Gene expression signatures as candidate biomarkers of response to PD-1 blockade in non-small cell lung cancers

Although anti-PD-1/PD-L1 monotherapy has achieved clinical success in non-small cell lung cancer (NSCLC), definitive predictive biomarkers remain to be elucidated. In this study, we performed whole-transcriptome sequencing of pretreatment tumor tissue samples and pretreatment and on-treatment whole blood samples (WB) samples obtained from a clinically annotated cohort of NSCLC patients (n = 40) treated with nivolumab (anti-PD-1) monotherapy. Using a single-sample gene set enrichment scoring method, we found that the tumors of responders with lung adenocarcinoma (LUAD, n = 20) are inherently immunogenic to promote antitumor immunity, whereas those with lung squamous cell carcinoma (LUSC, n = 18) have a less immunosuppressive tumor microenvironment. These findings suggested that nivolumab may function as a molecular targeted agent in LUAD and as an immunomodulating agent in LUSC. In addition, our study explains why the reliability of PD-L1 expression on tumor cells as a predictive biomarker for the response to nivolumab monotherapy is quite different between LUAD and LUSC.

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RAD51Bme as predictive biomarker for PD-1 blockade response in non-small cell lung cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e15235 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e15235-e15235

Author(s):

Inês Maria Guerreiro ◽

Daniela Barros-Silva ◽

Paula Lopes ◽

Ana Luísa Cunha ◽

João Lobo ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Clinical Benefit ◽

Checkpoint Inhibitors ◽

Predictive Biomarkers ◽

Predictive Biomarker ◽

Small Cell ◽

Small Cell Lung ◽

Dna Repair Gene

e15235 Background: Lung cancer (LC) cells frequently express high levels of programmed death-ligand 1 (PD-L1). Although these levels grossly correlate with likelihood of response to specific checkpoint inhibitors, prediction of response is rather imperfect and, thus, more accurate predictive biomarkers are mandatory. We examined the methylation profile of RAD51B, a DNA-repair gene, as candidate predictive biomarker for efficacy of anti-PD-1 therapy in patients with non-small cell lung cancer (NSCLC), correlating with patients’ outcome. Methods: PD-L1 immunoexpression and RAD51Bme levels were analysed in samples of NSCLC obtained from patients not treated with anti-PD-1 blockade (testing cohort) and patients treated with anti-PD-1 (validation cohort). Results: Of a total of 127 patients assessed, 58.3% depicted positivity for PD-L1 (PD-L1+). RAD51Bme levels significantly associated with PD-L1 immunoexpression. Patients with clinical benefit from immunotherapy disclosed higher RAD51Bme levels (p = 0.04) and significantly higher median progression free survival (PFS) (p = 0.02). PD-L1+ was also associated with longer overall survival (p = 0.03). Conclusions: We demonstrated that RAD51Bme levels might be combined with validated predictive biomarker PD-L1 immunostaining to select patients who will most likely experience clinical benefit from PD-1 blockade. The predictive value of RAD51Bme should be confirmed in prospective studies.

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Serum NY-ESO-1 and XAGE1 antibodies as predictive biomarkers in anti-PD-1 therapy for non-small-cell lung cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.8_suppl.106 ◽

2019 ◽

Vol 37 (8_suppl) ◽

pp. 106-106

Author(s):

Mikio Oka ◽

Yoshihiro Ohue ◽

Koji Kurose ◽

Takahiro Karasaki ◽

Takeshi Masuda ◽

...

Keyword(s):

Lung Cancer ◽

Serum Antibody ◽

Predictive Biomarkers ◽

Predictive Biomarker ◽

Tumor Burden ◽

Small Cell ◽

Small Cell Lung ◽

Antibody Positivity ◽

Clinical Benefits ◽

Antibody Titers

106 Background: Programmed death-1 (PD-1) inhibitors effectively treat non-small-cell lung cancer (NSCLC) and prolong survival, but the clinical benefits are limited in a small population. However, robust biomarkers for predicting clinical benefits with anti-PD-1 therapy have yet to be identified, therefore, predictive biomarkers are needed to select patients with benefits. On the other hand, NSCLC expresses NY-ESO-1 and XAGE1 cancer-testis antigens, which elicit spontaneous immune responses in NSCLC patients. Methods: We conducted a prospective multicenter study to investigate whether serum antibody against NY-ESO-1 and/or XAGE1 antigens was a predictive biomarker in anti-PD-1 therapy for NSCLC. Serum antibody was serially detected by ELISA, and antibody titers were monitored during anti-PD-1 therapy. Tumor tissues were analyzed by immunohistochemistry and whole exome sequencing. Objective response rate (ORR) and survival were the primary and secondary endpoint, respectively. Results: In the discovery cohort (n = 13), six antibody-positive NSCLC responded to anti-PD-1 therapy (two complete and four partial responses), whereas seven antibody-negative NSCLC did not. Antibody positivity was associated with good response and survival, regardless of tumor PD-ligand1 expression, mutation burden, and CD8 T-cell infiltration. In the independent validation cohort (n = 40), ten antibody-positive NSCLC obtained the significant clinical benefits with anti-PD-1 therapy as compared with 30 negative NSCLC (ORR 50% vs 6.7%, P = 0.006). In the multivariate analysis, only antibody positivity was a significantly better predictive biomarker of progression free survival (HR 0.04, 95% CI 0.0 to 0.3) and overall survival (HR 0.2, 95% CI 0.0 to 0.9) after anti-PD-1 therapy. Antibody titers in responders transiently increased with spikes and gradually decreased with tumor shrinkage after anti-PD-1 therapy, and strongly correlated with tumor reduction rates and tumor burden. Conclusions: Our results suggest that NY-ESO-1 and/or XAGE1 serum antibodies are useful biomarkers for predicting clinical benefits and monitoring tumor burden in anti-PD-1 therapy for NSCLC.

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Lung squamous cell carcinoma exhibits a targetable glucose dependency unique among non-small cell lung cancers

Molecular & Cellular Oncology ◽

10.1080/23723556.2017.1364211 ◽

2017 ◽

Vol 4 (5) ◽

pp. e1364211 ◽

Cited By ~ 2

Author(s):

Justin Goodwin ◽

Michael L. Neugent ◽

Jung-Whan Kim

Keyword(s):

Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Squamous Cell ◽

Lung Squamous Cell Carcinoma ◽

Small Cell ◽

Small Cell Lung ◽

Lung Cancers

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Development of a Prototype Immunohistochemistry Assay to Measure Programmed Death Ligand-1 Expression in Tumor Tissue

Archives of Pathology & Laboratory Medicine ◽

10.5858/arpa.2015-0544-oa ◽

2016 ◽

Vol 140 (11) ◽

pp. 1259-1266 ◽

Cited By ~ 37

Author(s):

Marisa Dolled-Filhart ◽

Darren Locke ◽

Tiffany Murphy ◽

Frank Lynch ◽

Jennifer H. Yearley ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Tumor Stroma ◽

Small Cell ◽

Small Cell Lung ◽

Scoring Method ◽

Tissue Samples ◽

Tumor Bank ◽

Programmed Death

Context.— With the abundance of therapeutics targeted against programmed death receptor-1 and its ligand (PD-L1) that are currently approved or in clinical development, there is interest in identifying those patients most likely to respond to these drugs. Expression of PD-L1 may be an indicator of an initial and robust inflammatory response to the presence of tumor cells. Therefore, tumors that express PD-L1 may be the most likely to respond to therapies that interrupt the negative feedback mechanism that leads to PD-L1 upregulation. Objective.— To develop a prototype immunohistochemistry assay using the anti–PD-L1 antibody clone 22C3. Design.— The assay was developed and optimized using commercially available reagents and archival tumor-bank tissue. Results.— The optimized immunohistochemistry method had high precision and reproducibility. Using the prototype assay in 142 non–small cell lung cancer and 79 melanoma archival tumor-bank tissue samples, PD-L1 staining was observed at the plasma membrane of nucleated tumor and nontumor cells and, in some cases, as a distinct lichenoid pattern at the tumor-stroma border. Using a preliminary scoring method, 56% (80 of 142) of non–small cell lung cancer and 53% (42 of 79) of melanoma samples were defined as PD-L1+ based on a modified H-score of 1 or more or the presence of a distinctive staining pattern at the tumor-stroma interface. Conclusions.— The immunohistochemistry assay using the anti–PD-L1 antibody 22C3 merits further investigation in clinical trials and prevalence assessments to further understand the prognostic and predictive value of PD-L1 expression in cancer.

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Changes in tumor mutational burden in serially biopsied non-small cell lung cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e14286 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e14286-e14286

Author(s):

James W. Smithy ◽

David H. Hwang ◽

Yvonne Y. Li ◽

Liam Spurr ◽

Andrew D. Cherniack ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Predictive Biomarker ◽

Small Cell ◽

Small Cell Lung ◽

Tissue Samples ◽

Primary Tumors ◽

Mutational Burden ◽

Tumor Mutational Burden

e14286 Background: High tumor mutational burden (TMB) has been associated with response to checkpoint blockade in non-small cell lung cancer (NSCLC) and other malignancies. However, the degree to which TMB changes over time, across anatomical sites, and with intervening treatment remains unknown. To evaluate TMB changes across time points, we compared TMB in tissue specimens from patients with serially-biopsied NSCLC. Methods: Clinicopathologic characteristicsand changes in TMB were analyzed from patients with NSCLC and more than one biopsy that had undergone targeted next generation sequencing (NGS, OncoPanel) at the Dana-Farber Cancer Institute. Those representing distinct primary tumors by histology and/or discordant mutational profiles were excluded. Results: 134 NSCLC patients with more than one interpretable NGS result were identified; 23 were excluded due to separate primary tumors. Of the 111 remaining patients included in the analysis, the median time between samples was 14 months (range: 0 to 114 months). TMB correlated closely across all matched tumor pairs (Pearson’s r = 0.89), and greater variability in TMB was seen in biopsies taken from different anatomic sites (p = 0.04) compared to biopsies obtained from the same lesion. There was no significant change in median TMB with any intervening therapy, as TMB increased in some patients and decreased in others. Conclusions: In this observational study, TMB correlated closely across tumor pairs. However, these data suggest that sampling from different tumor sites may be associated with greater discrepancies in TMB. It is possible these differences could account for challenges in using TMB as a predictive biomarker for immunotherapy response. Further prospective investigation is needed to inform decisions regarding the need for repeat biopsy in patients starting immunotherapy with remote tissue samples.

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RAD51Bme Levels as a Potential Predictive Biomarker for PD-1 Blockade Response in Non-Small Cell Lung Cancer

Journal of Clinical Medicine ◽

10.3390/jcm9041000 ◽

2020 ◽

Vol 9 (4) ◽

pp. 1000

Author(s):

Inês Maria Guerreiro ◽

Daniela Barros-Silva ◽

Paula Lopes ◽

Mariana Cantante ◽

Ana Luísa Cunha ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Clinical Benefit ◽

Lower Risk ◽

Predictive Biomarkers ◽

Predictive Biomarker ◽

Small Cell ◽

Small Cell Lung ◽

Risk Of Death

Lung cancer (LC) cells frequently express high levels of programmed death-ligand 1 (PD-L1). Although these levels grossly correlate with the likelihood of response to specific checkpoint inhibitors, the response prediction is rather imperfect, and more accurate predictive biomarkers are mandatory. We examined the methylation profile of RAD51B (RAD51Bme) as a candidate predictive biomarker for anti-PD-1 therapy efficacy in non-small cell lung cancer (NSCLC), correlating with patients’ outcome. PD-L1 immunoexpression and RAD51Bme levels were analysed in NSCLC samples obtained from patients not treated with anti-PD-1 (Untreated Cohort (#1)) and patients treated with PD-1 blockade (Treated Cohort (#2)). Of a total of 127 patients assessed, 58.3% depicted PD-L1 positivity (PD-L1+). RAD51Bme levels were significantly associated with PD-L1 immunoexpression. Patients with PD-1 blockade clinical benefit disclosed higher RAD51Bme levels (p = 0.0390) and significantly lower risk of disease progression (HR 0.37; 95% CI: 0.15–0.88; p = 0.025). Combining RAD51Bme+ with PD-L1+ improved the sensitivity of the test to predict immunotherapy response. PD-L1+ was also associated with lower risk of death (HR 0.35; 95% CI: 0.15–0.81; p = 0.014). Thus, RAD51Bme levels might be combined with validated predictive biomarker PD-L1 immunostaining to select patients who will most likely experience clinical benefit from PD-1 blockade. The predictive value of RAD51Bme should be confirmed in prospective studies.

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Neuroendocrine-Related Circulating Transcripts in Small-Cell Lung Cancers: Detection Methods and Future Perspectives

Cancers ◽

10.3390/cancers13061339 ◽

2021 ◽

Vol 13 (6) ◽

pp. 1339

Author(s):

Lucia Anna Muscarella ◽

Tommaso Mazza ◽

Federico Pio Fabrizio ◽

Angelo Sparaneo ◽

Vito D’Alessandro ◽

...

Keyword(s):

Small Cell ◽

Detection Methods ◽

Published Data ◽

Small Cell Lung ◽

Tissue Samples ◽

Great Opportunity ◽

Suitable Alternative ◽

Essential Information ◽

Lung Cancers ◽

New Findings

No well-established prognostic or predictive molecular markers of small-cell lung cancer (SCLC) are currently available; therefore, all patients receive standard treatment. Adequate quantities and quality of tissue samples are frequently unavailable to perform a molecular analysis of SCLC, which appears more heterogeneous and dynamic than expected. The implementation of techniques to study circulating tumor cells could offer a suitable alternative to expand the knowledge of the molecular basis of a tumor. In this context, the advantage of SCLC circulating cells to express some specific markers to be explored in blood as circulating transcripts could offer a great opportunity in distinguishing and managing different SCLC phenotypes. Here, we present a summary of published data and new findings about the detection methods and potential application of a group of neuroendocrine related transcripts in the peripheral blood of SCLC patients. In the era of new treatments, easy and rapid detection of informative biomarkers in blood warrants further investigation, since it represents an important option to obtain essential information for disease monitoring and/or better treatment choices.

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Computerized tomography-Guided Microwave Ablation of Patients with Stage I Non-small Cell Lung Cancers: A Single-Institution Retrospective Study

Journal of Clinical Imaging Science ◽

10.25259/jcis_224_2020 ◽

2021 ◽

Vol 11 ◽

pp. 7

Author(s):

Michael Nance ◽

Zain Khazi ◽

Jussuf Kaifi ◽

Diego Avella ◽

Mohammed Alnijoumi ◽

...

Keyword(s):

Computerized Tomography ◽

Microwave Ablation ◽

Clinical Success ◽

Univariate Analysis ◽

Small Cell ◽

Stage I ◽

Small Cell Lung ◽

Lung Cancers ◽

Risk Of Death

Objectives: The objective of the study was to retrospectively investigate the safety and efficacy of computerized tomography-guided microwave ablation (MWA) in the treatment of Stage I non-small cell lung cancers (NSCLCs). Material and Methods: This retrospective, single-center study evaluated 21 patients (10 males and 11 females; mean age 73.8 ± 8.2 years) with Stage I peripheral NSCLCs treated with MWA between 2010 and 2020. All patients were surveyed for metastatic disease. Clinical success was defined as absence of FDG avidity on follow-up imaging. Tumor growth within 5 mm of the original ablated territory was defined as local recurrence. Welch t-test and Fisher’s exact test were used for univariate analysis. Hazard ratio (HR) and odds ratio (OR) were determined using Cox regression and Firth logistic regression. Significance was P < 0.05. Data are expressed as mean ± standard deviation. Results: Ablated tumors had longest dimension 17.4 ± 5.4 mm and depth 19.7 ± 15.1 mm from the pleural surface. Median follow-up was 20 months (range, 0.6–56 months). Mean overall survival (OS) following lung cancer diagnosis or MWA was 26.2 ± 15.4 months (range, 5–56 months) and 23.7 ± 15.1 months (range, 3–55 months). OS at 1, 2, and 5 years was 67.6%, 61.8%, and 45.7%, respectively. Progression-free survival (PFS) was 19.1 ± 16.2 months (range, 1–55 months). PFS at 1, 2, and 5 years was 44.5%, 32.9%, and 32.9%, respectively. Technical success was 100%, while clinical success was observed in 95.2% (20/21) of patients. One patient had local residual disease following MWA and was treated with chemotherapy. Local control was 90% with recurrence in two patients following ablation. Six patients (28.6%) experienced post-ablation complications, with pneumothorax being the most common event (23.8% of patients). Female gender was associated with 90% reduction in risk of death (HR 0.1, P = 0.014). Tumor longest dimension was associated with a 10% increase in risk of death (P = 0.197). Several comorbidities were associated with increased hazard. Univariate analysis revealed pre-ablation forced vital capacity trended higher among survivors (84.7 ± 15.2% vs. 73 ± 21.6%, P = 0.093). Adjusted for age and sex, adenocarcinoma, and neuroendocrine histology trended toward improved OS (OR: 0.13, 0.13) and PFS (OR: 0.88, 0.37) compared to squamous cell carcinoma. Conclusion: MWA provides a safe and effective alternative to stereotactic brachytherapy resulting in promising OS and PFS in patients with Stage I peripheral NSCLC. Larger sample sizes are needed to further define the effects of underlying comorbidities and tumor biology.

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Exploring the prognostic value of SCARF1 in non-small cell lung cancers

10.1101/2021.01.28.428617 ◽

2021 ◽

Author(s):

Daniel A. Patten ◽

Shishir Shetty

Keyword(s):

Endothelial Cells ◽

Prognostic Value ◽

Therapeutic Potential ◽

Small Cell Lung Carcinoma ◽

Lung Squamous Cell Carcinoma ◽

Small Cell ◽

The Cancer Genome Atlas ◽

Small Cell Lung ◽

Cell Lung Carcinoma ◽

Lung Cancers

AbstractScavenger receptor class F member 1 (SCARF1) has previously been shown to be highly expressed within the human liver, hold prognostic value in hepatocellular carcinoma and mediate the specific recruitment of leukocytes to liver sinusoidal endothelial cells; however, to date, the liver remains the only major organ in which SCARF1 has been explored in any detail. Here, we utilised publically-available RNA-sequencing data from The Cancer Genome Atlas (TGCA) to identify the lungs as a site of significant SCARF1 expression and attribute the majority of its expression to endothelial cell populations. Next, we show that SCARF1 expression is significantly reduced in two histologically distinct types of non-small cell lung carcinoma cancers (NSCLCs), lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), compared to non-tumoural tissues. Interestingly, loss of SCARF1 expression was associated with aggressive tumour biology in LUAD tissues, but not in LUSC. Furthermore, increased SCARF1 expression was highly prognostic of better overall survival in LUAD tumour tissues, but this was again in contrast to LUSC tumours, in which SCARF1 held no prognostic value. Finally, we showed that SCARF1 is widely expressed in tumour endothelial cells of non-small cell lung cancers and that its total expression in LUAD tumour tissues correlated with immune score and CD4+ T cell infiltration. This study represents the first detailed exploration of SCARF1 expression in normal and diseased human lung tissues and further highlights the prognostic value and therapeutic potential of SCARF1 in immunologically active cancers.

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