Circulating Tumor DNA and Late Recurrence in High-Risk Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Breast Cancer.

PURPOSE: To examine the prevalence and dynamics of circulating tumor DNA (ctDNA) and its association with metastatic recurrence in patients with high-risk early-stage hormone receptor-positive breast cancer (HR+ BC) more than 5 years from diagnosis. METHODS: We enrolled 103 patients with high-risk stage II-III HR+ BC diagnosed more than 5 years prior without clinical evidence of recurrence. We performed whole-exome sequencing (WES) on primary tumor tissue to identify somatic mutations tracked via a personalized, tumor-informed ctDNA test to detect minimal residual disease (MRD). We collected plasma at the time of consent and at routine visits every 6-12 months. Patients were followed for clinical recurrence. RESULTS: In total, 85 of 103 patients had sufficient tumor tissue; of them, 83 of 85 (97.6%) patients had successful whole-exome sequencing. Personalized ctDNA assays were designed targeting a median of 36 variants to test 219 plasma samples. The median time from diagnosis to first sample was 8.4 years. The median follow-up was 10.4 years from diagnosis and 2.0 years from first sample. The median number of plasma samples per patient was two. Eight patients (10%) had positive MRD testing at any time point. Six patients (7.2%) developed distant metastatic recurrence, all of whom were MRD-positive before overt clinical recurrence, with median ctDNA lead time of 12.4 months. MRD was not identified in one patient (1.2%) with local recurrence. Two of eight MRD-positive patients had not had clinical recurrence at last follow-up. CONCLUSION: In this prospective study, in patients with high-risk HR+ BC in the late adjuvant setting, ctDNA was identified a median of 1 year before all cases of distant metastasis. Future studies will determine if ctDNA-guided intervention in patients with HR+ BC can alter clinical outcomes.

Exploring the Feasibility of Utilizing Limited Gene Panel Circulating Tumor DNA Clearance as a Biomarker in Patients With Locally Advanced Non-Small Cell Lung Cancer.

Introduction: Circulating tumor DNA (ctDNA) testing may identify patients at high risk for recurrence following chemoradiation (CRT) for locally advanced non-small cell lung cancer (LA-NSCLC). We evaluated the feasibility of ctDNA testing on a readily available commercial fixed-gene panel to predict outcomes in patients with LA-NSCLC. Methods: Plasma of 43 patients was collected at CRT initiation (pre-CRT), completion (post-CRT1), quarterly follow up for 12 months (post-CRT2, 3, 4, 5 respectively) after CRT, and at disease progression. ctDNA analysis was performed using InVisionFirst®-Lung to detect mutations in 36 cancer-related genes. ctDNA clearance was defined as absence of pre-CRT variants at post-CRT1. Patients without detectable pre-CRT variants or no post-CRT1 samples were excluded. Results: Twenty eight of 43 patients (65%) had detectable variants pre-CRT. Nineteen of 43 patients (44%) had detectable pre-CRT variants and post-CRT1 samples and were included in analysis. Median age at diagnosis was 65 years (43-82), and most patients had stage IIIB disease (10/19, 53%). Two patients died from non-cancer related causes before post-CRT2 and were excluded from further analysis. All three patients who did not clear ctDNA had tumor relapse with a median time to relapse of 74 days (30-238), while 50% (7/14) of those who cleared ctDNA have remained disease free. Progression free survival was longer in patients who cleared ctDNA compared to those who did not (median 567 vs 74 d, p = 0.01). Conclusions: Although it is feasible to use ctDNA testing on a limited gene panel to identify patients with LA-NSCLC who are at high risk for disease recurrence following CRT, further studies will be necessary to optimize these assays before they can be used to inform clinical care in patients with lung cancer.

Evaluation of a crystalline sirolimus-eluting coronary stent with a bioabsorbable polymer designed for rapid dissolution: two-year outcomes from the DESSOLVE I and II trials.

AIMS: Our aim was to evaluate the two-year clinical results of a new sirolimus-eluting stent (MiStent SES) with a bioabsorbable coating designed for rapid polymer dissolution but sustained drug delivery. METHODS AND RESULTS: Major adverse cardiac events (MACE), target lesion failure (TLF), target vessel failure (TVF), and stent thrombosis (ST) at two-year follow-up are reported for the DESSOLVE I and II trials. In DESSOLVE I, the MiStent SES (n=29) demonstrated a 3.4% two-year MACE rate without TLF or TVF. In DESSOLVE II, the MiStent group had a 6.7% (8/120) two-year MACE rate compared to 13.3% (8/60) for Endeavor (p=0.167). TLF was 5.0% in the MiStent and Endeavor groups (p=1.00). TVF was 5.0% for MiStent versus 11.7% for Endeavor (p=0.129). No probable or definite ST was reported with the MiStent up to two years. The median duration of dual antiplatelet therapy (DAPT) in DESSOLVE I and II was 364 and 366 days, respectively. CONCLUSIONS: The MiStent SES demonstrated good long-term safety and effectiveness with low two-year MACE, TLF, and TVF rates.

Randomised study of a bioabsorbable polymer-coated sirolimus-eluting stent: results of the DESSOLVE II trial.

AIMS: To compare the efficacy and safety of the MiStent absorbable polymer sirolimus-eluting stent (APSES) with a zotarolimus-eluting stent (ZES). METHODS AND RESULTS: The trial was a 2:1 randomisation at 26 sites of 184 patients implanted with an APSES (n=123) versus a ZES (n=61). Following stent implantation, all patients underwent quantitative coronary angiography at baseline and at nine months of follow-up, while a select subgroup also underwent optical coherence tomography (OCT). The primary efficacy hypothesis was superiority of in-stent late lumen loss (LLL) of APSES compared to ZES. At nine months, the primary endpoint was met, with a mean in-stent LLL of 0.27±0.46 mm in 103 APSES patients versus 0.58±0.41 mm in 52 ZES patients (p<0.001). The proportion of uncovered stent struts by OCT at nine months was very low in both groups. The mean neointimal thickness of covered struts (p=0.002) and percent net volume obstruction (p≤0.003) were significantly lower in the APSES than in the ZES group. Major adverse cardiac event and stent thrombosis rates were low and comparable between groups. CONCLUSIONS: The DESSOLVE II trial demonstrated superiority in the primary efficacy endpoint of nine-month mean LLL for APSES compared to ZES. Strut coverage by OCT was high with both stents and the clinical safety endpoints including stent thrombosis were equally low in both groups. ClinicalTrials.gov Identifier: NCT01294748.

Bioabsorbable polymer-coated sirolimus-eluting stent implantation preserves coronary vasomotion: A DESSOLVE II trial sub-study.

OBJECTIVES: We studied coronary vasomotion in patients treated with the Mistent(®) absorbable polymer sirolimus-eluting stent (APSES) and in patients implanted with the Endeavor(®) zotarolimus-eluting stent (ZES). BACKGROUND: First generation (1st-gen) drug-eluting stents (DES) induce persistent vasomotor dysfunction in the treated coronary artery. It is unknown whether and to what extent the implantation of an absorbable polymer DES impairs coronary vasomotion. METHODS: This sub-study of the DESSOLVE II trial included 19 APSES Mistent(®) and 10 ZES Endeavor(®) patients. Incremental atrial pacing and quantitative coronary angiography were used to assess vasomotion proximal and distal to the stent and in a reference segment at 9 months after implantation. Percent changes in vessel diameter with pacing versus baseline were calculated and compared. Vasomotor response of the APSES group was also compared with changes observed in a historical group of 17 patients implanted with a 1st-gen sirolimus-eluting stent (SES). RESULTS: Normal vasomotion (vasodilatation) was preserved and of comparable magnitude in the APSES and in the ZES group both proximally (P = 0.34) and distally (P = 0.38) to the stent. This finding was not observed in the 1st-gen SES group showing marked pacing-induced vasoconstriction at both stent edges (P < 0.05 vs. APSES). The results were practically unchanged after excluding patients with absolute changes in vessel diameter <3% between baseline and maximal pacing. CONCLUSIONS: The implantation of an absorbable polymer sirolimus-eluting stent is associated with preserved coronary vasomotion, comparable to that observed after implantation of the Endeavor(®) ZES, and distinct from 1st-gen SES which induce coronary vasomotor dysfunction.

First-in-human evaluation of a bioabsorbable polymer-coated sirolimus-eluting stent: imaging and clinical results of the DESSOLVE I Trial (DES with sirolimus and a bioabsorbable polymer for the treatment of patients with de novo lesion in the native coronary arteries).

OBJECTIVES: This first-in-human multicenter study sought to examine prospectively the safety and efficacy of a new, cobalt chromium thin-strut, coronary absorbable polymer-coated, sirolimus-eluting stent. BACKGROUND: Bioabsorbable polymers on drug-eluting stents may lower the long-term risks of inflammation, delayed healing, and adverse events. METHODS: We enrolled patients with symptomatic coronary artery disease with stable or unstable angina pectoris and >50% diameter stenosis, amenable to coverage with a ≤23-mm long stent in a vessel 2.5 to 3.5 mm in diameter. All patients received dual antiplatelet therapy after implantation. Patients, in groups of 10, underwent repeat angiography, intravascular ultrasound, and optical coherence tomography at 4, 6, or 8 months, and all patients were seen or contacted at 18 months of follow-up. RESULTS: The median (range) in-stent late lumen loss (LLL) was 0.03 mm (-0.22 to 0.21 mm), 0.10 mm (-0.03 to 1.2 mm), and 0.08 mm (-0.01 to 0.28 mm), at 4, 6, and 8 months, respectively. At 18 months, the median in-stent LLL was 0.08 mm (-0.30 to 0.46 mm). On optical coherence tomography, the proportion of uncovered stent struts decreased from a median of 7.3% (range 0.4% to 46.3%) at 4 months to 0% (range: 0% to 3.4%) at 18 months. The percentage of neointimal volume obstruction by intravascular ultrasound increased from a median of 5.3% to 9.1% between 4 and 6 months and remained nearly unchanged thereafter through 18 months of follow-up. The only recorded major adverse cardiac event was a myocardial infarction. CONCLUSIONS: At 18 months of follow-up, this absorbable polymer-coated, cobalt chromium sirolimus-eluting stent was associated with a low and stable in-stent LLL, complete strut coverage, and no stent thrombosis. (First-In-Human Trial of the MiStent Drug-Eluting Stent [DES] in Coronary Artery Disease [DESSOLVE-I]; NCT01247428).

Multicenter clinical trial of the NexStent coiled sheet stent in the treatment of extracranial carotid artery stenosis: immediate results and late clinical outcomes.

OBJECT: Carotid angioplasty with stent placement has been proposed as an alternative method for revascularization of carotid artery (CA) stenosis. A novel stent with a coiled sheet design (NexStent; EndoTex Interventional Systems, Inc., Cupertino, CA) has been introduced because it provides improved flexibility over conventional tubular designs during navigation through tortuous arterial segments. The authors report the results of a multicenter study in which they evaluated the safety, feasibility, and effectiveness of this stent in the treatment of CA stenosis. METHODS: Enrollment was limited to patients with 70% or more symptomatic or asymptomatic stenosis of the internal CA. The primary end point was a technically successful implantation procedure (delivery of the stent to the target siteand retrieval of the delivery device) resulting in less than 30% residual stenosis on angiograms obtained immediately postprocedure and no death or ipsilateral stroke immediately after or within 30 days following the procedure. The secondary effectiveness end point was prevention of an ipsilateral stroke within 31 days to 1 year postprocedure. The tertiary effectiveness end point was less than 70% residual stenosis demonstrated on CA Doppler ultrasonography performed at 6 and 12 months. Forty-four patients (mean age 71 years, range 51-89 years; 30 patients were men and 18 [41%] had symptomatic stenotic lesions) were treated using 45 NexStents (two stents were placed in one patient). Residual stenosis on postprocedure angiograms was less than 30% in all patients. The 1-month primary end point was achieved in 41 patients (93%). The three major adverse events that occurred within 30 days were one death related to congestive heart failure and two ipsilateral strokes, one of which resulted in death. No ipsilateral stroke occurred between 1 and 12 months postprocedure among 35 patients who completed the follow-up evaluation. Asymptomatic recurrent stenosis was identified in one patient at 6 months postprocedure, requiring the performance of repeated angioplasty. CONCLUSIONS: Placement of the NexStent was feasible and resulted in the effective treatment of patients with CA stenosis, with promising long-term results.