scholarly journals Tumor Mutation Burden as a Biomarker in Resected Non–Small-Cell Lung Cancer

2018 ◽  
Vol 36 (30) ◽  
pp. 2995-3006 ◽  
Author(s):  
Siddhartha Devarakonda ◽  
Federico Rotolo ◽  
Ming-Sound Tsao ◽  
Irena Lanc ◽  
Elisabeth Brambilla ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Adjuvant Chemotherapy ◽  
Disease Free Survival ◽  
Small Cell ◽  
Small Cell Lung ◽  
Free Survival ◽  
Tumor Mutation Burden ◽  
Resected Nsclc ◽  
Mutation Burden ◽  
Disease Free

Purpose The survival benefit with adjuvant chemotherapy for patients with resected stage II-III non–small-cell lung cancer (NSCLC) is modest. Efforts to develop prognostic or predictive biomarkers in these patients have not yielded clinically useful tests. We report findings from the Lung Adjuvant Cisplatin Evaluation (LACE)-Bio-II study, in which we analyzed next-generation sequencing and long-term outcomes data from > 900 patients with early-stage NSCLC treated prospectively in adjuvant landmark clinical trials. We used a targeted gene panel to assess the prognostic and predictive effect of mutations in individual genes, DNA repair pathways, and tumor mutation burden (TMB). Methods A total of 908 unmatched, formalin-fixed, paraffin-embedded, resected lung cancer tumor specimens were sequenced using a targeted panel of 1,538 genes. Stringent filtering criteria were applied to exclude germline variants and artifacts related to formalin fixation. Disease-free survival, overall survival, and lung cancer—specific survival (LCSS) were assessed in Cox models stratified by trial and adjusted for treatment, age, sex, performance score, histology, type of surgery, and stage. Results Nonsynonymous mutations were identified in 1,515 genes in 908 tumor samples. High nonsynonymous TMB (> 8 mutations/Mb) was prognostic for favorable outcomes (ie, overall survival, disease-free survival, and LCSS) in patients with resected NSCLC. LCSS benefit with adjuvant chemotherapy was more pronounced in patients with low nonsynonymous TMBs (≤ 4 mutations/Mb). Presence of mutations in DNA repair pathways, tumor-infiltrating lymphocytes, TP53 alteration subtype, and intratumor heterogeneity was neither prognostic nor predictive. Statistically significant effect of mutations in individual genes was difficult to determine due to high false-discovery rates. Conclusion High nonsynonymous TMB was associated with a better prognosis in patients with resected NSCLC. In addition, the benefit of adjuvant chemotherapy on LCSS was more pronounced in patients with low nonsynonymous TMBs. Studies are warranted to confirm these findings.

scholarly journals Pooled Analysis of the Prognostic and Predictive Effects of TP53 Comutation Status Combined With KRAS or EGFR Mutation in Early-Stage Resected Non–Small-Cell Lung Cancer in Four Trials of Adjuvant Chemotherapy

2017 ◽  
Vol 35 (18) ◽  
pp. 2018-2027 ◽  
Author(s):  
Frances A. Shepherd ◽  
Benjamin Lacas ◽  
Gwénaël Le Teuff ◽  
Pierre Hainaut ◽  
Pasi A. Jänne ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Adjuvant Chemotherapy ◽  
Small Cell Lung Cancer ◽  
Disease Free Survival ◽  
Pooled Analysis ◽  
Small Cell ◽  
Small Cell Lung ◽  
Free Survival ◽  
Prognostic Effect ◽  
Disease Free

Purpose Our previous work evaluated individual prognostic and predictive roles of TP53, KRAS, and EGFR in non–small-cell lung cancer (NSCLC). In this analysis, we explore the prognostic and predictive roles of TP53/KRAS and TP53/EGFR comutations in randomized trials of adjuvant chemotherapy versus observation. Patients and Methods Mutation analyses (wild-type [WT] and mutant) for TP53, KRAS, and EGFR were determined in blinded fashion in multiple laboratories. Primary and secondary end points of pooled analysis were overall survival and disease-free survival. We evaluated the role of TP53/KRAS comutation in all patients and in the adenocarcinoma subgroup as well as the TP53/EGFR comutation in adenocarcinoma only through a multivariable Cox proportional hazards model stratified by trial. Results Of 3,533 patients with NSCLC, 1,181 (557 deaths) and 404 (170 deaths) were used for TP53/KRAS and TP53/EGFR analyses. For TP53/KRAS mutation status, no prognostic effect was observed ( P = .61), whereas a borderline predictive effect ( P = .04) was observed with a deleterious effect of chemotherapy with TP53/KRAS comutations versus WT/WT (hazard ratio, 2.49 [95% CI, 1.10 to 5.64]; P = .03). TP53/EGFR comutation in adenocarcinoma was neither prognostic ( P = .83), nor significantly predictive ( P = .86). Similar results were observed for both groups for disease-free survival. Conclusion We could identify no prognostic effect of the KRAS or EGFR driver and TP53 tumor suppressor comutation. Our observation of a potential negative predictive effect of TP53/KRAS comutation requires validation.

Preoperative Chemotherapy Plus Surgery Versus Surgery Plus Adjuvant Chemotherapy Versus Surgery Alone in Early-Stage Non–Small-Cell Lung Cancer

2010 ◽  
Vol 28 (19) ◽  
pp. 3138-3145 ◽  
Author(s):  
Enriqueta Felip ◽  
Rafael Rosell ◽  
José Antonio Maestre ◽  
José Manuel Rodríguez-Paniagua ◽  
Teresa Morán ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Adjuvant Chemotherapy ◽  
Small Cell Lung Cancer ◽  
Preoperative Chemotherapy ◽  
Early Stage ◽  
Disease Free Survival ◽  
Small Cell ◽  
Small Cell Lung ◽  
Free Survival ◽  
Disease Free

Purpose To address whether preoperative chemotherapy plus surgery or surgery plus adjuvant chemotherapy prolongs disease-free survival compared with surgery alone among patients with resectable non–small-cell lung cancer. Patients and Methods In this phase III trial, 624 patients with stage IA (tumor size > 2 cm), IB, II, or T3N1 were randomly assigned to surgery alone (212 patients), three cycles of preoperative paclitaxel-carboplatin followed by surgery (201 patients), or surgery followed by three cycles of adjuvant paclitaxel-carboplatin (211 patients). The primary end point was disease-free survival. Results In the preoperative arm, 97% of patients started the planned chemotherapy, and radiologic response rate was 53.3%. In the adjuvant arm, 66.2% started the planned chemotherapy. Ninety-four percent of patients underwent surgery; surgical procedures and postoperative mortality were similar across the three arms. Patients in the preoperative arm had a nonsignificant trend toward longer disease-free survival than those assigned to surgery alone (5-year disease-free survival 38.3% v 34.1%; hazard ratio [HR] for progression or death, 0.92; P = .176). Five-year disease-free survival rates were 36.6% in the adjuvant arm versus 34.1% in the surgery arm (HR 0.96; P = .74). Conclusion In early-stage patients, no statistically significant differences in disease-free survival were found with the addition of preoperative or adjuvant chemotherapy to surgery. In this trial, in which the treatment decision was made before surgery, more patients were able to receive preoperative than adjuvant treatment.

scholarly journals Spatial architecture of tumour-infiltrating lymphocytes as a prognostic parameter in resected non-small-cell lung cancer

2020 ◽  
Vol 58 (3) ◽  
pp. 619-628 ◽  
Author(s):  
Giovanni Bocchialini ◽  
Costanza Lagrasta ◽  
Denise Madeddu ◽  
Giulia Mazzaschi ◽  
Davide Marturano ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Overall Survival ◽  
Disease Free Survival ◽  
Small Cell ◽  
Small Cell Lung ◽  
Free Survival ◽  
Resected Nsclc ◽  
Nsclc Patients ◽  
Infiltrating Lymphocytes ◽  
Disease Free

Abstract OBJECTIVES Tumour-infiltrating lymphocytes (TILs) are critically implicated in the clinical outcome and response to immunotherapy in non-small-cell lung cancer (NSCLC) patients. The functional competence of lymphocyte subpopulations is strongly conditioned by their spatial arrangement within the tumour immune microenvironment. The aim of this study was to determine whether the tissue localization of specific TIL subpopulations might have an impact on the risk of recurrence in surgically resected NSCLC. METHODS High-speed scanning of whole slide images was performed on immunohistochemically stained tissue sections from 97 NSCLC patients to assess the number and ratio of CD3+, CD8+ and PD-1+ T-lymphocytes. TIL distribution was computed considering the intratumoural (proximal or distal) and peripheral (invasive margin) localization as well as their location within the fibrotic tissue (immune excluded). The tumour proliferative index was assessed by Ki67 labelling. The impact of TILs number and distribution on clinical-pathological characteristics and outcomes were statistically analysed. RESULTS High density and percentage of proximal CD8+ TILs and low PD-1-to-CD8 ratio had a positive impact on disease-free-survival (P = 0.03) and overall survival (P = 0.003). An inverse correlation was observed between the abundance of intratumoural CD8+ TILs carrying PD-1 inhibitory receptor and cancer cell proliferation. Cases with high compared to low fraction of immune excluded CD8+ TILs had significantly reduced 5-year overall survival (n events: 22 vs 12; P = 0.04) and disease-free survival (n events: 24 vs 16; P = 0.03) rates while the amount of CD3+ and CD8+ TILs located at the invasive margin had a favourable effect on the clinical course. CONCLUSIONS Mapping TIL subpopulations may implement the definition of prognostic parameters in surgically resected NSCLC.

scholarly journals Acceptability and feasibility of S-1 plus cisplatin adjuvant chemotherapy for completely resected non-small cell lung cancer: an open-label, single arm, multicenter, phase 2 trial

2020 ◽  
Author(s):  
Shugo Uematsu ◽  
Atsushi Sano ◽  
Kazutoshi Isobe ◽  
Kazuhiro Usui ◽  
Jun Matsumoto ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Overall Survival ◽  
Survival Rate ◽  
Adjuvant Chemotherapy ◽  
Adverse Events ◽  
Disease Free Survival ◽  
Small Cell ◽  
Small Cell Lung ◽  
Free Survival ◽  
Disease Free

Abstract Background Although platinum-based chemotherapy is accepted as adjuvant chemotherapy for resectable advanced non-small cell lung cancer (NSCLC), its completion rate is low due to severe adverse events. S-1 plus cisplatin is associated with relatively low toxicity and an unimpaired quality of life, and has been used for unresectable advanced lung cancer. We investigated the acceptability and feasibility of combination therapy with S-1 plus cisplatin as postoperative adjuvant chemotherapy following complete resection of pathological stage II-IIIA NSCLC. Methods Enrolled patients received oral S-1 at a dose depending on their body weight twice daily for 21 days with intravenous cisplatin 60 mg/m2 on day 8, with 1 cycle comprising 5 weeks and 4 cycles. Patients received standard precautions against adverse events and received standard treatment when adverse events occurred. The primary endpoint was completion rate; secondary endpoints included safety, status of drug administration, disease-free survival, and overall survival. Results A total of 19 patients [14 men, 5 women; mean age, 59.1 years; mean body surface area, 1.688 m2; 17 with an Eastern Cooperative Oncology Group performance status (PS) of 0 and 2 with a PS of 1; 7 (36.8%) with stage II disease and 12 (63.2%) with stage IIIA disease] were enrolled. The rate of completion of 4 cycles was 68.4%. Grade 3 adverse events that occurred in ≥10% of patients included neutropenia (21.1%), nausea (21.1%), and anorexia (15.8%). No grade 4 adverse events, febrile neutropenia, or treatment-related deaths occurred. The mean relative dose intensity was 79% for S-1 and 80% for cisplatin. The 2-year disease-free survival rate was 42.1%, and 2-year overall survival rate was 83.3%. Conclusion This study demonstrated the acceptability and feasibility of using S-1 plus cisplatin as adjuvant chemotherapy.

scholarly journals Prognostic factors of local control and disease free survival in centrally located non-small cell lung cancer treated with stereotactic body radiation therapy

2020 ◽  
Vol 59 (7) ◽  
pp. 809-817
Author(s):  
Marloes Duijm ◽  
Noëlle C. van der Voort van Zyp ◽  
Patrick V. Granton ◽  
Paul van de Vaart ◽  
Mirjam E. Mast ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Radiation Therapy ◽  
Prognostic Factors ◽  
Local Control ◽  
Stereotactic Body Radiation Therapy ◽  
Disease Free Survival ◽  
Small Cell ◽  
Small Cell Lung ◽  
Free Survival ◽  
Disease Free

scholarly journals Determination of prognostic factors of surgically treated pathological Stage IIIA non-small cell lung cancer

2020 ◽  
Vol 28 (3) ◽  
pp. 496-504
Author(s):  
Muhammet Sayan
Keyword(s):  
Lung Cancer ◽  
Overall Survival ◽  
Prognostic Factors ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Disease Free Survival ◽  
Small Cell ◽  
Small Cell Lung ◽  
Free Survival ◽  
Disease Free

Background: This study aims to identify the prognostic factors in Stage IIIA non-small cell lung cancer and to investigate whether there was a significant difference in terms of overall survival and disease-free survival among the subgroups belonging to this disease stage. Methods: Between January 2010 and December 2018, a total of 144 patients (125 males, 19 females; median age 60 years; range, 41 to 80 years) who were operated for non-small cell lung cancer in our clinic and whose pathological stage was reported as IIIA were retrospectively analyzed. Data including demographic and clinical characteristics of the patients, histopathological diagnosis, the standardized uptake value of the mass on positron emission tomography-computed tomography, tumor diameter, type of surgery, lymph node metastasis status, visceral pleural invasion, and overall and disease-free survival rates were recorded. Results: The median survival was 39 (range, 27.8 to 46.1) months and the five-year overall survival rate was 28%. The mean tumor diameter was 4.3±2.7 cm. The median disease-free survival was 37 (range, 28.1 to 48.6) months and the five-year disease-free survival rate was 26.9%. In the multivariate analysis, overall survival and disease-free survival in T2N2M0 subgroup were significantly worse than the other subgroups. The other poor prognostic factors of survival were the standardized uptake value of the tumor, pneumonectomy, and histopathological subtypes other than squamous cell carcinoma and adenocarcinoma. Parietal pleural invasion was significantly associated with worse disease-free survival rates. Conclusion: Our results showed that there may be significant survival differences between subgroups created by tumor histopathology, lymph node invasion and the type of surgery in a heterogeneous lung cancer stage.

Correlation between outcomes and tumor size in >7 cm T4 non-small cell lung cancer patients: A tumor size-based comparison study

2021 ◽  
Vol 29 (8) ◽  
pp. 784-791
Author(s):  
Volkan Erdoğu ◽  
Necati Çitak ◽  
Celal B Sezen ◽  
Levent Cansever ◽  
Cemal Aker ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Overall Survival ◽  
Cancer Patients ◽  
Tumor Size ◽  
Disease Free Survival ◽  
Small Cell ◽  
Small Cell Lung ◽  
Free Survival ◽  
Lung Cancer Patients ◽  
Disease Free

Background We investigated whether all size-based pathological T4N0–N1 non-small cell lung cancer patients with tumors at any size >7 cm had the same outcomes. Methods We reviewed non-small cell lung cancer patients with tumors >7 cm who underwent anatomical lung resection between 2010 and 2016. A total of 251 size-based T4N0–N1 patients were divided into two groups based on tumor size. Group S ( n = 192) included patients with tumors of 7.1–9.9 cm and Group L ( n = 59) as tumor size ≥10 cm. Results The mean tumor size was 8.83 ± 1.7 cm (Group S: 8.06 ± 0.6 cm, Group L: 11.3 ± 1.6 cm). There were 146 patients with pathological N0 and 105 patients with pathological N1 disease. Mean overall survival and disease-free survival were 64.2 and 51.4 months, respectively. The five-year overall survival and disease-free survival rates were 51.2% and 43.5% (five-year OS; pT4N0:52.7%, pT4N1:47.9%, DFS; pT4N0:44.3%, pT4N1: 42.3%). No significant differences were observed between T4N0 and T4N1 patients in terms of five-year OS or DFS ( p = 0.325, p = 0.505 respectively). The five-year overall survival and disease-free survival rates were 52% and 44.6% in Group S, and 48.5% and 38.9% in Group L. No significant difference was observed between the groups in terms of five-year overall survival or disease-free survival ( p = 0.699, p = 0.608, respectively). Conclusions Above 7 cm, any further increase in tumor size in non-small cell lung cancer patients had no significant effect on survival, confirming it is not necessary to further discriminate among patients with tumors in that size class.

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