Anti-EGFR-resistant clones decay exponentially after progression: implications for anti-EGFR re-challenge.

BACKGROUND: Colorectal cancer (CRC) has been shown to acquire RAS and EGFR ectodomain mutations as mechanisms of resistance to epidermal growth factor receptor (EGFR) inhibition (anti-EGFR). After anti-EGFR withdrawal, RAS and EGFR mutant clones lack a growth advantage relative to other clones and decay; however, the kinetics of decay remain unclear. We sought to determine the kinetics of acquired RAS/EGFR mutations after discontinuation of anti-EGFR therapy. PATIENTS AND METHODS: We present the post-progression circulating tumor DNA (ctDNA) profiles of 135 patients with RAS/BRAF wild-type metastatic CRC treated with anti-EGFR who acquired RAS and/or EGFR mutations during therapy. Our validation cohort consisted of an external dataset of 73 patients with a ctDNA profile suggestive of prior anti-EGFR exposure and serial sampling. A separate retrospective cohort of 80 patients was used to evaluate overall response rate and progression free survival during re-challenge therapies. RESULTS: Our analysis showed that RAS and EGFR relative mutant allele frequency decays exponentially (r2=0.93 for RAS; r2=0.94 for EGFR) with a cumulative half-life of 4.4 months. We validated our findings using an external dataset of 73 patients with a ctDNA profile suggestive of prior anti-EGFR exposure and serial sampling, confirming exponential decay with an estimated half-life of 4.3 months. A separate retrospective cohort of 80 patients showed that patients had a higher overall response rate during re-challenge therapies after increasing time intervals, as predicted by our model. CONCLUSION: These results provide scientific support for anti-EGFR re-challenge and guide the optimal timing of re-challenge initiation.

Impact of genomic alterations on lapatinib treatment outcome and cell-free genomic landscape during HER2 therapy in HER2+ gastric cancer patients.

Background: To identify predictive markers for responders in lapatinib-treated patients and to demonstrate molecular changes during lapatinib treatment via cell-free genomics. Patients and methods: We prospectively evaluated the efficacy of combining lapatinib with capecitabine and oxaliplatin as first line neoadjuvant therapy in patients with previously untreated, HER2-overexpressing advanced gastric cancer. A parallel biomarker study was conducted by simultaneously performing immunohistochemistry and next-generation sequencing (NGS) with tumor and blood samples. Results: Complete response was confirmed in 7/32 patients (21.8%), 2 of whom received radical surgery with pathologic-confirmed complete response. Fifteen partial responses (46.8%) were observed, resulting in a 68.6% overall response rate. NGS of the 16 tumor specimens demonstrated that the most common co-occurring copy number alteration was CCNE1 amplification, which was present in 40% of HER2+ tumors. The relationship between CCNE1 amplification and lack of response to HER2-targeted therapy trended toward statistical significance (66.7% of non-responders versus 22.2% of responders harbored CCNE1 amplification; P = 0.08). Patients with high level ERBB2 amplification by NGS were more likely to respond to therapy, compared with patients with low level ERBB2 amplification (P = 0.02). Analysis of cfDNA showed that detectable ERBB2 copy number amplification in plasma was predictive to the response (100%, response rate) and changes in plasma-detected genomic alterations were associated with lapatinib sensitivity and/or resistance. The follow-up cfDNA genomics at disease progression demonstrated that there are emergences of other genomic aberrations such as MYC, EGFR, FGFR2 and MET amplifications. Conclusions: The present study showed that HER2+ GC patients respond differently according to concomitant genomic aberrations beyond ERBB2, high ERBB2 amplification by NGS or cfDNA can be a positive predictor for patient selection, and tumor genomic alterations change significantly during targeted agent therapy.

The effect of a single dose of vitamin D on glycemic status and C-reactive protein levels in type 2 diabetic patients with ischemic heart disease: a randomized clinical trial.

AIMS: To assess whether a single parental dose of 25-hydroxy vitamin D [25(OH)Vit D] could improve glucose control and inflammation in type 2 diabetic patients (T2D) with ischemic heart disease (IHD). METHODS: A randomized, placebo-controlled, double-blind trial was performed on 95 patients (47-placebo and 48-vitamin D groups). Participants were randomized using a randomization table to a single dose of either vitamin D (300,000 IU, IM) or a matching placebo. Fasting blood sugar (FBS), glycosylated hemoglobin (HbA1c), 25(OH)Vit D and high-sensitivity C-reactive protein (hs-CRP) were measured at baseline and at 8 weeks. RESULTS: No significant differences in baseline values were noted between groups, except in HbA1c, which was lower in the placebo group. In the supplemented group, the level of serum 25(OH)Vit D increased (29.6 ± 20.8 vs. 44.5 ± 19.2 ng/mL) and those of FBS and HbA1c decreased significantly [186.5 ± 64.1 vs. 165.1 ± 58.5 mg/dL and 8.2 ± 2.0 % (66.3 ± 21.8 mmol/mol) vs. 7.7 ± 1.8 % (61.7 ± 20.0 mmol/mol), respectively] (all p < 0.05), and no changes, however, were observed in the placebo group. We also compared change of marginal means of outcome variables (HbA1c, FBS, 25(OH)Vit D and hs-CRP) from baseline between the vitamin D versus placebo group, using ANCOVA, adjusted for the baseline of each variable itself, season at study entry, age and body mass index. During trial, only HbA1c level decreased significantly [0.48 % (standard error: 0.17), p = 0.04]. No any adverse effect was seen. CONCLUSIONS: A single parenteral dose of vitamin D in T2D patients with IHD improved glycemic control, but not inflammatory status. CLINICAL TRIAL REGISTRY: Australian New Zealand Clinical Trial Registry. CLINICAL TRIAL NUMBER: ACTRN12614000529640.

Integration of force reflection with tactile sensing for minimally invasive robotics-assisted tumor localization.

Tactile sensing and force reflection have been the subject of considerable research for tumor localization in soft-tissue palpation. The work presented in this paper investigates the relevance of force feedback (presented visually as well as directly) during tactile sensing (presented visually only) for tumor localization using an experimental setup close to one that could be applied for real robotics-assisted minimally invasive surgery. The setup is a teleoperated (master-slave) system facilitated with a state-of-the-art minimally invasive probe with a rigidly mounted tactile sensor at the tip and an externally mounted force sensor at the base of the probe. The objective is to capture the tactile information and measure the interaction forces between the probe and tissue during palpation and to explore how they can be integrated to improve the performance of tumor localization. To quantitatively explore the effect of force feedback on tactile sensing tumor localization, several experiments were conducted by human subjects to locate artificial tumors embedded in the ex vivo bovine livers. The results show that using tactile sensing in a force-controlled environment can realize, on average, 57 percent decrease in the maximum force and 55 percent decrease in the average force applied to tissue while increasing the tumor detection accuracy by up to 50 percent compared to the case of using tactile feedback alone. The results also show that while visual presentation of force feedback gives straightforward quantitative measures, improved performance of tactile sensing tumor localization is achieved at the expense of longer times for the user. Also, the quickness and intuitive data mapping of direct force feedback makes it more appealing to experienced users.