ABSTRACT
PURPOSE: The clinicopathological or genetic features related to the prognosis of mucinous adenocarcinoma are unknown because of its rarity. The clinicopathological or targetable features were investigated for better management of patients with mucinous adenocarcinoma of the lung. METHODS: We comprehensively evaluated the clinicopathological and genetic features of 60 completely resected mucinous lung adenocarcinomas. Targetable genetic variants were explored using nCounter and polymerase chain reaction, PD-L1 and TTF-1 expression were evaluated using immunohistochemistry. We analyzed the prognostic impact using the Kaplan-Meier method and log-rank test. RESULTS: Of the 60 enrolled patients, 13 (21.7%) had adenocarcinoma in situ/minimally invasive adenocarcinoma, and 47 (78.3%) had invasive mucinous adenocarcinoma (IMA). Fifteen patients (25%) showed a pneumonic appearance on computed tomography (CT). CD74-NRG1 fusion, EGFR mutations, and BRAF mutation were detected in three (5%), four (6.7%), and one (1.7%) patient(s), respectively. KRAS mutations were detected in 31 patients (51.7%). Two patients (3.5%) showed immunoreactivity for PD-L1. No in situ or minimally invasive cases recurred. IMA patients with pneumonic appearance had significantly worse recurrence-free survival (RFS) and overall survival (OS) (p < 0.001). Furthermore, IMA patients harboring KRAS mutations had worse RFS (p = 0.211). Multivariate analysis revealed that radiological pneumonic appearance was significantly associated with lower RFS (p < 0.003) and OS (p = 0.012). KRAS mutations served as an unfavorable status for RFS (p = 0.043). CONCLUSION: Mucinous adenocarcinoma had a low frequency of targetable genetic variants and PD-L1 immunoreactivity; however, KRAS mutations were frequent. Pneumonic appearance on CT imaging and KRAS mutations were clinicopathological features associated with a worse prognosis.
Subject(s)
Adenocarcinoma, Mucinous/genetics , Adenocarcinoma, Mucinous/pathology , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , Mutation , Neoplasm Recurrence, Local/genetics , Neoplasm Recurrence, Local/pathology , Prognosis , Progression-Free Survival , Proto-Oncogene Proteins p21(ras)/genetics , Retrospective StudiesABSTRACT
BACKGROUND: In a significant percentage of advanced non-small cell lung cancer (NSCLC) patients, tumor tissue is unavailable or insufficient for genetic analyses at time to progression. We prospectively analyzed the appearance of genetic alterations associated with resistance in liquid biopsies of advanced NSCLC patients progressing to targeted therapies using the NGS platform. METHODS: A total of 24 NSCLC patients were included in the study, 22 progressing to tyrosine kinase inhibitors and two to other treatments. Liquid biopsies samples were obtained and analyzed using the GeneReadTM QIAact Lung DNA UMI Panel, designed to enrich specific target regions and containing 550 variant positions in 19 selected genes frequently altered in lung cancer tumors. Previously, a retrospective validation of the panel was performed in clinical samples. RESULTS: Of the 21 patients progressing to tyrosine kinase inhibitors with valid results in liquid biopsy, NGS analysis identified a potential mechanism of resistance in 12 (57%). The most common were acquired mutations in ALK and EGFR, which appeared in 8/21 patients (38%), followed by amplifications in 5/21 patients (24%), and KRAS mutations in one patient (5%). Loss of the p.T790M was also identified in two patients progressing to osimertinib. Three of the 21 (14%) patients presented two or more concomitant alterations associated with resistance. Finally, an EGFR amplification was found in the only patient progressing to immunotherapy included in the study. CONCLUSIONS: NGS analysis in liquid biopsies of patients progressing to targeted therapies using the GeneReader platform is feasible and can help the oncologist to make treatment decisions.
ABSTRACT
Antecedentes. El oncogén HER2/neu es un determinante biológico predictivo esencial en el cáncer de mama por su papel como diana terapéutica del trastuzumab. No obstante, no se ha llegado aún a consensuar un método de referencia para su estudio. Métodos. En este trabajo, hemos aplicado y comparado, sobre 222 carcinomas de mama recopilados prospectivamente, los dos ensayos de uso más frecuente para determinar el estado de HER2/neu: inmunohistoquímica para expresión de la proteína p185 empleando dos anticuerpos monoclonales (CB11 y TAB250) e hibridación in situ fluorescente (FISH), utilizando secciones de tejido incluido en parafina. Resultados. Los resultados demuestran mayor sensibilidad y especificidad con CB11 (62,5% y 93,4% respectivamente) que con TAB250 (40% y 76,4% respectivamente). El estudio inmunohistoquímico con CB11 es adecuado como prueba inicial para predecir el estado del gen, proporciona un alto valor predictivo negativo (95,5%) en los casos de expresión débil o nula y positivo (96,2%) en los tumores con sobreexpresión. Si la expresión inmunohistoquímica es moderada debe considerarse no concluyente y es indispensable el estudio de FISH. También es recomendable aplicar FISH si hay discordancia entre la expresión de p185 y el perfil morfológico y/o molecular tumoral. Finalmente, aunque la tasa de falsos positivos producidos por estudios inmunohistoquímicos es inferior al 5%, debido a la toxicidad y coste de la terapia con trastuzumab es razonable considerar el empleo sistemático de FISH antes de indicar el tratamiento. Conclusión. En base a nuestros resultados proponemos un protocolo para el estudio molecular de HER2/neu
Background. The HER2/neu proto-oncogene is frequently over-expressed in breast cancer and serves as a biological target for trastuzumab therapy. However, there is no consensus regarding the technical aspects to be used to define HER2/neu status in clinical practice. Methods. The present study was conducted to address this critical issue by prospectively analysing a large cohort of breast cancer patients (n=222) and using a variety of methods. To define HER2/neu expression, detection of its encoded protein (p185) was performed by comparative immunohistochemical (IHC) analysis using two mouse monoclonal antibodies (mAb CB11 and mAb TAB250). To assess HER2/neu gene amplification, fluorescent in situ hybridisation (FISH) assays with gene-specific probes were conducted. All procedures were applied to de-paraffinised tissue sections of breast tumour samples. Results. Results showed that mAb CB11 had increased sensitivity and specificity (62.5% and 93.4%, respectively) compared to mAb TAB250 (40% and 76.4%, respectively) in defining HER2/neu amplification. We conclude that HER2/neu measurement by IHC using mAb CB11 is an appropriate strategy which provides a high negative predictive value (95.5%) for HER2/neu amplification in cases with low or undetectable p185 expression. Conversely, mAb CB11 has a high positive predictive value (96.2%) for HER2/neu amplification in cases with p185 overexpression. However, cases with moderate p185 expression need to be considered as inconclusive. In such cases, it is necessary to use FISH measurement to evaluate HER2/neu amplification. It is also advisable to conduct FISH if there is discordance between p185 expression and the histopathology classification of the lesion, or molecular profile of the tumour. Finally, even though the false positive rate of IHC assay is <5%, the toxicity and cost of trastuzumab therapy suggest that FISH be used systematically prior to implementation of treatment. Conclusion. We suggest the use of a molecular protocol for HER2/neu analysis in this type of tumor
