Omar Yumen

The KRAS-Variant and Cetuximab Response in Head and Neck Squamous Cell Cancer: A Secondary Analysis of a Randomized Clinical Trial.

Importance There is a significant need to find biomarkers of response to radiotherapy and cetuximab in locally advanced head and neck squamous cell carcinoma (HNSCC) and biomarkers that predict altered immunity, thereby enabling personalized treatment. Objectives To examine whether the Kirsten rat sarcoma viral oncogene homolog (KRAS)–variant, a germline mutation in a microRNA-binding site in KRAS, is a predictive biomarker of cetuximab response and altered immunity in the setting of radiotherapy and cisplatin treatment and to evaluate the interaction of the KRAS-variant with p16 status and blood-based transforming growth factor &bgr;1 (TGF-&bgr;1). Design, Setting, and Participants A total of 891 patients with advanced HNSCC from a phase 3 trial of cisplatin plus radiotherapy with or without cetuximab (NRG Oncology RTOG 0522) were included in this study, and 413 patients with available samples were genotyped for the KRAS-variant. Genomic DNA was tested for the KRAS-variant in a CLIA-certified laboratory. Correlation of the KRAS-variant, p16 positivity, outcome, and TGF-&bgr;1 levels was evaluated. Hazard ratios (HRs) were estimated with the Cox proportional hazards model. Main Outcomes and Measures The correlation of KRAS-variant status with cetuximab response and outcome, p16 status, and plasma TGF-&bgr;1 levels was tested. Results Of 891 patients eligible for protocol analyses (786 male [88.2%], 105 [11.2%] female, 810 white [90.9%], 81 nonwhite [9.1%]), 413 had biological samples for KRAS-variant testing, and 376 had plasma samples for TGF-&bgr;1 measurement. Seventy patients (16.9%) had the KRAS-variant. Overall, for patients with the KRAS-variant, cetuximab improved both progression-free survival (PFS) for the first year (HR, 0.31; 95% CI, 0.10-0.94; P = .04) and overall survival (OS) in years 1 to 2 (HR, 0.19; 95% CI, 0.04-0.86; P = .03). There was a significant interaction of the KRAS-variant with p16 status for PFS in patients treated without cetuximab. The p16-positive patients with the KRAS-variant treated without cetuximab had worse PFS than patients without the KRAS-variant (HR, 2.59; 95% CI, 0.91-7.33; P = .07). There was a significant 3-way interaction among the KRAS-variant, p16 status, and treatment for OS (HR, for KRAS-variant, cetuximab and p16 positive, 0.22; 95% CI, 0.03-1.66; HR for KRAS-variant, cetuximab and p16 negative, 1.43; 95% CI, 0.48-4.26; HR for KRAS-variant, no cetuximab and p16 positive, 2.48; 95% CI, 0.64-9.65; and HR for KRAS-variant, no cetuximab and p16 negative, 0.61; 95% CI, 0.23-1.59; P = .02). Patients with the KRAS-variant had significantly elevated TGF-&bgr;1 plasma levels (median, 23 376.49 vs 18 476.52 pg/mL; P = .03) and worse treatment-related toxic effects. Conclusions and Relevance Patients with the KRAS-variant with HNSCC significantly benefit from the addition of cetuximab to radiotherapy and cisplatin, and there is a significant interaction between the KRAS-variant and p16 status. Elevated TGF-&bgr;1 levels in patients with the KRAS-variant suggests that cetuximab may help these patients by overcoming TGF-&bgr;1–induced suppression of antitumor immunity. Trial Registration clinicaltrials.gov Identifier: NCT00265941

Dosimetric differences between intraoperative and postoperative plans using Cs-131 in transrectal ultrasound–guided brachytherapy for prostatic carcinoma

The aim of the study was to investigate the differences between intraoperative and postoperative dosimetry for transrectal ultrasound-guided transperineal prostate implants using cesium-131 ((131)Cs). Between 2006 and 2010, 166 patients implanted with (131)Cs had both intraoperative and postoperative dosimetry studies. All cases were monotherapy and doses of 115 were prescribed to the prostate. The dosimetric properties (D90, V150, and V100 for the prostate) of the studies were compared. Two conformity indices were also calculated and compared. Finally, the prostate was automatically sectioned into 6 sectors (anterior and posterior sectors at the base, midgland, and apex) and the intraoperative and postoperative dosimetry was compared in each individual sector. Postoperative dosimetry showed statistically significant changes (p < 0.01) in every dosimetric value except V150. In each significant case, the postoperative plans showed lower dose coverage. The conformity indexes also showed a bimodal frequency distribution with the index indicating poorer dose conformity in the postoperative plans. Sector analysis revealed less dose coverage postoperatively in the base and apex sectors with an increase in dose to the posterior midgland sector. Postoperative dosimetry overall and in specific sectors of the prostate differs significantly from intraoperative planning. Care must be taken during the intraoperative planning stage to ensure complete dose coverage of the prostate with the understanding that the final postoperative dosimetry will show less dose coverage.