scholarly journals The influence of genetic polymorphisms on the toxicity of platinum-based chemotherapy in the treatment of non-small cell lung cancer

2021 ◽  
Vol 72 (2) ◽  
pp. 40-47
Author(s):  
Jelena Spasić ◽  
Davorin Radosavljević ◽  
Ljudmila Nagorni-Obradović
Keyword(s):  
Lung Cancer ◽  
Immune Therapy ◽  
Treatment Algorithm ◽  
Genetic Alterations ◽  
Limiting Factor ◽  
Signal Pathways ◽  
Nucleotide Polymorphisms ◽  
Adequate Treatment ◽  
Chemotherapy Drugs ◽  
Platinum Based Chemotherapy

Lung cancer remains one of the most frequent and the deadliest of malignant diseases throughout the world. Target and immune therapy have revolutionalized the treatment of this disease, but platinum-based chemotherapy still has a place in the treatment algorithm. The toxicity profile of cisplatin is well known and can be a limiting factor in the adequate treatment delivery of the drug. There are important inter-individual differences in the efficacy and the toxicity of all chemotherapy drugs, which cannot be explained solely by the characteristics of the tumor. In order to define predictive factors for the occurrence of toxic effects, numerous genetic alterations have been investigated - especially single nucleotide polymorphisms (SNPs). The investigated genes are those involved in DNA repair mechanisms, signal pathways of apoptosis, DNA synthesis, transport mechanisms, but often with inconclusive and opposing results. It is clear that the effect of SNPs on the occurrence of cisplatin toxicity cannot be explained by investigating just one or several genes alone, but epigenetic interactions must be investigated, as well as interactions with outside factors. The study of SNPs is, however, a relatively simple and inexpensive method and, as such, can be used as one of the prognostic tools for everyday practice.

scholarly journals Future Options of Molecular-Targeted Therapy in Small Cell Lung Cancer

Cancers ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 690 ◽  
Author(s):  
Arik Bernard Schulze ◽  
Georg Evers ◽  
Andrea Kerkhoff ◽  
Michael Mohr ◽  
Christoph Schliemann ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Genetic Alterations ◽  
Small Cell ◽  
Molecular Pathways ◽  
Loss Of Function ◽  
Small Cell Lung ◽  
Therapeutic Concept ◽  
Platinum Based Chemotherapy

Lung cancer is the leading cause of cancer-related deaths worldwide. With a focus on histology, there are two major subtypes: Non-small cell lung cancer (NSCLC) (the more frequent subtype), and small cell lung cancer (SCLC) (the more aggressive one). Even though SCLC, in general, is a chemosensitive malignancy, relapses following induction therapy are frequent. The standard of care treatment of SCLC consists of platinum-based chemotherapy in combination with etoposide that is subsequently enhanced by PD-L1-inhibiting atezolizumab in the extensive-stage disease, as the addition of immune-checkpoint inhibition yielded improved overall survival. Although there are promising molecular pathways with potential therapeutic impacts, targeted therapies are still not an integral part of routine treatment. Against this background, we evaluated current literature for potential new molecular candidates such as surface markers (e.g., DLL3, TROP-2 or CD56), apoptotic factors (e.g., BCL-2, BET), genetic alterations (e.g., CREBBP, NOTCH or PTEN) or vascular markers (e.g., VEGF, FGFR1 or CD13). Apart from these factors, the application of so-called ‘poly-(ADP)-ribose polymerases’ (PARP) inhibitors can influence tumor repair mechanisms and thus offer new perspectives for future treatment. Another promising therapeutic concept is the inhibition of ‘enhancer of zeste homolog 2’ (EZH2) in the loss of function of tumor suppressors or amplification of (proto-) oncogenes. Considering the poor prognosis of SCLC patients, new molecular pathways require further investigation to augment our therapeutic armamentarium in the future.

Clinical significance of ERCC2 haplotype-tagging single nucleotide polymorphisms in patients with unresectable non-small cell lung cancer treated with first-line platinum-based chemotherapy.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e19156-e19156
Author(s):  
Seok-Hyun Kim ◽  
Gyeong-won Lee ◽  
Yi Yeong Jeong ◽  
Ho-Cheol Kim ◽  
Jong Deog Lee ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell ◽  
Rank Test ◽  
Nucleotide Polymorphisms ◽  
Small Cell Lung ◽  
First Line ◽  
Single Nucleotide ◽  
Log Rank Test ◽  
Platinum Based Chemotherapy ◽  
Grade 3

e19156 Background: DNA repair pathway is a crucial molecular mechanism potentially involved in resistance to platinum-based chemotherapy in the unresectable non-small cell lung cancer. Furthermore, single nucleotide polymorphisms (SNPs) and haplotypes in the ERCC2 gene are thought to be associated with the risk of developing lung cancer and clinical outcomes. Methods: We genotyped 8 ERCC2 htSNPs for 129 unresectable NSCLC (stage IIIA, 12; stage III, 36; stage IV, 82) cases treated with first-line platinum-based chemotherapy. Clinical characteristics, treatment outcomes, and predictive value of htSNPs in patient response, survival, and chemotherapy-related adverse events were analyzed according to each ERCC2 htSNP using chi-square test, Kaplan-Meier method, and Cox proportional hazard model. Results: No differences were observed in patient or disease characteristics and response according to ERCC2 htSNPs. In a survival analysis, rs50872 was significantly related to overall survival (OS) (log-rank test, p=0.014). The median survival duration of rs50872 G/G, A/G, and A/A genotypes was 35.75 (95% confidence interval [CI] 21.05-50.45), 36.07 (hazard ratio[HR] 1.02, 95% CI 25.20-46.94), and 16.75 (HR 3.49, 95% CI 5.73-27.77) months, respectively. A significant association was observed between grade 3-4 infections and poor survival: OS in patients with a grade 0-2 infection: 35.75 months (95% CI 28.15-43.35); OS in patients with a grade 3-4 infection: 12.86 months (95% CI 8.99-16.72, HR 3.57) (log-rank test, p<0.001). In a subgroup analysis, rs238405 genotype was significantly related to OS in the taxane-based group. However, rs238416 genotype was significantly associated with OS in the gemcitabine-based group. Conclusions: ERCC2 htSNPs rs50872 (overall), rs238405 (taxane-based group), and rs238416 (gemcitabine-based group) and infection related to first-line chemotherapy were associated with OS in unresectable NSCLC patients treated with first-line platinum-based chemotherapy. However, additional large prospective studies focusing on the role of ERCC2 htSNPs in unresectable NSCLC are needed.

Impact of large-scale nationwide genomic screening project for small cell lung cancer (LC-SCRUM-Japan).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 8559-8559
Author(s):  
Naoki Furuya ◽  
Shigeki Umemura ◽  
Hibiki Udagawa ◽  
Tadasuke Shimokawaji ◽  
Takashi Seto ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Large Scale ◽  
Genetic Alterations ◽  
Small Cell ◽  
Clinical Samples ◽  
Small Cell Lung ◽  
Platinum Based Chemotherapy ◽  
Genomic Screening

8559 Background: A variety of genetic analyses have been performed in small cell lung cancer (SCLC), however the clinical relevance of them remains unclear. We prospectively analyzed clinical samples of small-cell lung cancer using a nationwide genomic screening project (LC-SCRUM-Japan). Methods: Submitted tumor samples were subjected to a next-generation sequencing (NGS) system, Oncomine™ Comprehensive Assay, enabling the simultaneous analysis of 143 (ver.1) or 161 (ver.3) cancer-related genes. Results: From July 2015 to January 2019, 707 SCLC patients had been enrolled. The median age was 68 years. 77% were male and 94% were smokers. Among 588 samples completed analysis, we identified high prevalence of inactivating TP53/RB1 mutations in 426 (72%) /194 (33%) of cases, respectively. MYC/MYCL1/MYCN amplifications were detected in 21 (4%) /30 (5%) /9 (2%) of cases, respectively. This NGS analysis also showed that 32 (5%) of cases had well-known genetic alterations in receptor tyrosine kinase genes: 9 EGFR mutations, 9 KRAS mutations and 14 FGFR1 copy number gains. Mutations in the PI3K pathway were detected in 44 (7%) of the tumors. Among them, 8 cases enrolled in the investigator-initiated phase II study of gedatolisib (UMIN 000020585). Survival data was available in 463 patients receiving platinum-based chemotherapy. Multivariate analysis revealed that the presence of PIK3CA mutation (HR; 2.56; 95% CI 1.19 – 5.52; p = 0.016) and MYCN amplification (HR; 4.36; 95% CI 1.91 – 9.97; p < 0.001) were significantly associated with unfavorable survival. The frequency of amplifications in MYC family genes was higher in the samples obtained ≥ 90 days after the first-line platinum-based chemotherapy (18.1%) than in those < 90 days (8.1%, p = 0.01), suggesting MYC family amplification as one of the resistance mechanisms. Conclusions: This large-scale nationwide screening system is helpful for identifying therapeutically relevant genetic alterations, prognostic prediction, and exploring resistance mechanism in SCLC. Updated screening results will be presented at the 2019 ASCO Annual Meeting. Clinical trial information: UMIN000018656.

scholarly journals Highlights on the morphology, prognostic factors, diagnostics, and treatment (chemotherapy, chemotherapy + radiation, targeted therapy, immunotherapy, and surgery) in small cell lung cancer

2020 ◽  
Vol 25 (4) ◽  
pp. 127-135
Author(s):  
Mark B. Bychkov ◽  
A. E. Kuzminov
Keyword(s):  
Lung Cancer ◽  
Prognostic Factors ◽  
Targeted Therapy ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Treatment Algorithm ◽  
Genetic Alterations ◽  
Small Cell ◽  
Line Treatment ◽  
Small Cell Lung

The article present a review and experience from a a single institution on the morphology, diagnostics, and treatment (chemotherapy, radiation, targeted therapy, and immunotherapy)) of small cell lung cancer (SCLC). The characteristic molecular, genetic, histological, and immunohistochemical features of NSCLC and SCLC are compared. An important issue of SCLC histogenesis is highlighted, taking into account its neuroendocrine characteristics. Paraneoplastic syndromes associated with SCLC and other clinical features of SCLC are discussed. The algorithm of examination of a patient with histologically or cytologically confirmed SCLC, staging schemes, and main prognostic factors are presented. The following aspects of chemoradiotherapy of localized SCLC are considered: features of early, late, simultaneous, and sequential therapy, and the need for whole brain radiotherapy in patients with localized and extensive SCLC. The article discusses the treatment algorithm for extensive disease SCLC, taking into account the recent success of chemoimmunotherapy in the first-line treatment of SCLC. As is known, the combinations of atezolizumab, etoposide, carboplatin and durvalumab, etoposide, cisplatin, or carboplatin showed a real benefit compared to chemotherapy alone. Although the second line treatment has not changed, it is now possible to prescribe a third line therapy because of the proven effectiveness of immunotherapy. Targeted therapy, although not shown to be effective in SCLC, is discussed in terms of the key features of genetic alterations as a possible target for therapy. An important issue in the treatment of patients with superior vena cava syndrome is considered separately. The tasks of future prospective research in SCLC are described.

scholarly journals Algorithm for the treatment of advanced or metastatic squamous non-small-cell lung cancer: an evidence-based overview

2018 ◽  
Vol 25 ◽  
pp. 77 ◽  
Author(s):  
N. Daaboul ◽  
G. Nicholas ◽  
S. A. Laurie
Keyword(s):  
Lung Cancer ◽  
Growth Factor ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Treatment Algorithm ◽  
Growth Factor Receptor ◽  
Genetic Alterations ◽  
Small Cell ◽  
Current Evidence ◽  
Small Cell Lung

The treatment of squamous non-small-cell lung cancer (nsclc) is evolving. In the past, the backbone of treatment was chemotherapy, with very few other options available. Fortunately, that situation is changing, especially with a better understanding of tumour biology. Various strategies have been tried to improve patient outcomes. The most notable advance must be immunotherapy, which has revolutionized the treatment paradigm for lung cancer in patients without a driver mutation. Immunotherapy is now the treatment of choice in patients who have progressed after chemotherapy and is replacing chemotherapy as upfront therapy in a selected population. Other strategies have also been tried, such as the addition of targeted therapy to chemotherapy. Targeted agents include ramucirumab, an inhibitor of vascular endothelial growth factor receptor 2, and necitumumab, a monoclonal antibody against epithelial growth factor receptor. Recently, advances in molecular profiling have also been applied to tumours of squamous histology, in which multiple genetic alterations, including mutations and amplifications, have been described. Research is actively seeking targetable mutations and testing various therapies in the hopes of further improving prognosis for patients with squamous nsclc. Here, we review the various advances in the treatment of squamous nsclc and present a proposed treatment algorithm based on current evidence.

scholarly journals Targeted and Immune Therapies in Non-small Cell Lung Cancer—Latest Advances

2017 ◽  
Vol 13 (02) ◽  
pp. 77
Author(s):  
Suresh S Ramalingam ◽  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Transmembrane Protein ◽  
Immune Therapy ◽  
Genetic Alterations ◽  
Small Cell ◽  
Egfr Mutations ◽  
Small Cell Lung ◽  
Expert Interview

In recent years the treatment landscape of non-small cell lung cancer (NSCLC) has been transformed. The emergence of therapies targeting specific genetic alterations, such as epidermal growth factor (EGFR) mutations, as well as immune checkpoint inhibitors targeting the transmembrane protein programmed death-1 (PD1) and its ligand (PDL1), has increased the therapeutic options for patients with NSCLC. In an expert interview, Suresh S Ramalingam discusses recent advances in targeted and immune therapy and considers the role of chemotherapy within this rapidly evolving therapeutic paradigm.

scholarly journals Polymorphisms in EGFR Gene Predict Clinical Outcome in Unresectable Non-Small Cell Lung Cancer Treated with Radiotherapy and Platinum-Based Chemoradiotherapy

2021 ◽  
Vol 22 (11) ◽  
pp. 5605
Author(s):  
Dorota Butkiewicz ◽  
Małgorzata Krześniak ◽  
Agnieszka Gdowicz-Kłosok ◽  
Monika Giglok ◽  
Małgorzata Marszałek-Zeńczak ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Locoregional Recurrence ◽  
Therapy Resistance ◽  
Small Cell ◽  
Nucleotide Polymorphisms ◽  
Small Cell Lung ◽  
Egfr Gene ◽  
Platinum Based Chemotherapy

For non-small cell lung cancer (NSCLC), radiotherapy (RT) and platinum-based chemotherapy (CHT) are among the main treatment options. On the other hand, radioresistance and cytotoxic drug resistance are common causes of failure. The epidermal growth factor receptor (EGFR) plays an important role in radioresponse and therapy resistance. We hypothesized that single nucleotide polymorphisms (SNPs) in the EGFR gene might affect individual sensitivity to these treatments, and thus, therapy outcome and prognosis. The association between functional EGFR SNPs and overall (OS), locoregional recurrence-free (LFRS), and metastasis-free (MFS) survival was examined in 436 patients with unresectable NSCLC receiving RT and platinum-based CHTRT. In a multivariate analysis, the rs712830 CC homozygotes showed reduced OS in the whole group (p = 0.039) and in the curative treatment subset (p = 0.047). The rs712829 TT genotype was strongly associated with decreased LRFS (p = 0.006), and the T-C haplotype was a risk factor for locoregional recurrence in our patients (p = 0.003). The rs2227983 GG alone and in combination with rs712829 T was an indicator of unfavorable LRFS (p = 0.028 and 0.002, respectively). Moreover, significant independent effects of these SNPs on OS, LRFS, and MFS were observed. Our results demonstrate that inherited EGFR gene variants may predict clinical outcomes in NSCLC treated with DNA damage-inducing therapy.

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