Invasive Mucinous Adenocarcinoma Of Lung Research Articles

Abstract 6495: Lenvatinib as a potential treatment option for invasive mucinous lung adenocarcinoma

Abstract Introduction: Invasive mucinous adenocarcinoma (IMA) accounts for approximately 4-20% of non-small-cell lung carcinoma (NSCLC). Genetic alterations and RNA sequencing analysis of IMAs reveal a unique mucinous signature similar to gastrointestinal mucinous tumors. Due to its rarity, focused clinical trials for IMA patients are often not feasible. These patients respond poorly to platinum-based conventional chemotherapy, or immunotherapy. Lenvatinib is a multitargeted-TKI with demonstrated activity in patients with RET fusion-positive lung adenocarcinoma, thyroid, hepatocellular and gastric carcinoma. Methods: Here, we present two RET fusion-negative mucinous lung adenocarcinoma cases that received a multitargeted TKI lenvatinib with a clinical and survival benefit. Results: Case #1: An 81-year-old female initially diagnosed with cT4N0M0 IMA (TTF1 and CDX2 focally positive) was started on neoadjuvant treatment for a 12cm tumor. She underwent right thoracotomy/right lower lobectomy/mediastinal lymph node dissection, and pathology confirmed ypT4N1M0 mucinous adenocarcinoma. Three months post-operatively, the patient had disease progression in the lungs. She had no targetable mutations. She had four subsequent lines of treatment including nivolumab/nab-paclitaxel as the fourth-line treatment. After six months of nivolumab/nab-paclitaxel, lenvatinib was added to the combination due to clear disease progression evident on imaging. After twelve cycles of nivolumab/nab-paclitaxel/lenvatinib combination treatment, patient achieved a partial response per RECIST 1.1 (-35.7% change from baseline to current). The patient reported less dyspnea and increased activity tolerance. Approximately nine months after the start of the treatment, patient showed progressive lung disease. The patient died after one more line treatment with 41 months of total overall survival. Case#2: A 56-year-old male initially diagnosed with stage IVA IMA (TTF1 negative). After four lines of treatments, patient was started on lenvatinib alone. The patient reported marked improvement in dyspnea and pain and increased activity tolerance with lenvatinib. Imaging confirmed treatment response after three months of treatment. The patient was subsequently enrolled in the double lung transplant (DLT) registry aimed for lung-limited malignancies (D.R.E.A.M.) registry study (NCT05671887), and he is alive with 25 months follow-up since DLT. Conclusion: We report two cases of metastatic RET fusion-negative mucinous lung adenocarcinoma, in which treatment with the multitargeted TKI Lenvatinib led to significant clinical improvement. Biological rationale to explain the effect of lenvatinib in invasive mucinous lung adenocarcinoma needs to be explored. Citation Format: Tarik Demir, Carolyn Moloney, Liam Il-Young Chung, Young Kwang Chae. Lenvatinib as a potential treatment option for invasive mucinous lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6495.

Prognosis of spread through air spaces in invasive mucinous lung adenocarcinoma after curative surgery

IntroductionThe purpose of this study is to investigate the prognostic impact of spread through air spaces (STAS) in invasive mucinous adenocarcinoma (IMA). Materials and methodsFrom 2015 to 2019, patients who underwent complete resection of IMA were extracted from the prospective database. Multivariable Cox-regression analysis and inverse probability of treatment weight (IPTW) - adjusted log-rank test for 5-year recurrence-free survival (RFS) were performed. ResultsSTAS was observed in 39.1% (53 out of 133). The STAS (+) group shows larger tumor size (2.9 ± 2.4 cm vs 3.8 ± 2.4 cm, p = 0.031) and higher incidence of lympho-vascular invasion (6 [7.5%] vs 18 [34.0%], p < 00.001) compared to the STAS (−) group. The 5-year RFS was 66.1% in the STAS (+) group and 91.8% in the STAS (−) group (p < 00.001), and the incidence of locoregional recurrence was significantly higher in the STAS (+) group than the STAS (−) group (1 [1.2%] vs 12 [22.6%], p < 00.001). Multivariable analysis revealed that STAS was associated with poor prognosis for all-recurrence (hazard ratio 2.81, 95% confidence interval 1.01–7.81, p = 0.048). After IPTW adjustment, 5-year RFS was 66.3% in the STAS (+) group and 92.9% in the STAS (−) group (p = 0.007), and risk for locoregional recurrence was greater in the STAS (+) group than the STAS (−) group (1.1 [0.9%] vs 20.8 [16.6%], p < 00.001). ConclusionsSTAS showed negative prognostic impact on all-recurrence, especially due to locoregional recurrence, after curative resection of IMA.

Nomogram for predicting prognosis and identifying chemotherapy beneficiaries for completely resected stage I invasive mucinous lung adenocarcinoma.

At present, there is a lack of studies in invasive mucinous adenocarcinoma (IMA) that combine clinicopathological and imaging features to stratify risk and select optimal treatment regimen. We aimed to develop and validate a nomogram for predicting recurrence-free survival (RFS) and identifying adjuvant chemotherapy (ACT) beneficiaries for completely resected stage I primary IMA. This retrospective study included 750 patients from three hospitals. Patients from two hospitals were divided into training (n=424) and validating cohort (n=185), and patients from the remaining other one hospital constituted external test cohort (n=141) and preoperative computed tomography (CT) image features of each patient were consecutively evaluated. The nomogram was developed by integrating significant prognostic factors of RFS identified in the multivariate analysis. The risk score (RS) based on nomogram was calculated in the entire cohort and the optimal cut-off point for risk stratification was obtained by X-tile software. The Kaplan-Meier method, log-rank test and interaction were used to evaluate the difference in RFS and overall survival (OS) between different risk and treatment groups. Visceral pleural invasion (VPI, P<0.001), lymph-vascular invasion (LVI, P<0.001), tumor size (P<0.001), smoking history (P<0.001), lobulation (P<0.001) were identified as independent prognostic factors for RFS. The concordance index (C-index) of the nomogram was higher than that of tumor-node-metastasis (TNM) staging system (validation cohort: 0.73±0.09 vs. 0.62±0.08, P<0.001; external test cohort: 0.74±0.10 vs. 0.70±0.09, P=0.035). The patients with higher RS were associated with worse RFS [hazard ratios (HRs) ≥4.76] and OS (HRs ≥2.55) in all included cohorts. Chemotherapy benefits in terms of RFS and OS were observed for patients in higher RS group in both stage IB (interaction P=0.012 for RFS and P=0.037 for OS) and stage I IMA (interaction P<0.001 for both RFS and OS). The nomogram based on CT image and clinicopathologic features showed superior performance in predicting RFS for stage I IMA and might identify ACT candidates for personalized patient treatment.

Systemic immune-inflammation index predicts survival in patients with resected lung invasive mucinous adenocarcinoma

BackgroundThe prognostic-related factors of lung invasive mucinous adenocarcinoma(IMA) are unclear because of its rarity. Various inflammation-based biomarkers were reported to predict the survival of malignant diseases. This study aims to explore the prognostic significance of the systemic immune-inflammation index(SII), which is calculated using absolute platelet, neutrophil, and lymphocyte counts, among patients with invasive mucinous adenocarcinoma. MethodsFrom January 2015 to December 2019, 106 patients were identified as having IMA accepted radical resection and enrolled in the retrospective study. We analyzed the overall survival and disease-free survival using the Kaplan-Meier method and log-rank test. Receiver operating characteristic curve was used to find the optimal SII cut-off values for survival. A Cox regression model was carried out for multivariable analyses. ResultsThe study cohort included 53 men and 53 women, with a mean age of 60 years (range 29 to 78 years, median 61 years). The median SII measured before surgery was 378.47 (range: 79.87–1701.97). ROC analyses revealed that the optimal cut-off values of SII was 379.43 for predicting both OS and DFS. An elevated SII (≥379.43) was observed in 52 patients (49.1 %), and was associated with younger age (P = 0.02), advanced T staging (P = 0.042), lymph node metastasis (P = 0.018) and pneumonic-type IMA (P = 0.018). Multivariable analysis showed that SII and pneumonic-type IMA were independent prognostic predictors of OS and DFS in radically resected IMA patients (P < 0.05). ConclusionHigh SII is correlated with worse outcome and can be a novel prognostic biomarker for IMA patients accepted radical surgery.

EP07.01-01 Nomogram for Predicting Prognosis and Adjuvant Chemotherapy Benefits in Early-stage Invasive Mucinous Lung Adenocarcinoma

EP07.01-01 Nomogram for Predicting Prognosis and Adjuvant Chemotherapy Benefits in Early-stage Invasive Mucinous Lung Adenocarcinoma

Invasive mucinous adenocarcinoma of the lung: clinicopathological features, 18F-FDG PET/CT findings, and survival outcomes.

Invasive mucinous adenocarcinoma (IMA) is a rare subtype of lung adenocarcinoma. This study aimed to retrospectively evaluate the clinicopathological features, 18F-FDG PET/CT findings, and prognosis of IMA of the lung, as well as to investigate the associations among these variables, to improve the management of such patients. Clinicopathological and 18F-FDG PET/CT characteristics of 72 patients with pathologically confirmed IMA of the lung were retrospectively collected and investigated, and their predictive efficacy on progression-free survival (PFS) was evaluated. The median age of the enrolled 72 patients was 61years (range, 26-79years), and the male-to-female ratio was 1:1.25. According to the radiological morphology of IMA, solidary nodule/mass type (n = 59, 81.9%) was the most common, followed by GGO type (n = 8, 11.1%) and pneumonia type (n = 5, 6.9%). Lobulated or spiculated margin and pleural traction were the most common radiological signs. The median SUVmax of IMA lesions was 3.0, ranging from 0.5 to 23.1. Higher SUVmax was observed in IMA with non-GGO type, clinical symptom, advanced stage, lobulated margin, pleural traction or spread through air spaces (STAS) (P < 0.05). Moreover, higher SUVmax was related to larger tumor size in non-pneumonia-type IMA (r = 0.708, P < 0.001). The median PFS was 21.3months, and the 12-, 24- and 36-month PFS rates were 89.8%, 83.3% and 75.5%, respectively. A poorer PFS was significantly associated with SUVmax ≥ 3, advanced stage and STAS. 18F-FDG PET/CT combined with clinicopathological characteristics can aid the diagnosis and prognostic evaluation of lung IMA, which could provide guidance for the appropriate management of such patients.

Efficacy of afatinib in patients with advanced/metastatic solid tumors harboring NRG1 gene fusions: A novel, prospective real-world outcomes study based on single-patient protocol data.

TPS3180 Background: Oncogenic neuregulin 1 ( NRG1) gene fusions occur in ̃0.2% of solid tumors overall and in up to 31% of cases of invasive mucinous lung adenocarcinoma [Laskin et al. Ann Oncol. 2020;31(12):1693–1703; Cadranel et al. Oncologist. 2021;26(1):7–16]. NRG1 fusion proteins provide an extracellular anchor for the epidermal growth factor (EGF) domain of NRG1 to bind to ErbB3 (HER3), leading to HER3 heterodimerization and activation of downstream signaling pathways, resulting in oncogenesis. Afatinib, an irreversible pan-ErbB tyrosine kinase inhibitor, represents a potential treatment for NRG1-fusion positive ( NRG1+) tumors. This study aims to examine the safety and efficacy of afatinib in patients with NRG1+ solid tumors, for which no authorized targeted therapy exists. Methods: This prospective, decentralized, US study (NCT05107193) will include 40 evaluable patients aged ≥18 years. Participating molecular test providers across the USA will identify eligible fusions in the course of routine diagnostic assays. When a patient with an NRG1 fusion is identified, participating test providers will notify the treating physician of the study as a treatment option for the patient. Patients’ primary oncologists will then contact the trial sponsor to confirm patient eligibility. Once approved by the central Institutional Review Board, patients will receive afatinib on a single-patient protocol basis, until disease progression or treatment is no longer tolerated. The recommended dosage per SmPC is 40 mg orally QD. Patients will be screened and enrolled into the study at their existing point-of-care setting. Inclusion criteria include a histologically or cytologically confirmed diagnosis of an advanced, unresectable/metastatic, non-hematologic malignancy with an NRG1 fusion, evaluable per RECIST 1.1. Any coding gene as the NRG1 fusion partner is permitted. Fusion status will be confirmed prospectively by a contracted molecular test provider. Exclusion criteria include prior systemic anti-cancer therapy or investigational drug within 14 days or 5 half-lives (whichever is shorter) of the start of afatinib treatment; an actionable driver mutation other than NRG1 fusion for which FDA-approved targeted therapy is available; and prior treatment with an ErbB-targeted therapy. The primary endpoint of the study is confirmed objective response (OR) by independent central review per RECIST 1.1, defined as best overall response of either complete response or partial response and analysed as the proportion of patients with an OR. The key secondary endpoint is duration of response, defined as the time from the first documented OR to progression or death. Secondary endpoints include time to OR and disease control per investigator assessment. Safety will also be assessed. The study is open for recruitment. Clinical trial information: NCT05107193.

Anaplastic lymphoma kinase fusion protein expression is associated with a favorable prognosis in resected invasive mucinous lung adenocarcinoma: A retrospective study from two Chinese tertiary hospitals.

Invasive mucinous adenocarcinoma (IMA) is a distinct variant of lung adenocarcinoma, which typically has a worse survival. However, its pathogenesis is potentially associated with a high degree of molecular heterogeneity, which might determine its different prognosis. We retrospectively analyzed 2207 consecutive lung adenocarcinoma patients who underwent radical resection at Qilu Hospital of Shandong University and Shandong Provincial Hospital from 2013 to 2019. Anaplastic lymphoma kinase (ALK) fusion protein expression was routinely detected by immunohistochemistry. The clinicopathological characteristics and treatment outcomes of IMA patients were retrieved, and compared between ALK-positive and ALK-negative IMA patients as well as between pure IMA and mixed IMA patients. The last follow-up was on December 31, 2020, and the median follow-up was 42 months. A total of 98 patients (4.4%) were diagnosed with IMA. ALK protein expression was positive in 24.5% of IMAs, which was significantly higher than that of non-IMA lung adenocarcinomas (4.7%, P < 0.001). ALK-positive and ALK-negative IMA, as well as pure IMA and mixed IMA, showed similar distribution in terms of patients' age, gender and smoking history, stage, and primary tumor location, except for a higher rate of lymph node metastasis in mixed IMA (22.0% vs. 46.2%, P = 0.012). Five cases (20.8%) of ALK-positive IMAs and 28 cases (40.6%) of ALK-negative IMAs experienced recurrence. Multivariable-adjusted Cox regression analysis demonstrated that ALK expression was a favorable prognostic factor for both disease-free survival (hazard ratio [HR]: 0.354; 95% confidence interval [CI]: 0.131-0.960; P = 0.041) and overall survival (HR: 0.138; 95% CI: 0.029-0.658; P = 0.013) in resected IMA. No difference in disease-free survival (HR: 0.524; 95% CI: 0.237-1.157; P = 0.110) and OS (HR: 0.553; 95% CI: 0.199-1.537; P = 0.256) was observed between pure IMA and mixed IMA. Invasive mucinous lung adenocarcinoma showed higher ALK protein expression, which was a favorable prognostic factor for survival in early resected patients.

The HNF4α-BC200-FMR1-Positive Feedback Loop Promotes Growth and Metastasis in Invasive Mucinous Lung Adenocarcinoma.

Invasive mucinous lung adenocarcinoma (IMA) is a subtype of lung adenocarcinoma with a strong invasive ability. IMA frequently carries "undruggable" KRAS mutations, highlighting the need for new molecular targets and therapies. Nuclear receptor HNF4α is abnormally enriched in IMA, but the potential of HNF4α to be a therapeutic target for IMA remains unknown. Here, we report that P2 promoter-driven HNF4α expression promotes IMA growth and metastasis. Mechanistically, HNF4α transactivated lncRNA BC200, which acted as a scaffold for mRNA binding protein FMR1. BC200 promoted the ability of FMR1 to bind and regulate stability of cancer-related mRNAs and HNF4α mRNA, forming a positive feedback circuit. Mycophenolic acid, the active metabolite of FDA-approved drug mycophenolate mofetil, was identified as an HNF4α antagonist exhibiting anti-IMA activities in vitro and in vivo. This study reveals the role of a HNF4α-BC200-FMR1-positive feedback loop in promoting mRNA stability during IMA progression and metastasis, providing a targeted therapeutic strategy for IMA. SIGNIFICANCE: Growth and metastatic progression of invasive mucinous lung adenocarcinoma can be restricted by targeting HNF4α, a critical regulator of a BC200-FMR1-mRNA stability axis.

Development and validation of a nomogram for predicting survival in patients with surgically resected lung invasive mucinous adenocarcinoma.

BackgroundLung invasive mucinous adenocarcinoma (LIMA) is a unique and rare subtype of lung adenocarcinoma. We identified prognostic factors and developed a nomogram for predicting overall survival (OS) in LIMA patients after surgery.MethodsPatients diagnosed with LIMA between 2008 and 2016 from the Surveillance, Epidemiology, and End Results (SEER) database were randomized into training (n=1,254) and test (n=538) cohorts. A nomogram was established using the prognostic signature from the training cohort after multivariable Cox regression analysis. We externally validated the nomogram in a group of 369 patients from China. We separately tested for accuracy and clinical practicability using Harrell’s concordance-index (C-index), calibration plots, and decision curve analysis (DCA).ResultsWe included 2,161 patients in the analysis. Seven factors, all of which significantly affected OS, were incorporated into the final model, including age, sex, differentiation grade, the extent of surgery, lymphadenectomy, and T, N, and M stage. C-indexes for the training, test, and external validation cohorts were 0.735, 0.736, and 0.773, respectively. The areas under the time-dependent receiver operating characteristic curves at five years were 0.747, 0.798, and 0.777, respectively. The nomogram was discriminative and well-calibrated when applied to the test and external validation cohorts. Significant between-group differences in OS were observed when classifying groups by nomogram score (log-rank P<0.001). An online web server for clinical use was developed using the nomogram.ConclusionsThe nomogram facilitates accurate prediction of survival for patients with LIMA and can be used to stratify clinical risk groups for individualized treatment.

Clinical Relevance of PD-L1 Expression and CD8+ T Cells' Infiltration in Patients With Lung Invasive Mucinous Adenocarcinoma.

BackgroundInvasive mucinous adenocarcinoma (IMA) of the lung is a rare and distinct subtype of adenocarcinoma. At present, people have no idea whether IMA patients can benefit from immunotherapy and target therapy; thus there is an urgent need to clarify the immune microenvironment and genetic characteristics of this cohort.MethodsA total of 31 IMA patients matched with 27 non-mucinous adenocarcinoma (non-IMA) patients were enrolled in this study, and clinical data was collected. The expression of PD-L1, CD8+ tumor-infiltrating lymphocytes (TILs) and ALK was determined by immunohistochemistry. Polymerase Chain Reaction was used to determine the mutations of EGFR. The Chi-square test, Kaplan–Meier method and Cox proportional hazard regression model were used to explore the correlations between these clinicopathological variables, survival and identify risk factors.ResultsOf the patients with IMA 9.7% (3/31) revealed positive PD-L1 expression and 35.5% (11/31) showed CD8+ TIL infiltration, which were markedly lower than that of non-IMA group [PD-L1: 48.1% (13/27); CD8: 81.5% (22/27)]. Moreover, five (16.1%) patients in IMA group and 10 (37.0%) patients in non-IMA group had EGFR mutations, and nine (29.0%) patients in IMA group and zero (0.0%) patient in non-IMA group had ALK rearrangements. Additionally, we observed that IMA patients with CD8+ TIL infiltration had a worse prognosis than CD8-negative group (P = 0.024). Multivariate analyses showed that CD8 was an independent prognostic factor for patient’s survival (HR = 5.60, 95% CI: 1.35–23.22, P = 0.017).ConclusionPatients with IMA have down-regulated expression of PD-L1 and less CD8+ TIL infiltration in tumor microenvironment. Besides, a lower frequency of EGFR mutations was detected in patients with IMA than non-IMA patients while a higher rate of ALK rearrangements was found. Our results provide important reference for therapy of lung IMA.

Novel Preclinical Patient-Derived Lung Cancer Models Reveal Inhibition of HER3 and MTOR Signaling as Therapeutic Strategies for NRG1 Fusion-Positive Cancers

IntroductionNRG1 rearrangements produce chimeric ligands that subvert the ERBB pathway to drive tumorigenesis. A better understanding of the signaling networks that mediate transformation by NRG1 fusions is needed to inform effective therapeutic strategies. Unfortunately, this has been hampered by a paucity of patient-derived disease models that faithfully recapitulate this molecularly defined cancer subset. MethodsPatient-derived xenograft (PDX) and cell line models were established from NRG1-rearranged lung adenocarcinoma samples. Transcriptomic, proteomic, and biochemical analyses were performed to identify activated pathways. Efficacy studies were conducted to evaluate HER3- and MTOR-directed therapies. ResultsWe established a pair of PDX and cell line models of invasive mucinous lung adenocarcinoma (LUAD) (LUAD-0061AS3, SLC3A2-NRG1), representing the first reported paired in vitro and in vivo model of NRG1-driven tumors. Growth of LUAD-0061AS3 models was reduced by the anti-HER3 antibody GSK2849330. Transcriptomic profiling revealed activation of the MTOR pathway in lung tumor samples with NRG1 fusions. Phosphorylation of several MTOR effectors (S6 and 4EBP1) was higher in LUAD-0061AS3 cells compared with human bronchial epithelial cells and the breast cancer cell line MDA-MB-175-VII (DOC4-NRG1 fusion). Accordingly, LUAD-0061AS3 cells were more sensitive to MTOR inhibitors than MDA-MB-175-VII cells and targeting the MTOR pathway with rapamycin blocked growth of LUAD-0061AS3 PDX tumors in vivo. In contrast, MDA-MB-175-VII breast cancer cells had higher MAPK pathway activation and were more sensitive to MEK inhibition. ConclusionsWe identify the MTOR pathway as a candidate vulnerability in NRG1 fusion-positive lung adenocarcinoma that may warrant further preclinical evaluation, with the eventual goal of finding additional therapeutic options for patients in whom ERBB-directed therapy fails. Moreover, our results uncover heterogeneity in downstream oncogenic signaling among NRG1-rearranged cancers, possibly tumor type-dependent, the therapeutic significance of which requires additional investigation.

Nanog maintains stemness of Lkb1-deficient lung adenocarcinoma and prevents gastric differentiation.

Growing evidence supports that LKB1‐deficient KRAS‐driven lung tumors represent a unique therapeutic challenge, displaying strong cancer plasticity that promotes lineage conversion and drug resistance. Here we find that murine lung tumors from the KrasLSL‐G12D/+; Lkb1flox/flox (KL) model show strong plasticity, which associates with up‐regulation of stem cell pluripotency genes such as Nanog. Deletion of Nanog in KL model initiates a gastric differentiation program and promotes mucinous lung tumor growth. We find that NANOG is not expressed at a meaningful level in human lung adenocarcinoma (ADC), as well as in human lung invasive mucinous adenocarcinoma (IMA). Gastric differentiation involves activation of Notch signaling, and perturbation of Notch pathway by the γ‐secretase inhibitor LY‐411575 remarkably impairs mucinous tumor formation. In contrast to non‐mucinous tumors, mucinous tumors are resistant to phenformin treatment. Such therapeutic resistance could be overcome through combined treatments with LY‐411575 and phenformin. Overall, we uncover a previously unappreciated plasticity of LKB1‐deficient tumors and identify the Nanog‐Notch axis in regulating gastric differentiation, which holds important therapeutic implication for the treatment of mucinous lung cancer.

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.