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Background <p>The prognostic relevance of ultra-rare <i>TP53</i> and <i>KRAS</i> variants in advanced solid tumours treated with immune-checkpoint inhibitors (ICI) is unclear.</p> Methods <p>We performed a retrospective cohort study using the Memorial Sloan Kettering Cancer Center MSK-IMPACT clinical–genomic dataset (cBioPortal study ID: tmb_mskcc_2018). <i>TP53</i> and <i>KRAS</i> alterations were stratified by rarity (ultra-rare vs common) and analysed for overall survival (OS). Kaplan–Meier analyses and multivariable Cox proportional hazards models were fitted, adjusting for tumour type, tumour mutational burden (TMB), tumour purity, histology, age and sex.</p> Results <p>In the overall cohort, 51.4% of tumours harboured <i>TP53</i> or <i>KRAS</i> mutations. Ultra-rare variants were independently associated with worse OS (HR 1.34, 95% CI 1.14–1.56; <i>p</i> &lt; 0.001), with a median OS of 14.0&#xa0;months versus 22.0&#xa0;months in common/wild-type patients. Tumour-specific analyses suggested heterogeneity: non-small-cell lung cancer showed shorter OS for ultra-rare variants (approximately 10–13&#xa0;months vs 17&#xa0;months for wild type), whereas melanoma showed improved outcomes (HR 0.59, 95% CI 0.44–0.78; <i>p</i> &lt; 0.001).</p> Conclusion <p>Ultra-rare <i>TP53</i> and <i>KRAS</i> variants provide prognostic information in ICI-treated advanced solid tumours, but the direction and magnitude of effect vary by tumour type. These findings support tumour-specific interpretation and motivate mechanistic and therapeutic studies in this underserved molecular subgroup.</p> Graphical abstract <p></p>

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Ultra-rare TP53 and KRAS variants predict survival in ICI-treated solid tumours

  • 期刊论文

  • 发表日期：

    2026年3月20日

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  • Vicente Javier Clemente-Suárez,
  • Rodrigo Olivares,
  • Rodrigo Yáñez-Sepúlveda,
  • Eduardo Guzmán-Muñóz,
  • Alexandra Martín Rodríguez

摘要

Background

The prognostic relevance of ultra-rare TP53 and KRAS variants in advanced solid tumours treated with immune-checkpoint inhibitors (ICI) is unclear.

Methods

We performed a retrospective cohort study using the Memorial Sloan Kettering Cancer Center MSK-IMPACT clinical–genomic dataset (cBioPortal study ID: tmb_mskcc_2018). TP53 and KRAS alterations were stratified by rarity (ultra-rare vs common) and analysed for overall survival (OS). Kaplan–Meier analyses and multivariable Cox proportional hazards models were fitted, adjusting for tumour type, tumour mutational burden (TMB), tumour purity, histology, age and sex.

Results

In the overall cohort, 51.4% of tumours harboured TP53 or KRAS mutations. Ultra-rare variants were independently associated with worse OS (HR 1.34, 95% CI 1.14–1.56; p < 0.001), with a median OS of 14.0 months versus 22.0 months in common/wild-type patients. Tumour-specific analyses suggested heterogeneity: non-small-cell lung cancer showed shorter OS for ultra-rare variants (approximately 10–13 months vs 17 months for wild type), whereas melanoma showed improved outcomes (HR 0.59, 95% CI 0.44–0.78; p < 0.001).

Conclusion

Ultra-rare TP53 and KRAS variants provide prognostic information in ICI-treated advanced solid tumours, but the direction and magnitude of effect vary by tumour type. These findings support tumour-specific interpretation and motivate mechanistic and therapeutic studies in this underserved molecular subgroup.

Graphical abstract