Anand B. Desai

Univariate and Multivariable Cause-Specific Cox Models for KRAS as a Prognostic Biomarker for Distant Metastasis

Grade 3 to 4 treatment-related AEs over time by KRAS and assigned treatment. Rates of treatment-related AEs with 95% CI by treatment and KRAS-variant status, with KRAS-variant patients being depicted by blue (cisplatin-treated) and red (cetuximab-treated) and nonvariant patients depicted by green (cisplatin-treated) and brown (cetuximab-treated).

Multivariable Cox Models for KRAS as a Predictive Biomarker for Local-Regional Failure

Multivariable Cox Models for KRAS as a Predictive Biomarker for Distant Metastasis

Representativeness of Study Participants

LRF by KRAS and assigned treatment. Rates of local failure based on treatment and KRAS-variant status, with KRAS-variant patients being depicted by blue lines and nonvariant patients by red lines and dashed lines representing cetuximab-treated patients.

Purpose:NRG/RTOG 1016 was a phase III noninferiority trial comparing IMRT + cisplatin versus IMRT + cetuximab for human papillomavirus–positive oropharyngeal squamous cell cancer (HPV+ OPSCC). A germline mutation (the KRAS-variant) previously identified patients with improved outcomes to radiation + cetuximab + cisplatin; thus, we investigated whether there may be similar benefits for IMRT + cetuximab.Patients and Methods:562 patients were tested, with 16% positive for the KRAS-variant. Clinical endpoints were per NRG/RTOG 1016, and hazard ratios (HR) were estimated by Cox models. Negative binomial regression modeled treatment-related acute and late grade 3 to 5 adverse events (AE). All models included KRAS, assigned treatment, their interaction, and other prognostic variables tested at two-sided 0.05.Results:There was no association between the KRAS-variant and clinical outcomes. There were higher local–regional failure rates (LRF) in nonvariant patients treated with cetuximab [HR = 1.83 (1.19–2.82)] versus KRAS-variant patients [HR (95% CI), 0.90 (0.34–2.41)]. Grade 3 to 4 acute mucositis was higher in nonvariant patients treated with cetuximab [OR = 1.41 (95% CI, 0.98–2.03)] and lower in KRAS-variant patients [OR = 0.60 (95% CI, 0.25–1.41)]. However, the mean late toxicity ratio was lower in nonvariant patients [0.55 (95% CI, 0.35–0.87)] versus KRAS-variant patients [1.62 (95% CI, 0.57–4.62)]. KRAS by treatment interaction for acute and late AEs was not significant (P = 0.0717 and 0.0659, respectively).Conclusions:Possible lower LRF and less acute toxicity with cetuximab versus cisplatin for KRAS-variant patients seem to be offset by potentially increased late toxicity. Further evaluation of this class of biomarkers is warranted.Significance:Germline microRNA-disrupting biomarkers are functional biomarkers being studied to help guide treatment personalization in cancer. The work in this study is a hypothesis-generating evaluation of the KRAS-variant as a potential biomarker to help predict outcomes and toxicity in patients with head and neck cancer treated with radiation and cetuximab. Findings from this work suggest that these biomarkers may have the potential to differentiate patients at risk of acute versus late toxicity, supporting further study of these biomarkers in radiation studies.

Number of grade 3–5 treatment-relateda lateb AEs by KRAS and assigned treatment.