Purpose Molecular diagnostic testing has become an integral part of the evaluation of patients with metastatic colorectal cancer (CRC). Expanded mutational testing, such as next-generation sequencing (NGS), often identifies mutations with unclear clinical or prognostic implications. One such example is BRAF mutations that occur outside of codon 600 ( BRAF mutations). Methods We conducted this multicenter, retrospective cohort study to characterize the clinical, pathologic, and survival implications of BRAF mutations in metastatic CRC. We pooled patients in whom BRAF mutations were identified from NGS databases at three large molecular genetics reference laboratories. Results A total of 9,643 patients with metastatic CRC underwent NGS testing. We identified 208 patients with BRAF mutations, which occurred in 2.2% of all patients tested and accounted for 22% of all BRAF mutations identified. Cancers with BRAF mutations, compared with cancers with V600E BRAF ( BRAF) mutations, were found in patients who were significantly younger (58 v 68 years, respectively), fewer female patients (46% v 65%, respectively), and patients who had fewer high-grade tumors (13% v 64%, respectively) or right-sided primary tumors (36% v 81%, respectively). Median overall survival was significantly longer in patients with BRAF-mutant metastatic CRC compared with those with both BRAF-mutant and wild-type BRAF metastatic CRC (60.7 v 11.4 v 43.0 months, respectively; P < .001). In multivariable analysis, BRAF mutation was independently associated with improved overall survival (hazard ratio, 0.18; P< .001). Conclusion BRAF mutations occur in approximately 2.2% of patients with metastatic CRC and define a clinically distinct subtype of CRC with an excellent prognosis.

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ObjectiveTo demonstrate sarcomatoid differentiation is an independent prognostic feature for patients with grade 4 renal cell carcinoma (RCC) with or without distant metastases. To identify independent predictors of survival, evaluate the correlation between the amount of sarcomatoid differentiation and cancer-specific survival (CSS), and to design a multivariate prognostic model for patients with sarcomatoid RCC. Patients and MethodsWe used the Mayo Clinic Nephrectomy Registry to identify 204 post-nephrectomy patients with sarcomatoid-variant RCC, as well as 207 patients with unilateral grade 4 RCC without sarcomatoid features for comparison. All slides were reviewed by one pathologist. CSS was estimated using the Kaplan-Meier method. The associations of clinical and pathological features with death from RCC were evaluated using Cox proportional hazards regression models. ResultsFor all patients with grade 4 RCC, the presence of sarcomatoid differentiation was associated with a 58% increased risk of death from RCC (P < 0.001). For patients with grade 4 non-metastatic (M0) RCC, the presence of sarcomatoid differentiation was associated with an 82% increased risk of death from RCC (P < 0.001). For patients with sarcomatoid RCC, the 2009 primary tumour classifications, presence of regional lymph nodes and distant metastases, coagulative tumour necrosis, and the amount of sarcomatoid differentiation were each significantly associated with death from RCC in a multivariate setting. After adjusting for other prognostic variables, each 10% increase in the amount of sarcomatoid differentiation was associated with a 6% increased risk of death from RCC (P = 0.028). Patients whose tumours contained ≥30% (median amount) sarcomatoid differentiation were 52% more likely to die from RCC compared with patients whose tumours contained <30% sarcomatoid differentiation (hazard ratio 1.52; P = 0.018). ConclusionsAmong patients with grade 4 RCC, either with or without distant metastases at surgery, sarcomatoid differentiation is significantly associated with adverse survival in a multivariate setting. We also suggest for the first time that the percentage of sarcomatoid differentiation is an independent prognostic feature in a multivariate setting. The 2009 primary tumour classifications, regional lymph node status, the presence of distant metastases classifications, coagulative tumour necrosis, and the amount of sarcomatoid differentiation are independent predictors of survival for patients with sarcomatoid RCC.

Objective• To evaluate carbonic anhydrase IX (CAIX) expression as an independent prognostic marker for clear cell renal cell carcinoma (ccRCC). With recent smaller studies showing conflicting results, we aimed to update our initial analysis in 2007 with an additional 5-year follow-up. Patients and Methods• We provided long-term follow-up of the same cohort used in our 2007 study (730 patients with unilateral, sporadic ccRCC treated surgically between 1990 and 1999).• Associations of CAIX expression with RCC death and distant metastases were evaluated using Cox proportional hazards regression models. Results• CAIX was expressed in 708 (97.0%) of the specimens; 163 tumours (22.3%) had low (Յ85%) expression and 567 (77.7%) high (>85%) expression.• There were 483 deaths and 265 RCC-specific deaths. The median follow-up for the 247 patients still under observation was 13.8 years.• Univariately, low CAIX expression was associated with an increased risk of RCC death vs high expression (hazard ratio 1.62; P < 0.001).• Low CAIX expression was not statistically significantly associated with RCC death or distant metastases after adjusting for nuclear grade or coagulative tumour necrosis. Conclusion• After additional long-term follow-up of our large cohort, our results continue to suggest that CAIX is not an independent prognostic marker for ccRCC.