There is still a role for cytology in the ‘liquid biopsy’ era. A lesson from a TKI-treated patient showing adenocarcinoma to squamous cell carcinoma transition during disease progression

2017 ◽  
Vol 70 (9) ◽  
pp. 798-802 ◽  
Author(s):  
Eduardo Clery ◽  
Pasquale Pisapia ◽  
Salvatore Feliciano ◽  
Elena Vigliar ◽  
Antonio Marano ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Disease Progression ◽  
Squamous Cell ◽  
Liquid Biopsy ◽  
Treated Patient ◽  
Small Cell Lung Carcinoma ◽  
Resistance Mechanisms ◽  
Blood Draw ◽  
Cell Lung Carcinoma

Non-small cell lung carcinoma harbouring epidermal growth factor receptor (EGFR) mutation, usually progress after an initial response to tyrosine-kinase inhibitors (TKI). Liquid biopsy enables with a simple blood draw the accurate detection ofEGFRp.T790M mutation, the most common resistance mechanism, avoiding the more invasive tissue re-biopsy. However, in a subset of cases, resistance mechanisms are more complex featuring both genetic and morphological changes. Here we report the case of a 67 years-old woman, affected by anEGFRmutated lung adenocarcinoma and treated by TKI. At disease progression, the patient developed a morphological transition to squamous cell carcinoma in association to the arising of aPIK3CAp.E542K mutant subclone. This case illustrates that, even in the “liquid biopsy” era, cytology can have still a role by providing an overall assessment of both morphology and genetic TKI resistance mechanisms.

Exome scale liquid biopsy characterization of putative neoantigens and genomic biomarkers pre- and post anti-PD-1 therapy in squamous cell carcinoma of the head and neck.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 6557-6557
Author(s):  
Charles Abbott ◽  
Nikita Bedi ◽  
Simo V Zhang ◽  
Robin Li ◽  
Rachel Pyke ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Head And Neck ◽  
Squamous Cell ◽  
Solid Tumor ◽  
Liquid Biopsy ◽  
Resistance Mechanisms ◽  
Post Treatment ◽  
Plasma Samples ◽  
Liquid Biopsies

6557 Background: The reduced scope, and number of genes profiled by typical liquid biopsy panels can result in missed biomarkers including neoantigens, which may change with treatment, as well as potentially undetected resistance mechanisms and pathways beyond the scope of targets typically captured by panels. To address these limitations, we used a whole-exome scale liquid biopsy monitoring platform, NeXT Liquid Biopsy, to analyze head and neck squamous cell carcinoma (HNSCC) patients that have received anti-PD1 therapy. Presently, we sought to (1) monitor neoantigen changes in cfDNA as a complement to tumor biopsy-derived neoantigens, (2) compare the impact of tumor escape mechanisms, including HLA-LOH, on neoantigens identified in tissue and cfDNA and (3) to identify novel biological signatures that combine information from both solid tumor and liquid biopsies. Methods: Pre- and post-intervention matched normal, tumor and plasma samples were collected from a cohort of 12 patients with HNSCC. Following baseline sample collection all patients received a single dose of nivolumab, followed by resection approximately one month later when feasible, or a second biopsy where resection was impractical. Solid tumor and matched normal samples were profiled using ImmunoID NeXT, an augmented exome/transcriptome platform and analysis pipeline. Exome-scale somatic variants were identified in cfDNA from plasma samples using the NeXT Liquid Biopsy platform. Data from these two platforms were compared with corresponding clinical findings. Results: Concordant somatic events were detected between plasma and tumor at pre- and post-treatment timepoints. Neoantigens predicted to arise from these somatic events were reduced in solid tumor post-treatment, but increased in cfDNA, when compared to pre-treatment timepoints. HLA LOH was identified in a number of subjects, likely resulting in reduced neoepitope presentation in those cases. Immune cell infiltration increased in the tumor following treatment, with no changes to the CD8+/Treg cell ratio, suggesting consistent immunoregulation. Conclusions: Exome-wide neoantigen burden was reliably predicted from cfDNA, providing additional insight complementing data from solid tumor. Analyzing HLA LOH, and neoantigen burden from both solid and liquid biopsies together over the course of treatment creates a more comprehensive profile of therapeutic response and resistance mechanisms in HNSCC patients missed with typical liquid biopsy panels.

Association of serum level of YKL-40 in patients with squamous cell carcinoma of the head and neck with survival

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 5551-5551
Author(s):  
A. Roslind ◽  
J. S. Johansen ◽  
I. J. Christensen ◽  
J. Bentzen ◽  
D. L. Nielsen ◽  
...  
Keyword(s):  
Overall Survival ◽  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Head And Neck ◽  
Squamous Cell ◽  
Small Cell Lung Carcinoma ◽  
Univariate Analysis ◽  
High Serum ◽  
Cell Lung Carcinoma ◽  
Stage 1

5551 Background: High serum YKL-40 is associated with poor prognosis in breast-, colorectal-, ovarian-, prostate-, small cell lung carcinoma and malignant melanoma. YKL-40 is secreted by cancer cells, macrophages and neutrophils. Its function in cancer is unknown. It may be a growth factor, play a role in angiogenesis or protect against apoptosis. The aim was to examine serum YKL-40 in patients with squamous cell carcinoma of the head and neck (SCCHN). Methods: YKL-40 was determined by ELISA (Quidel, Santa Clara, CA) in serum samples from 138 patients with SCCHN (median age 60, range 44–92 years) before surgery and/or fractionated radiotherapy (total dose of 60–68 Gy, 2-Gy fractions). 42 patients had stage 1, 28 stage 2, 22 stage 3, and 46 stage 4 disease. The median follow-up time was 4.0 years (range 15 days–8.5 years). 91 patients had died. Results: Serum YKL-40 was increased (p < 0.001) in patients with SCCHN (median 120 μg/l, range 25–1848 μg/l) compared to healthy controls (43 μg/l, 20–184 μg/l, n = 245). Serum YKL-40 was elevated in 52% of the patients. Patients with stage 1 disease had lower, but non-significant, serum YKL-40 compared to patients with stage 2–4 disease (median 113 μg/l, range 25–1000 μg/l vs. 139 μg/l, 29–1848 μg/l, p = 0.06). Patients with high serum YKL-40 had significantly shorter survival than patients with normal serum YKL-40 (33 months vs. 74 months, p = 0.01 logrank test). Univariate analysis of serum YKL-40 (log transformed and treated as a continuous covariate) showed significant association with overall survival after start of therapy (HR = 1.4, 95% CI: 1.2–1.7, p = 0.0004). Multivariate Cox analysis including age, stage and serum YKL-40 (log transformed and treated as a continuous variable) showed that stage (stage 3–4 vs. stage 1–2, HR = 3.0, 95% CI: 1.9–4.6, p < 0.0001) and serum YKL-40 (HR = 1.5, 95% CI: 1.2–1.8, p = 0.0003) were independent prognostic variables of overall survival. Conclusions: Serum YKL-40 is a prognostic biomarker of overall survival in SCCHN patients. No significant financial relationships to disclose.

α-Methylacyl CoA Racemase in Pulmonary Adenocarcinoma, Squamous Cell Carcinoma, and Neuroendocrine Tumors: Expression and Survival Analysis

2007 ◽  
Vol 131 (10) ◽  
pp. 1555-1560
Author(s):  
Konstantin Shilo ◽  
Tatiana Dracheva ◽  
Haresh Mani ◽  
Junya Fukuoka ◽  
Isabell A. Sesterhenn ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Lung Carcinoma ◽  
Small Cell Lung Carcinoma ◽  
Large Cell ◽  
Small Cell ◽  
Stage I ◽  
Small Cell Lung ◽  
Cell Lung Carcinoma

Abstract Context.—α-Methylacyl CoA racemase (AMACR) is an oxidative enzyme involved in isomeric transformation of fatty acids entering the beta-oxidation pathway. AMACR serves as a useful marker in establishing a diagnosis of prostatic malignancy; however, limited information is available in regard to its presence in pulmonary neoplasms. Objective.—To investigate AMACR expression within a spectrum of lung carcinomas and its correlation with patients' survival. Design.—Four hundred seventy-seven pulmonary carcinomas, including 150 squamous cell carcinomas, 150 adenocarcinomas, 46 typical carcinoids, 31 atypical carcinoids, 28 large cell neuroendocrine carcinomas, and 72 small cell carcinomas, were studied immunohistochemically using tissue microarray–based samples. Results.—Overall, pulmonary tumors were positive for AMACR in a significant percentage (47%) of cases. Among tumor types, 22% of squamous cell carcinoma, 56% of adenocarcinoma, 72% of typical carcinoid, 52% of atypical carcinoid, 70% of large cell neuroendocrine carcinoma, and 51% of small cell lung carcinoma were positive for AMACR. Furthermore, the Kaplan-Meier analysis revealed that the patients with AMACR-positive small cell carcinoma had better survival (19% vs 5% after 5 years, P = .04) than patients with AMACR-negative tumors. Such survival advantage was seen for patients with stage I–II (P = .01) but not stage III–IV small cell carcinomas (P = .58). Conclusions.—These results indicate that, similar to prostate cancer, the overexpression of AMACR frequently occurs in pulmonary carcinomas. Additionally, its positive correlation with outcome of stage I–II small cell lung carcinoma warrants further investigation of the AMACR role in the prognosis of this tumor.

scholarly journals 20 Tumor-informed liquid biopsy monitoring of evolving therapeutic resistance mechanisms in head and neck squamous cell carcinoma patients receiving anti-PD-1 therapy

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A22-A22
Author(s):  
Charles Abbott ◽  
Nikita Bedi ◽  
Jing Wang ◽  
Josette Northcott ◽  
Rachel Pyke ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Head And Neck ◽  
Squamous Cell ◽  
Liquid Biopsy ◽  
Tumor Biology ◽  
Resistance Mechanisms ◽  
Neck Squamous Cell Carcinoma ◽  
Plasma Samples ◽  
Hla Alleles

BackgroundTypical liquid biopsy panels offer a limited understanding of tumor biology, potentially under-representing the heterogeneity of resistance in late-stage cancers. Here, diminished scope can result in undetected, therapeutically-relevant biomarkers which respond dynamically to treatment, as well as potentially missed resistance mechanisms and pathway-level events. To address the challenges associated with identifying multiple concurrent heterogeneous resistance mechanisms in individual patients, we evaluated longitudinal exome-scale tumor-informed cell-free DNA (cfDNA) data from head and neck squamous cell carcinoma (HNSCC) patients receiving anti-PD1 therapy.MethodsPre- and post-intervention matched tumor, normal and plasma samples were retrospectively obtained from 15 stage II-IV HNSCC patients. Following baseline sample collection, all patients received a single dose of nivolumab or pembrolizumab. The primary tumor was then resected approximately one month later when possible, or a second biopsy collected where resection was impractical. Paired tumor and normal samples were then profiled using ImmunoID NeXT Platform®, an augmented exome/transcriptome platform and analysis pipeline. Exome-scale cfDNA profiling of matched plasma samples was performed using the NeXT Liquid BiopsyTM platform to detect somatic variants.ResultsPatient neoantigen presentation score (NEOPSTM) rapidly and significantly contracted following therapy (p=.00098). Novel neoantigens arising post-treatment which were predicted to be presented on lost HLA alleles were significantly higher in patients with longer overall survival (p=.019). Variant detection across same-patient serial cfDNA samples revealed significantly correlated VAFs (R=.62, p<.0001) despite significant contraction of mutational burden in solid tumor (p=.0039), suggesting complex clonal/subclonal dynamics. Investigation of the evolving tumor and cfDNA subclonal architecture revealed significant association between decreasing cellular prevalence and NOTCH signaling (q=.001) and the innate immune system (q=.002), while increasing cellular prevalence was associated with p53 signalling (q=.02) and hypoxia (q=.02). These findings were complimented by transcriptomic data which showed significant enrichment of multiple immune pathways across treatment.ConclusionsWe found that immune checkpoint blockade precipitates rapid evolution of the HNSCC tumor microenvironment. By leveraging comprehensive, tumor-informed liquid biopsy data we were able to identify contracting cellular populations enriched for NOTCH pathway mutations. Longer OS following either intervention was associated with an expansion of novel neoantigens predicted to be presented by lost HLA alleles. Our results suggest that tumor-informed liquid biopsy provides a more robust understanding of therapeutic response and resistance mechanisms than that attainable with typical liquid biopsy panels alone.Ethics ApprovalThis study obtained ethics approval from Human Subjects Research at Stanford University. ID number is 40425. All participants gave informed consent prior to enrollment.

scholarly journals Case Report: Partial Response Following Nivolumab Plus Docetaxel in a Patient With EGFR Exon 20 Deletion/Insertion (p.N771delinsGF) Mutant Lung Adenocarcinoma Transdifferentiated From Squamous Cell Carcinoma

2022 ◽  
Vol 9 ◽  
Author(s):  
Lingling Zhu ◽  
Yanyang Liu ◽  
Honglin Gao ◽  
Jiewei Liu ◽  
Qinghua Zhou ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Lung Adenocarcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Small Cell Lung Carcinoma ◽  
Lung Squamous Cell Carcinoma ◽  
Insertion Mutation ◽  
Cell Lung Carcinoma ◽  
Histological Transformation ◽  
Exon 20

The histological transformation from lung squamous cell carcinoma (LUSC) to lung adenocarcinoma (LUAD) and p. N771delinsGF mutations in EGFR exon 20 (ex20) are exceedingly rare in non–small cell lung carcinoma (NSCLC). EGFR ex20 mutations are insensitive to EGFR tyrosine kinase inhibitors in NSCLC. Here, we present a 76-year-old male smoker harboring LUAD with a novel p. N771delinsGF deletion/insertion mutation in EGFR ex20 transdifferentiating from advanced LUSC after chemoradiotherapy. The patient presented reduced hydrothorax and relieved tightness with the treatment of nivolumab plus docetaxel and carboplatin after the failure of second-line chemotherapy. The case highlights the importance of rebiopsy and molecular retesting after the progression of lung cancer and supports the idea that the combination of immune checkpoint blockade and chemotherapy may be an attractive option for patients with EGFR ex20 mutations associated with LUSC–LUAD transformation.

Expression of programmed death-ligand 1 protein in pulmonary squamous cell carcinoma correlates with tumour necrosis but not with tumour differentiation

2021 ◽  
pp. jclinpath-2020-207171
Author(s):  
Vladimír Tancoš ◽  
Anna Farkašová ◽  
Zuzana Kviatkovská ◽  
Marián Grendár ◽  
Alena Líšková ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Tumour Necrosis ◽  
Small Cell Lung Carcinoma ◽  
Tumour Mass ◽  
Cell Lung Carcinoma ◽  
Programmed Death Ligand 1 ◽  
Programmed Death ◽  
Tumour Differentiation

AimsPulmonary squamous cell carcinoma (SqCC) represents the second most common non-small cell lung carcinoma type. The mechanisms which regulate programmed death ligand 1 (PD-L1) expression in this form of lung cancer are not fully elucidated yet.MethodsWe immunohistochemically determined the level of PD-L1 expression using the Tumour Proportion Score system in surgical resections of 133 patients with pulmonary SqCC. The results from PD-L1 immunohistochemistry were analysed in relation to tumour differentiation and the presence of necrotic areas comprising at least 20% of the tumour mass.ResultsNo significant differences in terms of PD-L1 expression were found between SqCC subtypes as defined by the current WHO classification: better differentiated, keratinising tumours (12/24, 50.0 %) compared with less differentiated, non-keratinising and basaloid forms (62/109, 56.9 %) were PD-L1 positive in a comparable proportion of cases (p=0.1903). Contrary to that, SqCCs with the presence of necrosis (51/61, 83.6 %) had significantly more PD-L1-positive cases (p<0.001) compared with SqCCs without necrotic areas (23/72, 32.0 %)ConclusionsWe demonstrated that PD-L1 expression in pulmonary SqCCs does not correlate with the traditionally defined degree of differentiation of these tumours. On the other hand, we found a significant association between the positive result of PD-L1 immunohistochemistry and tumour necrosis. Further investigation regarding the role of hypoxic pathways as presumable inducers of PD-L1 expression in pulmonary SqCCs might contribute to the understanding of this phenomenon.

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