IMPORTANCEHereditary factors play a key role in the risk of developing several cancers. Identification of a germline predisposition can have important implications for treatment decisions, risk-reducing interventions, cancer screening, and germline testing.OBJECTIVE To examine the prevalence of pathogenic germline variants (PGVs) in patients with cancer using a universal testing approach compared with targeted testing based on clinical guidelines and the uptake of cascade family variant testing (FVT). DESIGN, SETTING, AND PARTICIPANTSThis prospective, multicenter cohort study assessed germline genetic alterations among patients with solid tumor cancer receiving care at Mayo Clinic cancer centers and a community practice between April 1, 2018, and March 31, 2020. Patients were not selected based on cancer type, disease stage, family history of cancer, ethnicity, or age.EXPOSURES Germline sequencing using a greater than 80-gene next-generation sequencing platform.MAIN OUTCOMES AND MEASURES Proportion of PGVs detected with a universal strategy compared with a guideline-directed approach and uptake of cascade FVT in families.RESULTS A total of 2984 patients (mean [SD] age, 61.4 [12.2] years; 1582 [53.0%] male) were studied. Pathogenic germline variants were found in 397 patients (13.3%), including 282 moderate-and high-penetrance cancer susceptibility genes. Variants of uncertain significance were found in 1415 patients (47.4%). A total of 192 patients (6.4%) had incremental clinically actionable findings that would not have been detected by phenotype or family history-based testing criteria. Of those with a high-penetrance PGV, 42 patients (28.2%) had modifications in their treatment based on the finding. Only younger age of diagnosis was associated with presence of PGV. Only 70 patients (17.6%) with PGVs had family members undergoing no-cost cascade FVT.CONCLUSIONS AND RELEVANCE This prospective, multicenter cohort study found that universal multigene panel testing among patients with solid tumor cancer was associated with an increased detection of heritable variants over the predicted yield of targeted testing based on guidelines. Nearly 30% of patients with high-penetrance variants had modifications in their treatment. Uptake of cascade FVT was low despite being offered at no cost.

Background Esophageal carcinoma is the eighth most common cancer in the world. Volumetric‐modulated arc therapy (VMAT) is widely used to treat distal esophageal carcinoma due to high conformality to the target and good sparing of organs at risk (OAR). It is not clear if small‐spot intensity‐modulated proton therapy (IMPT) demonstrates a dosimetric advantage over VMAT. In this study, we compared dosimetric performance of VMAT and small‐spot IMPT for distal esophageal carcinoma in terms of plan quality, plan robustness, and interplay effects. Methods 35 distal esophageal carcinoma patients were retrospectively reviewed; 19 patients received small‐spot IMPT and the remaining 16 of them received VMAT. Both plans were generated by delivering prescription doses to clinical target volumes (CTVs) on phase‐averaged 4D‐CT's. The dose‐volume‐histogram (DVH) band method was used to quantify plan robustness. Software was developed to evaluate interplay effects with randomized starting phases for each field per fraction. DVH indices were compared using Wilcoxon rank‐sum test. For fair comparison, all the treatment plans were normalized to have the same CTVhigh D95% in the nominal scenario relative to the prescription dose. Results In the nominal scenario, small‐spot IMPT delivered statistically significantly lower liver Dmean and V30Gy[RBE], lung Dmean, heart Dmean compared with VMAT. CTVhigh dose homogeneity and protection of other OARs were comparable between the two treatments. In terms of plan robustness, the IMPT and VMAT plans were comparable for kidney V18Gy[RBE], liver V30Gy[RBE], stomach V45Gy[RBE], lung Dmean, V5Gy[RBE], and V20Gy[RBE], cord Dmax and D0.03boldcboldm3, liver Dmean, heart V20Gy[RBE], and V30Gy[RBE], but IMPT was significantly worse for CTVhigh D95%, D2boldcboldm3, and D5%‐D95%, CTVlow D95%, heart Dmean, and V40Gy[RBE], requiring careful and experienced adjustments during the planning process and robustness considerations. The small‐spot IMPT plans still met the standard clinical requirements after interplay effects were considered. Conclusions Small‐spot IMPT decreases doses to heart, liver, and total lung compared to VMAT as well as achieves clinically acceptable plan robustness. Our study supports the use of small‐spot IMPT for the treatment of distal esophageal carcinoma.

Purpose: Approximate dose calculation methods were used in the nominal dose distribution and the perturbed dose distributions due to uncertainties in a commercial treatment planning system (CTPS) for robust optimization in intensity-modulated proton therapy (IMPT). We aimed to investigate whether the approximations influence plan quality, robustness, and interplay effect of the resulting IMPT plans for the treatment of locally advanced lung cancer patients. Materials and methods: Ten consecutively treated locally advanced nonsmall cell lung cancer (NSCLC) patients were selected. Two IMPT plans were created for each patient using our in-house developed TPS, named "Solo," and also the CTPS, Eclipse TM (Varian Medical Systems, Palo Alto, CA, USA), respectively. The plans were designed to deliver prescription doses to internal target volumes (ITV) drawn by a physician on averaged four-dimensional computed tomography (4D-CT). Solo plans were imported back to CTPS, and recalculated in CTPS for fair comparison. Both plans were further verified for each patient by recalculating doses in the inhalation and exhalation phases to ensure that all plans met clinical requirements. Plan robustness was quantified on all phases using dose-volume-histograms (DVH) indices in the worst-case scenario. The interplay effect was evaluated for every plan using an in-house developed software, which randomized starting phases of each field per fraction and accumulated dose in the exhalation phase based on the patient's breathing motion pattern and the proton spot delivery in a time-dependent fashion. DVH indices were compared using Wilcoxon rank-sum test. Results: Compared to the plans generated using CTPS on the averaged CT, Solo plans had significantly better target dose coverage and homogeneity (normalized by the prescription dose) in the worst-case scenario [ITV D 95% : 98.04% vs 96.28%, Solo vs CTPS, P = 0.020; ITV D 5% -D 95% : 7.20% vs 9.03%, P = 0.049] while all DVH indices were comparable in the nominal scenario. On the inhalation phase, Solo plans had better target dose coverage and cord D max in the nominal scenario [ITV D 95% : 99.36% vs 98.45%, Solo vs CTPS, P = 0.014; cord D max : 20.07 vs 23.71 Gy (RBE), P = 0.027] with better target coverage and cord D max in the worst-case scenario [ITV D 95% : 97.89% vs 96.47%, Solo vs CTPS, P = 0.037; cord D max : 24.57 vs 28.14 Gy(RBE), P = 0.037]. On the exhalation phase, similar phenomena were observed in the nominal scenario [ITV D 95% : 99.63% vs 98.87%, Solo vs CTPS, P = 0.037; cord D max : 19.67 vs 23.66 Gy(RBE), P = 0.039] and in the worst-case scenario [ITV D 95% : 98.20% vs 96.74%, Solo vs CTPS, P = 0.027; cord D max : 23.47 vs 27.93 Gy(RBE), P = 0.027]. In terms of interplay effect, plans generated by Solo had significantly better target dose coverage and homogeneity, less hot spots, and lower esophageal D mean , and cord D max [ITV D 95% : 101.81% vs 98.68%, Solo vs CTPS, P = 0.002; ITV D 5% -D 95% : 2.94% vs 7.51%, P = 0.002; cord D max : 18.87 vs 22.29 Gy(RBE), P = 0.014]. C...