative IMA cases and otherwise negative for known driver oncogenes and could represent an attractive therapeutic target. Published data suggest that NRG1 fusions occur essentially in nonsmoking Asian women. From an IMA cohort of 25 French patients of known ethnicity, driver oncogenes EGFR, KRAS, BRAF, ERBB2 mutations, and ALK and ROS1 rearrangements presence were analyzed. In the IMA samples remaining negative for these driver oncogenes, an NRG1 rearrangement detection was performed by FISH. A driver oncogene was identified in 14/25 IMA, namely 12 KRAS mutations (48%), one ROS1 rearrangement (4%), and one ALK rearrangement (4%). The detection of NRG1 rearrangement by FISH was conducted in the 11 pan‐negative IMA. One sample was NRG1 FISH‐positive and 100% of the tumor nuclei analyzed were positive. This NRG1‐positive patient was a 61‐year‐old nonsmoking woman of Vietnamese ethnicity and was the sole patient of Asian ethnicity of the cohort. She died 6 months after the diagnosis with a pulmonary multifocal disease. NRG1 FISH detection should be considered in patients with IMA pan‐negative for known driver oncogenes. These results might suggest that NRG1 fusion is more frequent in IMA from Asian patient. Larger studies are needed.

Abstract 97: A novel PTPRK-FILIP1 fusion gene in invasive mucinous adenocarcinoma of lung without known driver mutations

Abstract Invasive mucinous adenocarcinoma (IMA) accounts for 2 to 10% of all adenocarcinoma cases of the lung and has a poor prognosis. The KRAS mutation is the most commonly detected genetic alteration in IMAs. Recent progress has permitted the identification of novel fusions such as NRG1. In an effort to further discovery of new driver oncogenes, we have carried out whole-transcriptome sequencing of IMA. To exclude IMA cases with known driver oncogenes, we performed targeted sequencing using the Ion AmpliSeq Cancer Hotspot Panel. We also tested other currently known fusion genes in lung cancer including CD74-NRG1, TPM3-ROS1, SDC4-ROS1, SLC34A2-ROS1, CD74-ROS1, EZR-ROS1, LRIG-ROS1, KIF5B-RET, CCDC6-RET1, EZR-ERBB4, TRIM24-BRAF, KIAA1468-RET, EML4-ALK, and KIF5B-ALK using RT-PCR. Finally we found 10 IMA cases without known driver oncogenes and performed transcriptome paired-end sequencing (the Illumina HiSeq platform). We utilized and compared 3 bioinformatic pipelines, FusionMap, deFuse, and ChimeraScan to identify fusion events. Of 10 IMA cases tested, we found 2 novel fusions, PTPRK-FILIP1 and CEP85L-RNGTT, from a never-smoking female patient. They were shared across all three fusion-finder and never reported in TCGA fusion gene data portal. Only PTPRK-FILIP1 was showed an in-frame fusion between exon 2 of PTPRK and 5’ UTR of FILIP1. It was confirmed by RT-PCR analysis and Sanger sequencing. This precise fusion was not present in the matched normal tissue. The reading frame is preserved that both the start codon of PTPRK and FILIP1. However, PTPRK mRNA expression is increased until exon 2 because of the fusion includes only two exons of PTPRK. Otherwise, expression analysis showed significant increase of FILIP1 mRNA expression in the affected tumor pair sample. The protein product from FILIP1 is closely associated with the protein filamin A, which is associated with tumor proliferation, cell migration, and metastasis. Many studies have reported that filamin A as a poor prognostic factor. Considering its implication in tumor proliferation, cell migration, and metastasis, PTPRK-FILIP1 could be a novel target for IMA. This is the first report of PTPRK-FILIP1 fusion gene in IMA without known driver mutations. Further functional validation of FILIP1 fusion is planned. Citation Format: Sung-Hye Hong, Geon Kook Lee, Sang Hoon Song, Seung Youn Lee, Jin Young Kim, Ji-Youn Han. A novel PTPRK-FILIP1 fusion gene in invasive mucinous adenocarcinoma of lung without known driver mutations. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 97.

Association between the histological subtype of lung adenocarcinoma, EGFR/KRAS mutation status and the ALK rearrangement according to the novel IASLC/ATS/ERS classification.

The present study aimed to investigate the association between epidermal growth factor receptor (EGFR)/Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations, anaplastic lymphoma receptor tyrosine kinase (ALK) rearrangements and the morphological characteristics of lung adenocarcinoma (LAC), according to the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society (IASLC/ATS/ERS) classification in a large group of patients with primary LAC. A total of 200 patients with invasive LAC who had undergone complete resections at the Beijing Chest Hospital (Beijing, China) were randomly selected. The morphology of the samples was reassessed in 5% increments by two pathologists, according to the IASLC/ATS/ERS scheme. EGFR and KRAS mutations were tested by direct DNA sequencing. ALK rearrangements were screened by immunohistochemistry on a Benchmark XT stainer. The data revealed that EGFR and KRAS mutations, and ALK rearrangements were identified in 46.0% (92/200), 9.0% (18/200) and 11.5% (23/200) of the patients, respectively. The EGFR/KRAS mutations and ALK rearrangements were mostly exclusive. However, 1 patient exhibited the coexistence of the EGFR (at exon 20) and KRAS (codon 12) mutations, and another patient exhibited the coexistence of the EGFR mutation (at exon 21) and the ALK gene fusion. EGFR mutations were indicated to be closely associated with the acinar predominant (43/77; 55.8%; P=0.030) and papillary predominant (26/49; 53.1%; P=0.006) subtypes. KRAS mutations were more commonly associated with the solid predominant subtype (9/52; 17.3%; P=0.023) and invasive mucinous LAC (5/10; 50.0%; P=0.004), and less commonly associated with the acinar predominant subtype (1/77; 1.3%; P=0.002). ALK rearrangements more commonly occurred in the solid predominant subtype compared with other subtypes (13/52; 25%; P=0.002), and less commonly occurred in the papillary predominant subtype (1/49; 2.0%; P=0.004). Tumors harboring ALK rearrangements were characterized by signet-ring cell (7/9; 77.8%; P<0.0001) and cribriform (7/12; 58.3%; P<0.0001) patterns. The association between the mutation status and histological subtype in LAC was distinct. The predominant subtype according to the IASLC/ATS/ERS classification provided important information for gene mutations and integrated clinical findings to improve the treatment of LAC patients.

Abstract 4669: Druggable oncogene fusions in lung invasive mucinous adenocarcinoma

Abstract Invasive mucinous adenocarcinoma (IMA) of lung, a subtype of lung adenocarcinoma, is known to be strongly associated with KRAS mutation. Genetic aberration is unknown in IMA without KRAS mutation. From an IMA cohort of 90 cases, consisting of 56 cases (62%) with KRAS mutations, we conducted whole-transcriptome sequencing on 32 IMAs, including 27 cases without KRAS mutation. We identified oncogenic fusions that occurred mutually exclusively with KRAS mutations: CD74-NRG1, SLC3A2-NRG1 (NRG1 fusions: 6/90), EZR-ERBB4, TRIM24-BRAF, and KIAA1468-RET. The CD74-NRG1 and SLC3A2-NRG1 fusion proteins contained the transmembrane domain of CD74 and SLC3A2 and retained the EGF-like domain of the NRG1 protein (NRG1 III-β3 form). Membrane-tethered EGF-like domain might activate juxtacrine signaling through HER2:HER3 receptors. To reveal the mechanism of the oncogenicity, exposing EFM-19 cells which express HER2 and HER3 to conditioned media from H1299 cells expressing exogenous CD74-NRG1 fusion protein resulted in phosphorylation of HER2 and HER3, and downstream mitogen-activated kinase and AKT. The phosphorylation was suppressed by lapatinib and afatinib. When EZR-ERBB4 or TRIM24-BRAF cDNA was exogenously expressed in NIH3T3 cells, ERBB4 or downstream mediator of BRAF was phosphorylated under serum-free condition. The expression of fusion genes induced anchorage-independent growth. The phosphorylation and growth were suppressed by the kinase inhibitors targeting fusion-induced signaling. These results show that the NRG1, ERBB4 and BRAF fusions are novel driver mutations and potential targets. About 15% (13/90; 14.4%) of IMAs harbor druggable aberrations, taken together a small fraction of known driver aberrations. Citation Format: Takashi Nakaoku, Koji Tsuta, Hitoshi Ichikawa, Kouya Shiraishi, Hiromi Sakamoto, Masato Enari, Koh Furuta, Yoko Shimada, Hideaki Ogiwara, Shun-ichi Watanabe, Hiroshi Nokihara, Kazuki Yasuda, Masaki Hiramoto, Takao Nammo, Young Hak Kim, Michiaki Mishima, Jun Yokota, Teruhiko Yoshida, Takashi Kohno. Druggable oncogene fusions in lung invasive mucinous adenocarcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4669. doi:10.1158/1538-7445.AM2015-4669

Comparison of clinical features, molecular alterations, and prognosis in morphological subgroups of lung invasive mucinous adenocarcinoma.

PurposeWe performed this analysis to distinguish the differences in two subtypes of lung invasive mucinous adenocarcinoma (IMA) with different kinds of morphological performances, in clinicopathological and molecular features, as well as prognosis.MethodsOn the basis of morphological performance, we divided lung IMAs into two subgroups, mucus-in-cell adenocarcinoma (MICA) and mucus-out-of-cell adenocarcinoma (MOCA). We investigated differences in clinicopathological characteristics, recurrence-free survival (RFS), overall survival (OS), and a spectrum of well-identified driver-gene mutations, including EGFR, KRAS, HER2, BRAF, ALK, ROS1, and RET, between the two subgroups.ResultsOf 1,699 lung adenocarcinomas, 148 were identified as IMAs (97 MICAs and 51 MOCAs). The MICA patient group had significantly better RFS than did the MOCA group (39.4 months versus 33.0 months, respectively, log rank P=0.020) and significantly better OS (54.2 months versus 45.1 months, log rank P=0.034). There were no differences in RFS and OS between those with IMAs and those with mucus-negative adenocarcinomas. The frequency of the EGFR gene mutation was significantly higher in MOCAs than in MICAs (P<0.001). In contrast, the KRAS gene had a significantly higher mutational frequency in MICAs (P=0.01). MOCAs also had a significantly higher incidence of lymph-node metastasis (P<0.05).ConclusionTo our knowledge, this study represents the first comparison of clinical features, molecular alterations, and prognosis in morphological subgroups of lung IMAs. Clinical and pathological features in conjunction with molecular data indicate that IMA should be divided into different subgroups.

Druggable oncogene fusions in invasive mucinous lung adenocarcinoma.

To identify druggable oncogenic fusions in invasive mucinous adenocarcinoma (IMA) of the lung, a malignant type of lung adenocarcinoma in which KRAS mutations frequently occur. From an IMA cohort of 90 cases, consisting of 56 cases (62%) with KRAS mutations and 34 cases without (38%), we conducted whole-transcriptome sequencing of 32 IMAs, including 27 cases without KRAS mutations. We used the sequencing data to identify gene fusions, and then performed functional analyses of the fusion gene products. We identified oncogenic fusions that occurred mutually exclusively with KRAS mutations: CD74-NRG1, SLC3A2-NRG1, EZR-ERBB4, TRIM24-BRAF, and KIAA1468-RET. NRG1 fusions were present in 17.6% (6/34) of KRAS-negative IMAs. The CD74-NRG1 fusion activated HER2:HER3 signaling, whereas the EZR-ERBB4 and TRIM24-BRAF fusions constitutively activated the ERBB4 and BRAF kinases, respectively. Signaling pathway activation and fusion-induced anchorage-independent growth/tumorigenicity of NIH3T3 cells expressing these fusions were suppressed by tyrosine kinase inhibitors approved for clinical use. Oncogenic fusions act as driver mutations in IMAs without KRAS mutations, and thus represent promising therapeutic targets for the treatment of such IMAs.