Abstract
PurposeIn mCRC, disease dynamics may play a critical role in the understanding of long-term outcome. We evaluated depth of response (DpR), time to DpR, and post-DpR survival as relevant endpoints.MethodsWe analyzed DpR by central review of computer tomography images (change from baseline to smallest tumor diameter), early tumor shrinkage (≥ 20% reduction in tumor diameter at first reassessment), time to DpR (study randomization to DpR-image), post-DpR progression-free survival (pPFS = DpR-image to tumor progression or death), and post-DpR overall survival (pOS = DpR-image to death) with special focus on BRAF status in 66 patients and primary tumor site in 86 patients treated within the VOLFI-trial, respectively.ResultsBRAF wild-type (BRAF-WT) compared to BRAF mutant (BRAF-MT) patients had greater DpR (− 57.6% vs. − 40.8%, p = 0.013) with a comparable time to DpR [4.0 (95% CI 3.1–4.4) vs. 3.9 (95% CI 2.5–5.5) months; p = 0.8852]. pPFS was 6.5 (95% CI 4.9–8.0) versus 2.6 (95% CI 1.2–4.0) months in favor of BRAF-WT patients (HR 0.24 (95% CI 0.11–0.53); p < 0.001). This transferred into a significant difference in pOS [33.6 (95% CI 26.0–41.3) vs. 5.4 (95% CI 5.0–5.9) months; HR 0.27 (95% CI 0.13–0.55); p < 0.001]. Similar observations were made for patients stratified for primary tumor site.ConclusionsBRAF-MT patients derive a less profound treatment response compared to BRAF-WT patients. The difference in outcome according to BRAF status is evident after achievement of DpR with BRAF-MT patients hardly deriving any further disease control beyond DpR. Our observations hint towards an aggressive tumor evolution in BRAF-MT tumors, which may already be molecularly detectable at the time of DpR.
Highlights
Colorectal cancer (CRC) represents one of the most commonly diagnosed cancers in the Western World (Boyle and Langman 2000).Extended author information available on the last page of the articleWithin the entity of metastatic colorectal cancer, there are substantial differences in tumor biology (i.e., RASmutant tumors, BRAF-mutant tumors, tumors with microsatellite-instability or Her2/neu expression) that determine treatment choices and outcome (Douillard et al 2013; Heinemann et al 2014; Kopetz et al 2019; Overman et al 2018; Sartore-Bianchi et al 2016; Van Cutsem et al 2016)
A clinical database was established including the following information for each patient: treatment arm, age, sex, performance status according to Eastern Cooperative Oncology Group (ECOG), tumor characteristics, laboratory parameters, molecular characteristics (RAS and BRAF status), prior antitumor treatment, and survival parameters (PFS, Overall survival (OS))
We evaluated the depth of response, early tumor shrinkage (> 20% reduction in tumor diameter at first reassessment) as described in the previous publication, time to DpR, post-DpR Progression-free survival (PFS), and post-DpR OS by central review of computed tomography images (Modest et al 2019b)
Summary
Colorectal cancer (CRC) represents one of the most commonly diagnosed cancers in the Western World (Boyle and Langman 2000).Extended author information available on the last page of the articleWithin the entity of metastatic colorectal cancer (mCRC), there are substantial differences in tumor biology (i.e., RASmutant tumors, BRAF-mutant tumors, tumors with microsatellite-instability or Her2/neu expression) that determine treatment choices and outcome (Douillard et al 2013; Heinemann et al 2014; Kopetz et al 2019; Overman et al 2018; Sartore-Bianchi et al 2016; Van Cutsem et al 2016). The association of ETS and DpR with long-term survival is interpreted as an early identification of treatment-sensitive tumors, maybe providing a valuable tool in the context of secondary resection of metastases (Modest et al 2020). To the best of our knowledge, the dynamics and clinical course of mCRC beyond these early endpoints (i.e., ETS and in particular DpR) have been explored less rather in terms of a definition of endpoints related to progression-free survival (Chibaudel et al 2011). (progression-free) survival outcomes after DpR that might reflect the ability of a disease to overcome a certain treatment are potentially representing an interesting assessment to identify tumors with biological aggressiveness despite initial disease control
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