RAS Amplification as a Negative Predictor of Benefit from Anti-EGFR-Containing Therapy Regimens in Metastatic Colorectal Cancer.

BACKGROUND: RAS short variant (SV) mutations in colorectal cancer (CRC) are associated with lack of benefit from epidermal growth factor receptor (EGFR) monoclonal antibody (EGFRmAb). However, the clinical implications for RAS amplification (RASa) as a biomarker for anti-EGFR therapy in CRC remain ill defined. METHODS: Genomic analysis was performed using the Foundation Medicine (FM) comprehensive genomic profiling database of 37,233 CRC cases. Clinical outcomes were assessed using two independent cohorts: the City of Hope (COH) cohort of 338 patients with metastatic CRC (mCRC) and the Flatiron Health-FM real-world clinicogenomic database (CGDB) of 3,904 patients with mCRC. RESULTS: RASa was detected in 1.6% (614/37,233) of primarily mCRC. RASa 6-9 (n = 241, 39%), 10-19 (n = 165, 27%), and ≥ 20 (n = 209, 34%) copy number subsets had co-RAS SV/BRAF V600E in 63%/3%, 31%/0.6%, and 4.8%/0% of cases, respectively. In the COH cohort, six patients with RASa (13-54 copies) received EGFRmAb, four of six had progressive disease, two had stable disease, and median time to treatment discontinuation (TTD) was 2.5 months. Of the CGDB EGFRmAb-treated patients, those with RASa (n = 9) had median TTD of 4.7 months and overall survival (OS) of 11.4 months, those with RAS SV (n = 101) had median TTD and OS of 5.3 and 9.4 months, and those with RAS/BRAF wild-type (n = 608) had median TTD and OS of 7.6 and 13.7 months. CONCLUSION: Patients with RASa without RAS mutations (1.1% of mCRC) may have poor outcomes on EGFRmAb, although numbers herein were small, and interpretation is confounded by combination chemotherapy. Larger independent studies are warranted to determine if RASa, including degree of amplification, may act similarly to RAS mutation as a resistance mechanism to EGFRmAb therapies. IMPLICATIONS FOR PRACTICE: Genomic data suggest that RAS amplification occurs as the sole RAS/RAF alteration in >1% of colorectal cancer cases and that degree of amplification inversely correlates with co-occurring MAPK pathway alterations. Preliminary clinical evidence suggests that RAS amplification may function similarly to RAS mutation as a negative predictor of benefit from anti-epidermal growth factor receptor therapies in colorectal cancer. More clinical data are needed, and comprehensive genomic profiling, including detection of RAS amplification, should be used in trial design to inform therapy selection.

Federally Qualified Health Center Substitution of Local Health Department Services.

INTRODUCTION: Strategic and budgetary considerations have shifted local health departments (LHDs) away from safety net clinical services and toward population-focused services. Federally Qualified Health Centers (FQHCs) play an increasing role in the safety net, and may complement or substitute for LHD clinical services. The authors examined the association between FQHC service levels in communities and the presence of specific LHD clinical services in 2010 and 2013. METHODS: Data from LHD surveys and FQHC service data were merged for 2010 and 2013. Multivariate regression and instrumental variable methods were used to examine FQHC service levels that might predict related LHD service presence or discontinuation from 2010 to 2013. RESULTS: There were modest reductions in LHD service presence and increases in FQHC service volume over the time period. LHD primary care and dental service presence were inversely associated with higher related FQHC service volume. LHD prenatal care service presence, as well as a measure of change in general service approach, were not significantly associated with FQHC service volume. CONCLUSIONS: LHDs were less likely to provide certain clinical services where FQHCs provide a greater volume of services, suggesting a substitution effect. However, certain clinical services, such as prenatal care, may complement the public health mission-and LHDs may be strategically placed to continue to deliver these services.