Feasibility and outcome of reproducible clinical interpretation of high-dimensional molecular data: a comparison of two molecular tumor boards.

BACKGROUND: Structured and harmonized implementation of molecular tumor boards (MTB) for the clinical interpretation of molecular data presents a current challenge for precision oncology. Heterogeneity in the interpretation of molecular data was shown for patients even with a limited number of molecular alterations. Integration of high-dimensional molecular data, including RNA- (RNA-Seq) and whole-exome sequencing (WES), is expected to further complicate clinical application. To analyze challenges for MTB harmonization based on complex molecular datasets, we retrospectively compared clinical interpretation of WES and RNA-Seq data by two independent molecular tumor boards. METHODS: High-dimensional molecular cancer profiling including WES and RNA-Seq was performed for patients with advanced solid tumors, no available standard therapy, ECOG performance status of 0-1, and available fresh-frozen tissue within the DKTK-MASTER Program from 2016 to 2018. Identical molecular profiling data of 40 patients were independently discussed by two molecular tumor boards (MTB) after prior annotation by specialized physicians, following independent, but similar workflows. Identified biomarkers and resulting treatment options were compared between the MTBs and patients were followed up clinically. RESULTS: A median of 309 molecular aberrations from WES and RNA-Seq (n = 38) and 82 molecular aberrations from WES only (n = 3) were considered for clinical interpretation for 40 patients (one patient sequenced twice). A median of 3 and 2 targeted treatment options were identified per patient, respectively. Most treatment options were identified for receptor tyrosine kinase, PARP, and mTOR inhibitors, as well as immunotherapy. The mean overlap coefficient between both MTB was 66%. Highest agreement rates were observed with the interpretation of single nucleotide variants, clinical evidence levels 1 and 2, and monotherapy whereas the interpretation of gene expression changes, preclinical evidence levels 3 and 4, and combination therapy yielded lower agreement rates. Patients receiving treatment following concordant MTB recommendations had significantly longer overall survival than patients receiving treatment following discrepant recommendations or physician's choice. CONCLUSIONS: Reproducible clinical interpretation of high-dimensional molecular data is feasible and agreement rates are encouraging, when compared to previous reports. The interpretation of molecular aberrations beyond single nucleotide variants and preclinically validated biomarkers as well as combination therapies were identified as additional difficulties for ongoing harmonization efforts.

Negative Hyperselection of Resistance Mutations for Panitumumab Maintenance in RAS Wild-Type Metastatic Colorectal Cancer (PanaMa Phase II Trial, AIO KRK 0212).

PURPOSE: We evaluated additional mutations in RAS wild-type (WT) metastatic colorectal cancer (mCRC) as prognostic and predictive biomarkers for the efficacy of added panitumumab to a 5-fluorouracil plus folinic acid (FU/FA) maintenance as pre-specified analysis of the randomized PanaMa trial. PATIENTS AND METHODS: Mutations (MUT) were identified using targeted next-generation sequencing (NGS; Illumina Cancer Hotspot Panel v2) and IHC. RAS/BRAF V600E/PIK3CA/AKT1/ALK1/ERBB2/PTEN MUT and HER2/neu overexpressions were negatively hyperselected and correlated with median progression-free survival (PFS) and overall survival (OS) since start of maintenance treatment, and objective response rates (ORR). Univariate/multivariate Cox regression estimated hazard ratios (HR) and 95% confidence intervals (CI). RESULTS: 202 of 248 patients (81.5%) of the full analysis set (FAS) had available NGS data: hyperselection WT, 162 (80.2%); MUT, 40 (19.8%). From start of maintenance therapy, hyperselection WT tumors were associated with longer median PFS as compared with hyperselection MUT mCRC (7.5 vs. 5.4 months; HR, 0.75; 95% CI, 0.52-1.07; P = 0.11), OS (28.7 vs. 22.2 months; HR, 0.53; 95% CI, 0.36-0.77; P = 0.001), and higher ORR (35.8% vs. 25.0%, P = 0.26). The addition of panitumumab to maintenance was associated with significant benefit in hyperselection WT tumors for PFS (9.2 vs. 6.0 months; HR, 0.66; 95% CI, 0.47-0.93; P = 0.02) and numerically also for OS (36.9 vs. 24.9 months; HR, 0.91; 95% CI, 0.61-1.36; P = 0.50), but not in hyperselection MUT tumors. Hyperselection status interacted with maintenance treatment arms in terms of PFS (P = 0.06) and OS (P = 0.009). CONCLUSIONS: Extended molecular profiling beyond RAS may have the potential to improve the patient selection for anti-EGFR containing maintenance regimens.

Consensus Molecular Subtypes as Biomarkers of Fluorouracil and Folinic Acid Maintenance Therapy With or Without Panitumumab in RAS Wild-Type Metastatic Colorectal Cancer (PanaMa, AIO KRK 0212).

PURPOSE: Consensus molecular subtypes (CMSs) were evaluated as prognostic and predictive biomarkers of patients with RAS wild-type metastatic colorectal cancer (mCRC) receiving fluorouracil and folinic acid (FU/FA) with or without panitumumab (Pmab) after Pmab + mFOLFOX6 induction within the randomized phase II PanaMa trial. METHODS: CMSs were determined in the safety set (ie, patients that received induction) and full analysis set (FAS; ie, randomly assigned patients who received maintenance) and correlated with median progression-free survival (PFS) and overall survival (OS) since the start of induction or maintenance treatment and objective response rates (ORRs). Hazard ratios (HRs) and 95% CI were calculated by univariate/multivariate Cox regression analyses. RESULTS: Of 377 patients of the safety set, 296 (78.5%) had available CMS data: CMS1/2/3/4: 29 (9.8%)/122 (41.2%)/33 (11.2%)/112 (37.8%) and unclassifiable: 17 (5.7%). The CMSs were prognostic biomarkers in terms of PFS (P < .0001), OS (P < .0001), and ORR (P = .02) since the start of induction treatment. In FAS patients (n = 196), with CMS2/4 tumors, the addition of Pmab to FU/FA maintenance therapy was associated with longer PFS (CMS2: HR, 0.58 [95% CI, 0.36 to 0.95], P = .03; CMS4: HR, 0.63 [95% CI, 0.38 to 1.03], P = .07) and OS (CMS2: HR, 0.88 [95% CI, 0.52 to 1.52], P = .66; CMS4: HR, 0.54 [95% CI, 0.30 to 0.96], P = .04). The CMS interacted significantly with treatment in terms of PFS (CMS2 v CMS1/3: P = .02; CMS4 v CMS1/3: P = .03) and OS (CMS2 v CMS1/3: P = .03; CMS4 v CMS1/3: P < .001). CONCLUSION: The CMS had a prognostic impact on PFS, OS, and ORR in RAS wild-type mCRC. In PanaMa, Pmab + FU/FA maintenance was associated with beneficial outcomes in CMS2/4, whereas no benefit was observed in CMS1/3 tumors.

Intramedullary Single-Kirschner-Wire Fixation in Displaced Fractures of the Fifth Metacarpal Neck (Boxer's Fracture).

The fracture of the fifth metacarpal neck (also called a boxer's fracture) is the most common fracture of the hand1,3. Displaced fractures often result in volar angulation of the metacarpal head, shortening, and residual malrotation4-7. The present video article demonstrates the steps of performing intramedullary single-Kirschner-wire fixation of the fifth metacarpal neck1, with the aim of the procedure being to achieve a closed reduction and internal stabilization of such a fracture. Although many fractures can be treated with a splint only, surgery should be performed in patients with excessive volar angulation, relevant shortening, or rotational deformity5-7. Description: For this procedure, the injured arm of the patient is placed on an arm table. The incision is made 1 to 2 cm longitudinally over the ulnar base of the fifth metacarpal bone. The cortical bone is opened with an awl, and a bent 1.6-mm Kirschner wire is inserted into the medullary canal. After reaching the fracture region, the fracture is anatomically reduced. The Kirschner wire is then advanced into the head of the fifth metacarpal, securing the reduction. Malrotation can be addressed in this stage by rotating the wire under fluoroscopic control. After ensuring anatomical reduction clinically and by fluoroscopy, the wire is shortened under the skin, followed by closure of the incision. We utilize a mid-hand brace for splinting. Alternatives: Nonoperative treatment is common for fifth metacarpal neck fractures in the absence of malrotation, excessive angulation, and shortening. Other surgical techniques include a similar procedure that involves the use of multiple Kirschner wires, plate fixation, transverse Kirschner wire pinning, and, less commonly, retrograde headless screw fixation2,7-9. Rationale: The main advantage of this technique is the preservation of the metacarpophalangeal joint and the minimal soft-tissue damage. Additionally, the use of a single Kirschner wire provides stability at low cost. With some experience, this surgery can be performed within 20 minutes1,9. Expected Outcomes: This procedure provides good fracture reduction and stabilization8. The outcome is usually satisfactory, with very low Disabilities of the Arm, Shoulder, and Hand scores1. Malrotation, angulation, and shortening are sufficiently addressed, and the technique shows the same results as fixation performed with use of 2 intramedullary wires. Important Tips: Bending the Kirschner wire to ensure easy gliding in the medullary canal provides the opportunity to reduce the metacarpal neck once the wire is safely in the head.Aim distally as you open the cortical bone with the awl in order to facilitate the insertion of the Kirschner wire.The primary reduction should be made manually, not by the wire. Subacute fractures and substantially displaced fractures require direct force for a satisfactory reduction, which cannot be achieved by rotation of the wire only.The cortical bone on the metacarpal head is very thin. Take care not to drive the Kirschner wire through the cortical bone and into the joint.Shorten the wire under the skin approximately 1 cm above the bone surface; this ensures easy removal and prevents skin irritation. Acronyms and Abbreviations: K-wire = Kirschner wire.

Valve embolization during transcatheter aortic valve implantation: Incidence, risk factors and follow-up by computed tomography.

Background: In most cases of transcatheter valve embolization and migration (TVEM), the embolized valve remains in the aorta after implantation of a second valve into the aortic root. There is little data on potential late complications such as valve thrombosis or aortic wall alterations by embolized valves. Aims: The aim of this study was to analyze the incidence of TVEM in a large cohort of patients undergoing transcatheter aortic valve implantation (TAVI) and to examine embolized valves by computed tomography (CT) late after TAVI. Methods: The patient database of our center was screened for cases of TVEM between July 2009 and July 2021. To identify risk factors, TVEM cases were compared to a cohort of 200 consecutive TAVI cases. Out of 35 surviving TVEM patients, ten patients underwent follow-up by echocardiography and CT. Results: 54 TVEM occurred in 3757 TAVI procedures, 46 cases were managed percutaneously. Horizontal aorta (odds ratio [OR] 7.51, 95% confidence interval [CI] 3.4-16.6, p < 0.001), implantation of a self-expanding valve (OR 4.63, 95% CI 2.2-9.7, p < 0.01) and a left ventricular ejection fraction < 40% (OR 2.94, 95% CI 1.1-7.3, p = 0.016) were identified as risk factors for TVEM. CT scans were performed on average 26.3 months after TAVI (range 2-84 months) and detected hypoattenuated leaflet thickening (HALT) in two patients as well as parts of the stent frame protruding into the aortic wall in three patients. Conclusion: TVEM represents a rare complication of TAVI. Follow up-CT detected no pathological findings requiring intervention.

Liquid Biopsy in Colorectal Cancer: Quo Vadis? Implementation of Liquid Biopsies in Routine Clinical Patient Care in Two German Comprehensive Cancer Centers.

Objectives: The use of liquid biopsies (LB) in patients with solid malignancies enables comprehensive genomic profiling (CGP) of circulating tumor DNA (ctDNA) and has the potential to guide therapy stratification and support disease monitoring. To examine clinical uptake of LB in a real-world setting, LB implementation was analyzed at two German cancer centers (LMU Munich and Charité - Universitätsmedizin Berlin) between 2017 and 2021, with focus on colorectal cancer (CRC) patients. Methods: In this retrospective analysis, all patients who received a LB between January 2017 and December 2021 as part of routine clinical management were included. To provide adequate context, we collected disease characteristics and technical specifications of the LB methods applied. Additionally, we examined the concordance of RAS status in tumor tissue and LB. Finally, we discuss the potential of LB as a diagnostic tool to drive personalized treatment in CRC patients and how to implement LB in clinical routine. Results: In total, our cohort included 86 CRC patients and 161 LB conducted in these patients between 2017 and 2021. In 59 patients, comparison between tissue-based and liquid-based molecular diagnostics, revealed a divergence in 23 (39%) of the evaluable samples. Conclusion: Our real-world data analysis indicates that the possibilities of LB are not yet exploited in everyday clinical practice. Currently, the variety of methods and lack of standardization, as well as restricted reimbursement for liquid based CGP hinder the use of LB in clinical routine. To overcome these issues, prospective clinical trials are needed to provide evidence driving the implementation of LB into the management of CRC patients and to support their implementation into clinical guidelines.

NeoRAS wild-type in metastatic colorectal cancer: Myth or truth?-Case series and review of the literature.

Upfront KRAS and NRAS gene testing ('RAS') is the standard of care for metastatic colorectal cancer (mCRC), to guide first-line treatment. The presence of RAS mutation (MT) is a negative predictor for the efficacy of anti-EGFR antibodies and the use of cetuximab and panitumumab is restricted to RAS wild-type (WT) mCRC. Conversion from RAS WT to RAS MT mCRC after treatment with anti-EGFR antibodies is a known and well-described acquired resistance mechanism. The by far less frequent 'NeoRAS wild-type' phenomenon (reversion from RAS MT to RAS WT) has recently drawn attention. The proposed effect of chemotherapy on RAS status in mCRC patients is not fully understood. Because of the intriguing biological consequence of a RAS MT to RAS WT reversion, subsequent treatment of NeoRAS WT patients with anti-EGFR antibodies is increasingly being discussed. Here, we report three clinical cases of NeoRAS WT mCRC patients, which received standard-of-care regimens for RAS MT mCRC. Anti-EGFR antibodies were used in two out of three patients after progression of the disease. One of the patients had a long-term response. In line with our observations, NeoRAS WT phenomenon occurs in clinical practice. Retesting of RAS status during treatment should be discussed in patients with unusual long-term clinical courses of RAS MT mCRC to optimise treatment strategy and to evaluate the use of anti-EGFR antibodies.