Zhang, Nicole J.

Abstract Background Impact of BRAF V600E mutations (BRAFV600E), a poor prognostic factor in metastatic colorectal cancer, is lacking in non-CRC gastrointestinal (GI) cancers including pancreatic (PDAC), gastric/gastroesophageal (GEA), hepatocellular carcinoma (HCC), and cholangiocarcinoma (CCA). Due to tumor-agnostic approvals for patients with BRAFV600E, understanding the frequency and impact of BRAF alterations across non-CRC GI cancers is essential for clinical decision-making. Methods Patients with PDAC, GEA, HCC, or CCA who had cell-free DNA detected on Guardant360 (Guardant Health) from 2020 to 2023 were queried. Prevalence of characterized BRAF genomic alterations (GA) was calculated; GAs were grouped by class (Class I/II/III). The Chi-squared test assessed differences between cancer types. A subset of patients had outcomes analysis using GuardantINFORM, a real-world clinicogenomic database, to derive real-world overall survival (rwOS). Results Of 32 480 included patients, BRAF GAs were identified in 4.4%; 19% were BRAFV600E (0.81% prevalence overall). CCA had the highest rate of BRAF GAs and BRAFV600E (P < .01); HCC and GEA had the highest rates of BRAF class II/III alterations. There were no significant differences in rwOS by alteration class or cancer type; numeric differences were observed by alteration class. Few patients were treated with BRAF inhibitors (2.2%). Prevalence of co-occurring alterations was unique by cancer type. Conclusions Frequency of BRAF GAs, including BRAFV600E, in non-CRC GI cancers detected by liquid biopsy is similar to tissue-based rates and can be reliably used to assess BRAF status. BRAF GAs have mixed prognostic implications on survival for patients with non-CRC GI malignancies that warrant further exploration.

MSI-H identified by ctDNA: prevalence across 21 advanced cancers and outcomes from >700 patients.

Background: HER2 amplification (HER2+) occurs in approximately 3% of patients with metastatic colorectal cancer (mCRC). Despite the recent addition of HER2-directed therapies to treatment recommendations in the NCCN Guidelines, until more recently there were no FDA-approved treatments. This study examined real-world treatment patterns in patients with HER2+ mCRC in the United States before and after the emerging awareness of HER2-directed therapies in 2018. Methods: This was a retrospective observational study of patients with HER2+ mCRC from the GuardantINFORM database, which contains claims data for patients with Guardant360 genomic testing results. Patients were aged ≥18 years, were diagnosed with mCRC between January 2014 and September 2020, and had confirmed ERBB2 amplification via the blood-based Guardant360 test. Treatment patterns and real-world time to next treatment (rwTTNT) were evaluated. Results: This study included 142 patients with a median age of 59 years; 31 (21.8%) patients with ERBB2 amplifications also had ERBB2 mutations. Treatment patterns were heterogeneous and evolved over time; before 2018, the most common regimen prescribed after detection of ERBB2 amplification was anti-VEGF therapy with or without chemotherapy (31.6%; n=25), and after 2018, HER2-directed therapies were the most commonly prescribed (36.5%; n=23). Median rwTTNT among the overall cohort was 8.4 months (95% CI, 6.5–10.0); rwTTNT was numerically longer in patients who received HER2-directed therapy compared with those who received non–HER2-directed therapies (11.0 months [95% CI, 6.3–12.3] vs 7.2 months [95% CI, 5.8–9.6]). Conclusions: This real-world study of the largest clinically annotated dataset of patients with HER2+ mCRC showed that many patients do not receive HER2-directed therapy despite its inclusion in NCCN Guidelines, with heterogeneous treatment patterns suggesting that standard of care remains undefined and targeted therapy remains underutilized. Greater awareness of the unmet need in this patient population, together with new effective therapies, will facilitate strategies for improved, targeted treatment approaches.