Significance of <i>TP53</i> mutations as predictive markers of adjuvant cisplatin‐based chemotherapy in completely resected non‐small‐cell lung cancer

Ma, Xiaoli; Rousseau, Vanessa; Sun, H.Y.; Lantuéjoul, Sylvie; Filipits, Martin; Pirker, Robert; Popper, Helmut; Mendiboure, Jean; Vataire, Anne-Lise; Chevalier, Thierry Le; Soria, Jean Charles; Brambilla, Élisabeth; Dunant, Ariane; Hainaut, Pierre

doi:10.1016/j.molonc.2013.12.015

Cited by 39 publications

(49 citation statements)

References 31 publications

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“…In a 35-patient study, the presence of mutant TP53 was highly indicative of resistance to cisplatin (P ¼ 0.002) (42), while in a study involving 253 patients, TP53-positive patients had a significantly greater survival benefit from adjuvant chemotherapy compared with TP53-negative patients (43). Another report in the International Adjuvant Lung Cancer Trial (IALT), a randomized trial of adjuvant cisplatin-based chemotherapy, found no correlation between TP53 mutation and outcome in 524 patients (44). Overall, it will be important to extend analysis to a greater number of explants/patients to robustly determine the prognostic value of TP53 mutation.…”

Section: Discussionmentioning

confidence: 96%

Ex Vivo Explant Cultures of Non–Small Cell Lung Carcinoma Enable Evaluation of Primary Tumor Responses to Anticancer Therapy

et al. 2017

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To improve treatment outcomes in non-small cell lung cancer (NSCLC), preclinical models that can better predict individual patient response to novel therapies are urgently needed. Using freshly resected tumor tissue, we describe an optimized ex vivo explant culture model that enables concurrent evaluation of NSCLC response to therapy while maintaining the tumor microenvironment. We found that approximately 70% of primary NSCLC specimens were amenable to explant culture with tissue integrity intact for up to 72 hours. Variations in cisplatin sensitivity were noted with approximately 50% of cases responding ex vivo. Notably, explant responses to cisplatin correlated significantly with patient survival (P ¼ 0.006) irrespective of tumor stage. In explant tissue, cisplatin-resistant tumors excluded platinum ions from tumor areas in contrast to cisplatin-sensitive tumors. Intact TP53 did not predict cisplatin sensitivity, but a positive correlation was observed between cisplatin sensitivity and TP53 mutation status (P ¼ 0.003). Treatment of NSCLC explants with the targeted agent TRAIL revealed differential sensitivity with the majority of tumors resistant to single-agent or cisplatin combination therapy. Overall, our results validated a rapid, reproducible, and low-cost platform for assessing drug responses in patient tumors ex vivo, thereby enabling preclinical testing of novel drugs and helping stratify patients using biomarker evaluation.

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Section: Discussionmentioning

confidence: 96%

Ex Vivo Explant Cultures of Non–Small Cell Lung Carcinoma Enable Evaluation of Primary Tumor Responses to Anticancer Therapy

et al. 2017

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“…When applied to non-small-cell lung cancer (NSCLC), the algorithm does not identify any prognostic value associated with either mutation class. However, in a randomized trial of platinium-based therapy after surgery (525 patients, 221 with mutation; 42%), non-DBM mutations were associated with poor overall survival in the group that received chemotherapy but not in the group treated by surgery only (Ma et al 2014). This effect was not seen with predicted null or DBM mutations.…”

Section: Classifying Tp53 Mutations For Clinical Usementioning

confidence: 98%

“…A multitude of cohort studies has failed to identify a prognostic effect for TP53 mutations on NSCLC survival, even in AdC and after separating TP53 into different classes (see, e.g., Scoccianti et al 2012;Ma et al 2014). However, in a comprehensive analysis of 1255 clinically annotated lung cancers by the Clinical Lung Cancer Genome Project (CLCGP), TP53 mutation was found to be associated with a significant negative prognostic value in AdC with mutated EGFR (Fig.…”

Section: Breast Cancer (Bc)mentioning

confidence: 99%

“…4). TP53 mutations have been reported as having a predictive effect on the survival of patients treated with adjuvant platinum-based therapy, a standard treatment regimen for stage II-III completely resected NSCLC (Ma et al 2014). This effect predicts a marginal benefit of adjuvant therapy in patients with wild-type TP53 and marginal detrimental effect in patients with mutated TP53 mutation.…”

Section: Breast Cancer (Bc)mentioning

confidence: 99%

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SomaticTP53Mutations in the Era of Genome Sequencing

Hainaut

Pfeifer

2016

Cold Spring Harb Perspect Med

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179

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Amid the complexity of genetic alterations in human cancer, TP53 mutation appears as an almost invariant component, representing by far the most frequent genetic alteration overall. Compared with previous targeted sequencing studies, recent integrated genomics studies offer a less biased view of TP53 mutation patterns, revealing that .20% of mutations occur outside the DNA-binding domain. Among the 12 mutations representing each at least 1% of all mutations, five occur at residues directly involved in specific DNA binding, four affect the tertiary fold of the DNA-binding domain, and three are nonsense mutations, two of them in the carboxyl terminus. Significant mutations also occur in introns, affecting alternative splicing events or generating rearrangements (e.g., in intron 1 in sporadic osteosarcoma). In aggressive cancers, mutation is so common that it may not have prognostic value (all these cancers have impaired p53 function caused by mutation or by other mechanisms). In several other cancers, however, mutation makes a clear difference for prognostication, as, for example, in HER2-enriched breast cancers and in lung adenocarcinoma with EGFR mutations. Thus, the clinical significance of TP53 mutation is dependent on tumor subtype and context. Understanding the clinical impact of mutation will require integrating mutationspecific information (type, frequency, and predicted impact) with data on haplotypes and on loss of heterozygosity.

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“…However, these studies failed to categorize by tumor stage or subtype. 12,18 The Pro-allele of the R72P polymorphism acted as a strong predictor for poorer OS in stage I tumors in our study cohort. One previous study took tumor stage into account and found a similar worse OS in the presence of at least one Pro-allele in stage I tumors, although this effect was not significant and subtype was not taken into account.…”

Section: Discussionmentioning

confidence: 62%

Deep sequencing of the TP53 gene reveals a potential risk allele for non–small cell lung cancer and supports the negative prognostic value of TP53 variants

et al. 2017

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The TP53 gene remains the most frequently altered gene in human cancer, of which variants are associated with cancer risk, therapy resistance, and poor prognosis in several tumor types. To determine the true prognostic value of TP53 variants in non-small cell lung cancer, this study conducted further research, particularly focusing on subtype and tumor stage. Therefore, we determined the TP53 status of 97 non-small cell lung cancer adenocarcinoma patients using next generation deep sequencing technology and defined the prognostic value of frequently occurring single nucleotide polymorphisms and mutations in the TP53 gene. Inactivating TP53 mutations acted as a predictor for both worse overall and progression-free survival in stage II-IV patients and patients treated with DNA-damaging (neo)adjuvant therapy. In stage I tumors, the Pro-allele of the TP53 R72P polymorphism acted as a predictor for worse overall survival. In addition, we detected the rare R213R (rs1800372, minor allele frequency: 0.0054) polymorphism in 7.2% of the patients and are the first to show the significant association with TP53 mutations in non-small cell lung cancer adenocarcinoma patients (p = 0.003). In conclusion, Our findings show an important role for TP53 variants as negative predictors for the outcome of non-small cell lung cancer adenocarcinoma patients, especially for TP53 inactivating mutations in advanced stage tumors treated with DNA-damaging agents, and provide the first evidence of the R213R G-allele as possible risk factor for non-small cell lung cancer.

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Significance of TP53 mutations as predictive markers of adjuvant cisplatin‐based chemotherapy in completely resected non‐small‐cell lung cancer

Cited by 39 publications

References 31 publications

Ex Vivo Explant Cultures of Non–Small Cell Lung Carcinoma Enable Evaluation of Primary Tumor Responses to Anticancer Therapy

Ex Vivo Explant Cultures of Non–Small Cell Lung Carcinoma Enable Evaluation of Primary Tumor Responses to Anticancer Therapy

SomaticTP53Mutations in the Era of Genome Sequencing

Deep sequencing of the TP53 gene reveals a potential risk allele for non–small cell lung cancer and supports the negative prognostic value of TP53 variants

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