scholarly journals Co-Occurring Alteration of NOTCH and DDR Pathways Serves as Novel Predictor to Efficacious Immunotherapy in NSCLC

2021 ◽  
Vol 11 ◽  
Author(s):  
Zhimin Zhang ◽  
Yanyan Gu ◽  
Xiaona Su ◽  
Jing Bai ◽  
Wei Guan ◽  
...  
Keyword(s):  
Progressive Disease ◽  
Checkpoint Inhibitors ◽  
Notch Pathway ◽  
Progression Free Survival ◽  
The Cancer Genome Atlas ◽  
Expression Data ◽  
Free Survival ◽  
Future Clinical Practice ◽  
Cancer Genome Atlas ◽  
Nsclc Patients

Although immune checkpoint inhibitors (ICIs) have shown remarkable benefit for treatment of advanced non-small lung cancer (NSCLC), only a minority of patients can achieve durable responses and the most patients produce an ultra-rapid progressive disease. Here, we collected the availably published datasets and mined the determinants of response to immunotherapy on pathway levels. One hundred six NSCLC patients treated with immunotherapy were combined from Rizvi et al. and Hellman et al. studies (whole exon sequencing). Two independent validation datasets consisted of the MSKCC cohort (targeted sequencing) and data by Anagnostou and colleagues (whole exon sequencing). The Cancer Genome Atlas (TCGA) somatic mutation and gene expression data were applied to explore the immunobiology features. In the first combined cohort, we detected NOTCH pathway altered in 71% patients with durable clinical benefit (DCB) while only 36% among no durable benefit (NDB) (p = 0.005). Compared to NDB group, co-occurrence of NOTCH and at least two DDR (co-DDR) pathway was discovered in DCB group and contributed to a prolonged progression-free survival (PFS) [22.1 vs 3.6 months, p < 0.0001, HR, 0.34, 95% confidence interval (CI), 0.2–0.59]. In two independent datasets, co-occurrence of NOTCH+/co-DDR+ was also validated to be a better immunotherapy efficacy [Cohort 2: 13 vs 6 months, p = 0.034, HR, 0.55, 95% CI, 0.31–0.96; Cohort 3: 21 vs 11 months, p = 0.067, HR, 0.45, 95% CI, 0.18–1.1]. By analyzing TCGA cohort, we found patients with coexisting NOTCH+/co-DDR+ pathway had a higher TMB, more infiltration of CD4+T cells. Overall, co-occurrence of NOTCH and co-DDR pathway reflect a better immunotherapy efficacy in advanced NSCLC. This genomic predictor show promise in stratifying patients that suit for immunotherapy for future clinical practice.

Co-occurring alteration of NOTCH and DDR pathways serve as novel predictor to efficacious immunotherapy in NSCLC.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e21106-e21106
Author(s):  
Zhimin Zhang ◽  
Yanyan Gu ◽  
Xiaona Su ◽  
Jing Bai ◽  
Wei Guan ◽  
...  
Keyword(s):  
Progressive Disease ◽  
Checkpoint Inhibitors ◽  
Notch Pathway ◽  
Progression Free Survival ◽  
The Cancer Genome Atlas ◽  
Expression Data ◽  
Free Survival ◽  
Future Clinical Practice ◽  
Cancer Genome Atlas ◽  
Nsclc Patients

e21106 Background: Although immune checkpoint inhibitors (ICIs) have shown remarkable benefit for treatment of advanced non-small lung cancer (NSCLC), only a minority of patients can achieve durable responses and the majority produce an ultra-rapid progressive disease. Methods: Here, we collected the availably published datasets and mined the determinants of response to immunotherapy on pathway levels. 106 NSCLC patients treated with immunotherapy were combined from Rizvi et. al and Hellman et. al studies (whole exon sequencing) as the discovery dataset. Two independent validation datasets were comprised of the MSKCC cohort (targeted sequencing) and data by Anagnostou and colleagues (whole exon sequencing). The Cancer Genome Atlas (TCGA) somatic mutation and gene expression data were applied to explore the immunobiology features. Results: In the first combined cohort, we detected NOTCH pathway altered in 71% patients with durable clinical benefit (DCB) while only 36% among no durable benefit (NDB) (p = 0.005). Compared to NDB group, co-occurrence of NOTCH and at least two DDR (co-DDR) pathway was discovered in DCB group and contributed to a prolonged progression-free survival (PFS) [ 22.1 vs 3.6 months, p < 0.0001, HR, 0.34, 95% confidence interval (CI), 0.2-0.59]. In two independent datasets, co-occurrence of NOTCH+/co-DDR+ was also validated to be a better immunotherapy efficacy [ Cohort 2: 13 vs 6 months, p = 0.034, HR, 0.55, 95% CI, 0.31-0.96 ; Cohort 3: 21 vs 11 months, p = 0.067, HR, 0.45, 95% CI, 0.18-1.1 ]. By analyzing TCGA cohort, we found patients with coexisting NOTCH and co-DDR pathway had a higher TMB, more infiltration of CD4+T cells. Conclusions: Overall, co-occurrence of NOTCH and co-DDR pathway reflect a better immunotherapy efficacy in advanced NSCLC. This genomic predictor show promise in stratifying patients that suit for immunotherapy for future clinical practice.

scholarly journals Somatic copy number alteration predicts clinical benefit of lung adenocarcinoma patients treated with cytokine-induced killer plus chemotherapy

2022 ◽  
Author(s):  
Fan Kou ◽  
Lei Wu ◽  
Ye Zhu ◽  
Baihui Li ◽  
Ziqi Huang ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Copy Number ◽  
Immune Cell ◽  
Checkpoint Inhibitors ◽  
Progression Free Survival ◽  
The Cancer Genome Atlas ◽  
Whole Exome ◽  
Mutation Burden ◽  
Cancer Genome Atlas ◽  
Nsclc Patients

AbstractSomatic copy number alterations (SCNA), which are widespread in cancer, can predict the efficacy of immune checkpoint inhibitors in non-small-cell lung cancer (NSCLC). However, the usefulness of SCNA for predicting the survival of patients treated with cytokine-induced killer (CIK) cells or chemotherapy (CT) is unknown. This study aimed to explore the correlation between SCNA and clinical outcome in NSCLC patients treated with CIK + CT or CT alone. We performed whole-exome sequencing on 45 NSCLC patients treated with CIK + CT, as well as 305 NSCLC patients treated with CT alone, from The Cancer Genome Atlas, which showed SCNA had a superiority in predicting the progression-free survival (PFS) over tumor mutation burden (TMB) and SCNA + TMB in NSCLC patients treated with CIK + CT, especially in lung adenocarcinoma, while SCNA could not predict the efficacy of CT alone. Additionally, we investigated the association between SCNA and immune cell infiltration by RNA sequencing and immunohistochemistry. The results revealed that SCNA was negatively associated with the expression of dendritic cells. Collectively, this study revealed a negative correlation between SCNA and response to CIK + CT and showed that SCNA is a predictive indicator in LUAD patients treated with CIK + CT.

Baseline systemic inflammatory immune index may predict overall survival and progression-free survival in patients with non-small cell lung cancer patients on immune checkpoint inhibitors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e21202-e21202
Author(s):  
John P. Palmer ◽  
Yenong Cao ◽  
Samer Ibrahim ◽  
Natasha Dhawan ◽  
Muhammad Zubair Afzal ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Overall Survival ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Progression Free Survival ◽  
Small Cell ◽  
Small Cell Lung ◽  
Free Survival ◽  
The Mean ◽  
Nsclc Patients

e21202 Background: Increased systemic inflammatory state and increased inflammation within tumor micro-environment (TME) have been associated with a worse prognosis and lower responsiveness to immune checkpoint inhibitors (ICI). Systemic inflammatory immune index (SII) reflects the changes in the systemic inflammatory matrix. Studies have shown the association of SII with cancer survival and treatment outcomes. We aim to study the effect of SII on treatment outcomes in non-small cell lung cancer (NSCLC) patients being treated with ICI. Methods: We conducted a retrospective analysis on 178 NSCLC patients treated with ICIs (pembrolizumab, nivolumab, ipilimumab/nivolumab or atezolizumab) alone or in combination with chemotherapy. SII is the product of platelets multiplied by neutrophils divided by lymphocytes. Baseline and 8-week SIIs were obtained. Radiographic response, duration of radiographic response (date of best response to radiographic progression), overall survival (OS), and progression-free survival (PFS) were evaluated. A high SII was defined as a value greater than the median SII. Cox regression univariate and multivariate analyses were performed. Logistic regression, t-test, and Chi-square tests were applied. Results: Overall, 81% patients had adenocarcinoma and 19% patients had squamous, adenosquamous or large cell carcinoma. The majority of the patients were female (56.2% vs. 43.8%). Median SII at baseline was 1335. The objective response rate (ORR) was 45.1%. The disease control rate was 75.8%. The ORR was 51% in patients receiving ICI first-line compared to 35% in those who received ICI as a second-line therapy. At baseline, there was no difference in the mean SII between responders and non-responders (2146.2 vs. 1917.5, P = 0.5); however at 8 weeks, the mean SII was significantly lower in responders compared to non-responders (1198.8 vs. 2880.2, P = 0.02). A total of 15 (10.9%) patients were found to have pseudoprogression or mixed response on follow-up imaging. Among these, 11(73.3%) patients had low SII at 8 weeks (P = 0.04). The median OS was significantly higher in patients with low SII at baseline (29.6 months vs. 10.1 months, P = 0.001 95% CI 10.6 – 22.1). Similarly, there was a significant difference in median PFS in patients with low SII (14.6 months vs. 6.7 months, P = 0.002, 95% CI 5.6 – 11.6). There was no correlation between high or low SII on the incidence of immune-related adverse events. Conclusions: SII may have significant impact on OS and PFS and could be serially monitored to assess the response to ICI. A low SII may help to differentiate pseudoprogression vs. true progression. Prospective studies are needed to validate these findings. Further, it will be interesting to see if SII could be incorporated into predictive models to determine the duration of cytotoxic therapy in selected patients.

scholarly journals PTHrP, A Biomarker for CNS Metastasis in Triple-Negative Breast Cancer and Selection for Adjuvant Chemotherapy in Node-Negative Disease

2019 ◽  
Vol 4 (1) ◽  
Author(s):  
Gloria Assaker ◽  
Anne Camirand ◽  
Bassam Abdulkarim ◽  
Atilla Omeroglu ◽  
Jean Deschenes ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Adjuvant Chemotherapy ◽  
Prognostic Factor ◽  
Poor Prognosis ◽  
Triple Negative ◽  
Progression Free Survival ◽  
The Cancer Genome Atlas ◽  
Free Survival ◽  
Node Negative ◽  
Cancer Genome Atlas

Abstract Background Triple-negative breast cancer (TNBC) is characterized by poor prognosis and lack of targeted therapies and biomarkers to guide decisions on adjuvant chemotherapy. Parathyroid hormone-related protein (PTHrP) is frequently overexpressed in breast cancer and involved in proliferation and metastasis, two hallmarks of poor prognosis for node-negative breast cancer. We investigated the prognostic value of PTHrP with respect to organ-specific metastasis and nodal status in TNBC. Methods We assessed PTHrP expression using immunohistochemistry in a clinically annotated tissue microarray for a population-based study of 314 patients newly diagnosed with TNBC, then analyzed its correlation to progression and survival using Kaplan-Meier and Cox regression analyses. The Cancer Genome Atlas (TCGA) validation analysis was performed through Bioconductor. All statistical tests were two-sided. Results PTHrP overexpression (160 of 290 scorable cases, 55.2%) was statistically significantly associated in univariate analysis with decreased overall survival (OS) in our cohort (P = .0055) and The Cancer Genome Atlas (P = .0018) and decreased central nervous system (CNS)-progression-free survival (P = .0029). In multivariate analysis, PTHrP was a statistically significant independent prognostic factor for CNS-progression-free survival in TNBC (hazard ratio [HR] = 5.014, 95% confidence interval [CI] = 1.421 to 17.692, P = .0122) and for OS selectively in node-negative TNBC (HR = 2.423, 95% CI = 1.129 to 5.197, P = .0231). Strikingly, PTHrP emerged as the only statistically significant prognostic factor (HR = 2.576, 95% CI = 1.019 to 6.513, P = .0456) for OS of low-clinical risk node-negative patients who did not receive adjuvant chemotherapy. Conclusions PTHrP is a novel independent prognostic factor for CNS metastasis and adjuvant chemotherapy selection of low-clinical risk node-negative TNBC. Its predictive value needs to be prospectively assessed in clinical trials.

scholarly journals The Prognostic Significance of the Continuous Administration of Anti-PD-1 Antibody via Continuation or Rechallenge After the Occurrence of Immune-Related Adverse Events

2021 ◽  
Vol 11 ◽  
Author(s):  
Toshiya Fujisaki ◽  
Satoshi Watanabe ◽  
Takeshi Ota ◽  
Kohei Kushiro ◽  
Yusuke Sato ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Adverse Events ◽  
Checkpoint Inhibitors ◽  
Prognostic Significance ◽  
Progression Free Survival ◽  
Continuous Administration ◽  
Free Survival ◽  
Programmed Cell Death 1 ◽  
Third Line ◽  
Nsclc Patients

ObjectivesAlthough immune checkpoint inhibitors (ICIs) have been shown to improve overall survival (OS) in advanced non-small-cell lung cancer (NSCLC) patients, ICIs sometimes cause various types of immune-related adverse events (irAEs), which lead to the interruption of ICI treatment. This study aims to evaluate the clinical significance of the continuation of ICIs in NSCLC patients with irAEs and to assess the safety and efficacy of the readministration of ICIs after their discontinuation due to irAEs.MethodsWe retrospectively identified patients with advanced NSCLC who were treated with first- to third-line anti-programmed cell death-1 (PD-1) therapy from January 2016 through October 2017 at multiple institutions belonging to the Niigata Lung Cancer Treatment Group. Progression-free survival (PFS) and OS from the initiation of ICI treatment were analyzed in patients with and without irAEs, with and without ICI interruption, and with and without ICI readministration. A 6-week landmark analysis of PFS and OS was performed to minimize the lead-time bias associated with time-dependent factors.ResultsOf 231 patients who received anti-PD-1 antibodies, 93 patients (40%) developed irAEs. Of 84 eligible patients with irAEs, 32 patients (14%) continued ICIs, and OS was significantly longer in patients who continued ICIs than that in patients who discontinued ICIs [not reached (95% CI: NE-NE) vs. not reached (95% CI: 22.4–NE); p = 0.025]. Of 52 patients who discontinued ICIs, 14 patients (6.1%) readministered ICIs, and OS in patients with ICI readministration was significantly longer than that in patients without ICI readministration [not reached (95% CI: NE-NE) vs. not reached (95% CI: 8.4–NE); p = 0.031].ConclusionThe current study demonstrated that both the continuation and readministration of ICIs after irAE occurrence improved OS compared to the permanent interruption of ICIs in NSCLC patients with ICI-related irAEs.

scholarly journals ctDNA-Profiling-Based UBL Biological Process Mutation Status as a Predictor of Atezolizumab Response Among TP53-Negative NSCLC Patients

2021 ◽  
Vol 12 ◽  
Author(s):  
Jun Lu ◽  
Yanwei Zhang ◽  
Yuqing Lou ◽  
Bo Yan ◽  
Benkun Zou ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Biological Process ◽  
Checkpoint Inhibitors ◽  
Clinical Information ◽  
Progression Free Survival ◽  
Predictive Values ◽  
Mutation Status ◽  
Free Survival ◽  
History Of ◽  
Nsclc Patients

Atezolizumab, an immune checkpoint inhibitor, has been approved for use in clinical practice in non-small cell lung cancer (NSCLC) patients, but potential biomarkers for response stratification still need further screening. In the present study, a total of 399 patients with high-quality ctDNA profiling results were included. The mutation status of ubiquitin-like conjugation (UBL) biological process genes (including ABL1, APC, LRP6, FUBP1, KEAP1, and TOP2A) and clinical information were further integrated. The results suggested that the patients with the clinical characteristics of male or history of smoking had a higher frequency of UBL mutation positivity [UBL (+)]; the patients who were UBL (+) had shorter progression-free survival (PFS) (1.69 vs. 3.22 months, p = 0.0007) and overall survival (8.61 vs. 16.10 months, p &lt; 0.0001) than those patients with UBL mutation negativity [UBL (–)]; and more promising predictive values were shown in the smoker subgroup and ≤ 3 metastasis subgroup. More interestingly, we found the predictor has more performance in TP53-negative cohorts [training in an independent POPLAR and OAK cohorts (n = 200), and validation in an independent MSKCC cohort (n = 127)]. Overall, this study provides a predictor, UBL biological process gene mutation status, not only for identifying NSCLC patients who may respond to atezolizumab therapy but also for screening out the potential NSCLC responders who received other immune checkpoint inhibitors.

scholarly journals Multicenter imaging outcomes study of The Cancer Genome Atlas glioblastoma patient cohort: imaging predictors of overall and progression-free survival

2015 ◽  
Vol 17 (11) ◽  
pp. 1525-1537 ◽  
Author(s):  
Pattana Wangaryattawanich ◽  
Masumeh Hatami ◽  
Jixin Wang ◽  
Ginu Thomas ◽  
Adam Flanders ◽  
...  
Keyword(s):  
Progression Free Survival ◽  
Cancer Genome ◽  
The Cancer Genome Atlas ◽  
Free Survival ◽  
Patient Cohort ◽  
Glioblastoma Patient ◽  
Cancer Genome Atlas ◽  
Outcomes Study ◽  
Genome Atlas

scholarly journals Impact of Intercurrent Introduction of Steroids on Clinical Outcomes in Advanced Non-Small-Cell Lung Cancer (NSCLC) Patients under Immune-Checkpoint Inhibitors (ICI)

Cancers ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 2827 ◽  
Author(s):  
Andrea De Giglio ◽  
Laura Mezquita ◽  
Edouard Auclin ◽  
Félix Blanc-Durand ◽  
Mariona Riudavets ◽  
...  
Keyword(s):  
Patient Outcomes ◽  
Checkpoint Inhibitors ◽  
Progression Free Survival ◽  
Prognostic Impact ◽  
Steroid Use ◽  
Free Survival ◽  
Cancer Symptoms ◽  
Steroid Group ◽  
Poor Outcomes ◽  
Nsclc Patients

Background: Baseline steroids before ICI have been associated with poor outcomes, particularly when introduced due to cancer symptoms. Methods: Retrospective analysis of advanced NSCLC patients treated with ICI. We collected the use of intercurrent steroids (≥10 mg of prednisone-equivalent) within the first eight weeks of ICI. We correlated steroid use with patient outcomes according to the indications. Results: 413 patients received ICI, 299 were steroids-naïve at baseline. A total of 49 patients received intercurrent steroids (16%), of whom 38 for cancer-related symptoms and 11 for other indications, such as immune-related events. Overall, median (m) progression-free survival (PFS) was 1.9 months (mo.) [95% CI, 1.8-2.4] and overall survival (OS) 10 mo. [95% CI, 8.1–12.9]. Intercurrent steroids under ICI correlated with a shorter PFS/OS (1.3 and 2.3 mo. respectively, both p < 0.0001). Intercurrent steroids for cancer-related symptoms correlated with poorest mPFS [1.1 mo.; 95% CI, 0.9–1.5] and mOS [1.9 mo.; 95%CI, 1.5–2.4; p < 0.0001)]. No mOS and mPFS differences were found between cancer-unrelated-steroid group and no-steroid group. Steroid use for cancer-related symptoms was an independent prognostic factor for poor PFS [HR 2.64; 95% CI, 1.2–5.6] and OS [HR 4.53; 95% CI, 1.8–11.1], both p < 0.0001. Conclusion: Intercurrent steroids during ICI had no detrimental prognostic impact if the indication was unrelated to cancer symptoms.

Overweight or obese patients may take longer to respond and be less responsive to immune checkpoint inhibitors in non-small cell lung cancer: A retrospective review.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e21209-e21209
Author(s):  
John P. Palmer ◽  
Yenong Cao ◽  
Samer Ibrahim ◽  
Natasha Dhawan ◽  
Muhammad Zubair Afzal ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Response Rate ◽  
Checkpoint Inhibitors ◽  
Progression Free Survival ◽  
Normal Weight ◽  
Obese Patients ◽  
Small Cell Lung ◽  
Free Survival ◽  
Radiographic Response ◽  
Nsclc Patients

e21209 Background: Immune checkpoint inhibitors (ICI) are now the standard of care in the treatment of non-small cell lung cancer (NSCLC). ICIs may be used as monotherapy or in combination with chemotherapy. Increased recruitment of inflammatory cells in the tumor micro-environment is associated with a poor response to ICIs. Although obesity is a risk factor for many types of cancers, including lung cancer, it is associated with a low systemic inflammation state. This creates an effect known as the “obesity paradox,” resulting in better treatment-related outcomes in overweight and obese patients receiving ICIs. However, in obese patients, the neutralizing interleukin (IL) - 1β level is high, which can decrease the responsiveness to ICI. We aim to study the effect of increased weight on treatment-related outcomes in NSCLC patients receiving ICI. Methods: We conducted a retrospective analysis on 178 NSCLC patients treated with ICIs, such as pembrolizumab, nivolumab, ipilimumab/nivolumab or atezolizumab, alone or in combination with chemotherapy. Overweight was defined as having a BMI of 25 – 29.9 while obesity was defined as having a BMI of ≥ 30. Overall survival (OS), progression free survival (PFS), best radiographic response, and the time to achieve radiographic response were evaluated. Cox regression univariate and multivariate analyses were performed. Logistic regression and Chi-square tests were applied. Results: Of the 178 patients with NSCLC, 81% had adenocarcinoma, and 19% had squamous, adenosquamous, or large cell carcinoma. The majority of patients were female (56.2% vs. 43.8%). Overall, 48.6% patients were overweight or obese. The objective response rate (ORR) was 45.1% and the disease control rate (DCR) was 75.8%. The ORR was 37% in overweight/obese patients compared to 52% in patients with a normal weight (p = 0.06). The DCR was 76% vs. 73.9%, (p = 0.7). The median time to achieve the best radiographic response was 3.7 months in overweight/obese patients compared to 2.5 months in those of normal weight (p = 0.2). A considerably higher proportion of the patients progressed in overweight/obese category (80.7% vs. 69.3%, P = 0.08). However, there was no significant difference in median PFS between the two categories (7.4 vs. 8.1 months, P = 0.2). The overall survival was not significant different between both categories (15.9 vs. 16.8 months, P = 0.5). Conclusions: Our study suggests that obesity and overweight status can result in a low response rate to ICIs in NSCLC patients and can delay the time to achieve the best radiographic response per RECIST criteria. However, we did not observe any significant impact on the overall or progression-free survival. A large, population-based study will help to elucidate the impact of weight on the responsiveness to ICI.

Mir-34a as predictor of immunotherapy efficacy in NSCLC patients.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e21191-e21191
Author(s):  
Alexia Monastirioti ◽  
Chara Papadaki ◽  
Konstantinos Rounis ◽  
Despoina Kalapanida ◽  
Dimitrios Makrakis ◽  
...  
Keyword(s):  
Clinical Outcomes ◽  
Progressive Disease ◽  
Checkpoint Inhibitors ◽  
Binary Logistic Regression ◽  
Progression Free Survival ◽  
Predictive Biomarker ◽  
Immune Checkpoints ◽  
Binary Logistic Regression Analysis ◽  
Expression Levels ◽  
Nsclc Patients

e21191 Background: MicroRNAs are critical modulators of the immune response and regulate the expression of various immune checkpoints during immunotherapy. In the present study we evaluated the predictive significance of immune related miRNAs in the plasma of non-small cell lung cancer (NSCLC) patients treated with immune checkpoint inhibitors. Methods: Plasma was obtained from 62 NSCLC patients before the initiation of immunotherapy, administered as second- or third-line treatment. The expression profile of immune-related miR-34a, miR-146a, miR-155, miR-200b, miR-202 and miR-223 was assessed by RT-qPCR. Patients were classified in high and low expression groups according to the median value of each miRNA. Patients that had achieved partial response (PR) or stable disease (SD) were classified as responders, whereas patients with progressive disease (PD) were classified as non-responders. Results: No statistical correlations were observed among miRNA expression and clinical outcomes in the whole group of patients (N = 62). However, in the non-squamous subgroup (N = 36) lower miR-34a expression levels were observed in non-responders compared to responders (80% vs 20%; p = 0.029). Univariate binary logistic regression analysis revealed that only low miR-34a expression (HR: 8.000, 95% CI: 1.215-52.693; p = 0.031) was correlated with the probability of developing progressive disease as best response to immunotherapy. Patients with low miR-34a expression levels were associated with shorter progression free survival (PFS) and overall survival (OS) compared to patients with high 34a expression (1.97 vs 6.33 months; p = 0.042 and 2.93 vs 9,60 months; p = 0.012, respectively). Furthermore, low miR-34a expression emerged as an independent predictor of shorter PFS and OS (HR: 2.449; p = 0.049 and HR: 3.203; p = 0.016, respectively). No other correlations were observed among the rest of the miRNAs and clinical outcomes. Conclusions: Our findings suggest that circulating miR-34a may serve as a potential predictive biomarker in NSCLC patients treated with immunotherapy. These observations need to be further validated in a larger cohort of patients.

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