TP53 Co-mutation With KRAS Or EGFR Has No Impact On Resected NSCLC Survival

Co-mutation status assessed in resected non-small-cell lung cancer patients assigned to receive adjuvant chemotherapy or observation

medwireNews: Carrying a TP53 mutation alongside a KRAS or EGFR mutation has no impact on the overall survival (OS) of patients who have undergone surgery for early-stage non-small-cell lung cancer (NSCLC), research suggests.

However, the investigators did detect a reduced benefit from adjuvant chemotherapy in patients carrying mutations in TP53 and KRAS, or TP53 alone, compared with those carrying neither aberration.

“Dual TP53/KRAS mutation seems to be predictive of shortened survival in patients who are treated with platinum-based [adjuvant chemotherapy], but the statistically significant result must be interpreted with caution in view of the small sample size, and validation studies are needed in both the adjuvant and advanced disease settings”, observe Frances Shepherd, from Princess Margaret Cancer Centre in Toronto, Ontario, Canada, and co-authors in the Journal of Clinical Oncology.

For the study, the researchers collated data from the Lung Adjuvant Cisplatin Evaluation (LACE) JBR.10, IALT and ANITA trials, as well as the CALGB-9633 study of carboplatin-based adjuvant chemotherapy, including a total of 3533 patients, followed-up for a median of 5.5 years.

In all, 1534 patients had mutation data available for analysis, including 404 patients with adenocarcinoma who were assessed for TP53 and EGFR. Mutation status did not significantly affect the OS benefit associated with receipt of adjuvant chemotherapy, even when analysis was restricted to adenocarcinoma patients, who are most likely to have such a double mutation.

A further 1181 patients were assessed for TP53 and KRAS status. OS was not significantly associated with TP53–KRAS mutation status in the 300 patients who were assigned to observation. Nor did OS significantly differ between patients given adjuvant chemotherapy with a KRAS mutation and those with double wild-type tumours.

However, patients given adjuvant chemotherapy who had both KRAS and TP53 mutations had significantly poorer OS than their counterparts who were wild-type for both mutations, with a hazard ratio (HR) of 2.49.

“This marginal predictive effective was homogeneous across trials (P=.04) and histology (P=.73)”, the researchers note, adding that a similar pattern was observed for disease-free survival.

“With recent improvements in technology, next-generation sequencing is now cost effective and should be considered for all newly diagnosed patients with NSCLC to assess the mutational profile of each cancer”, the team concludes.

“Although not a therapeutic target at this time, routine inclusion of TP53 mutation testing may clarify the role that this tumor suppressor gene plays, both alone and in combination with other driver mutations in lung cancer, and determine whether there is a negative interaction with treatment.”


Shepherd FA, Lacas B, Le Teuff G, et al. Pooled analysis of the prognostic and predictive effects of TP53 comutation status combined with KRAS or TP53 mutation in early-stage resected non-small-cell lung cancer in four trials of adjuvant chemotherapy. J Clin Oncol; Advance online publication 28 April 2017. DOI: 10.1200/JCO.2016.71.2893

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