Highlights of This Issue

Abstract

Low endoxifen levels are associated with an impaired outcome in breast cancer patients treated with tamoxifen. Endoxifen relies on CYP2D6 metabolism but genotype does not consistently correlate with outcome. In 122 tamoxifen-treated patients, Fox and colleagues found that concomitant medications (14%), CYP2D6 genotype (24%), compliance and absorption (21%), and unknown factors (52%) all contributed to low endoxifen. The authors then increased the tamoxifen dose in those with low endoxifen and found that the best predictor for reaching a therapeutic level was the baseline endoxifen level and not CYP2D6 genotype. It was concluded that therapeutic monitoring of endoxifen requires more attention.Antitumor immunity likely plays a role in mediating response to trastuzumab-based therapy in HER2-positive breast cancer. To explore the in vivo effects of trastuzumab on the immune-related microenvironment, Varadan and colleagues studied two prospective, multicenter, preoperative trials that incorporated collection of core biopsies after a run-in of trastuzumab prior to combination chemotherapy. Predefined gene expression signatures of immune cell infiltration and specific T-cell subsets, evaluated at the run-in timepoint, were shown to be predictive of subsequent response across both trials. These signatures show promise for enabling triage of HER2-positive early breast cancer patients to the most effective preoperative therapy.Acquired resistance to cetuximab in colorectal cancer (CRC) patients is driven by the emergence of mutations in EGFR extracellular domain (ECD) in approximately 15% of cases. Sánchez-Martín and colleagues evaluated the efficacy of Sym004, a novel second-generation anti-EGFR antibody mixture, in in vitro and in vivo cetuximab-resistant CRC models and found that Sym004 is a valid strategy to treat CRC tumors harboring EGFR ECD mutations. As a proof-of-concept, one patient with an EGFR ECD mutation (G465R) benefited from treatment with Sym004, thus providing the basis for Sym004 current evaluation in clinical trials in patients harboring EGFR ECD mutations.The role of mitochondrial reprogramming in breast cancer progression remains enigmatic. In this study, Kannan and colleagues identified that a vesicular endocytosis-associated cytoplasmic protein, SH3GL2, translocates to mitochondria, becomes phosphorylated, and induces mitochondrial fusion, superoxide (O2−) production, and CYTC release in concert with enhanced expression of various mitochondrial proteins. These cascades of events reduced spontaneous lung and liver metastases and primary tumor growth. Mitochondrial fusion protein MFN2 was identified as a partner of SH3GL2, and the loss of their coexpression predicted poor progression and was detectable in the circulating exosomes. Monitoring SH3GL2 and MFN2 loss has the potential for biomarker development.