Gene Expression Markers of Efficacy and Resistance to Cetuximab Treatment in Metastatic Colorectal Cancer: Results from CALGB 80203 (Alliance)

Abstract

Purpose Formalin-fixed, paraffin-embedded tumor samples from CALGB 80203 were analyzed for expression of EGFR axis–related genes to identify prognostic or predictive biomarkers for cetuximab treatment. Patients and Methods Patients (238 total) with first-line metastatic colorectal cancer (mCRC) were randomized to FOLFOX or FOLFIRI chemotherapy ± cetuximab. qRT-PCR analyses were conducted on tissues from 103 patients at baseline to measure gene expression levels of HER-related genes, including amphiregulin (AREG), betacellulin (BTC), NT5E (CD73), DUSP4, EGF, EGFR, epigen (EPGN), epiregulin (EREG), HBEGF, ERBB2 (HER2), ERBB3 (HER3), ERBB4 (HER4), PHLDA1, and TGFA. The interactions between expression levels and treatment with respect to progression-free survival (PFS) and overall survival (OS) were modeled using multiplicative Cox proportional hazards models. Results High tumor mRNA levels of HER2 [hazard ratio (HR), 0.64; P = 0.002] and EREG (HR, 0.89; P = 0.016) were prognostic markers associated with longer PFS across all patients. HER3 and CD73 expression levels were identified as potential predictive markers of benefit from cetuximab. In KRAS wild-type (WT) tumors, low HER3 expression was associated with longer OS from cetuximab treatment, whereas high HER3 expression was associated with shorter OS from cetuximab treatment (chemo + cetuximab: HR, 1.15; chemo-only: HR, 0.48; Pinteraction = 0.029). High CD73 expression was associated with longer PFS from cetuximab treatment in patients with KRAS-WT (chemo + cetuximab: HR, 0.91; chemo-only: HR, 1.57; Pinteraction = 0.026) and KRAS-mutant (Mut) tumors (chemo + cetuximab: HR, 0.80; chemo-only: HR, 1.29; P = 0.025). Conclusions Gene expression of HER3 and CD73 was identified as a potential predictive marker for cetuximab. These data implicate HER axis signaling and immune modulation as potential mechanisms of cetuximab action and sensitivity.

Characterization of 1577 Primary Prostate Cancers Reveals Novel Biological and Clinicopathologic Insights into Molecular Subtypes

“…Interestingly, although m-ETS + PCa was associated with lower PSA when compared to TripleNeg PCa, this subtype was specifically associated with increased SVI when compared to both m-ERG + and TripleNeg. On the other hand, m-SPINK1 + PCa was specifically associated with Black/African American race, in line with recent findings from an IHC based RP study assessing molecular subtypes and race [39]. …”

HER3 expression is correlated to distally located and low-grade colon cancer

“…Cushman and Gaborit report a predictive value of HER3 expression in CRC patients treated with targeting monoclonal antibodies. When regarding upcoming anti-HER3 agents, this area needs to be investigated further [21,22]. Selecting therapy in a more stratified, individual approach has been successful in breast cancer HER2 animal models by defining molecular subtypes that respond differently to treatments.…”

Anti-CD73 in Cancer Immunotherapy: Awakening New Opportunities

“…Over the past few years, studies on the modulation of CD73 expression and activity in various preclinical models of neoplastic disorders have highlighted the value of this enzyme as a potential therapeutic target for cancer treatment [7–12]. Engineered mice lacking CD73 display resistance to the onset of neoplasia and metastasis[13–15], while targeting CD73 with small molecule inhibitors or monoclonal antibodies shows antitumor effects[16–23].…”