Serial Postoperative Circulating Tumor DNA Assessment Has Strong Prognostic Value During Long-Term Follow-Up in Patients With Breast Cancer.

PURPOSE: Here, we report the sensitivity of a personalized, tumor-informed circulating tumor DNA (ctDNA) assay (Signatera) for detection of molecular relapse during long-term follow-up of patients with breast cancer. METHODS: A total of 156 patients with primary breast cancer were monitored clinically for up to 12 years after surgery and adjuvant chemotherapy. Semiannual blood samples were prospectively collected, and analyzed retrospectively to detect residual disease by ultradeep sequencing using ctDNA assays, developed from primary tumor whole-exome sequencing data. RESULTS: Personalized Signatera assays detected ctDNA ahead of clinical or radiologic relapse in 30 of the 34 patients who relapsed (patient-level sensitivity of 88.2%). Relapse was predicted with a lead interval of up to 38 months (median, 10.5 months; range, 0-38 months), and ctDNA positivity was associated with shorter relapse-free survival (P < .0001) and overall survival (P < .0001). All relapsing triple-negative patients (n = 7/23) had a ctDNA-positive test within a median of 8 months (range, 0-19 months), while the 16 nonrelapsed patients with triple-negative breast cancer remained ctDNA-negative during a median follow-up of 58 months (range, 8-99 months). The four patients who had negative tests before relapse all had hormone receptor-positive (HR+) disease and conversely, five of the 122 nonrelapsed patients (all HR+) had an occasional positive test. CONCLUSION: Serial postoperative ctDNA assessment has strong prognostic value, provides a potential window for earlier therapeutic intervention, and may enable more effective monitoring than current clinical tests such as cancer antigen 15-3. Our study provides evidence that those with serially negative ctDNA tests have superior clinical outcomes, providing reassurance to patients with breast cancer. For select cases with HR+ disease, decisions about treatment management might require serial monitoring despite the ctDNA-positive result.

Scientist Spotlights in Secondary Schools: Student Shifts in Multiple Measures Related to Science Identity after Receiving Written Assignments.

Based on theoretical frameworks of scientist stereotypes, possible selves, and science identity, written assignments were developed to teach science content through biographies and research of counter-stereotypical scientists-Scientist Spotlights (www.scientistspotlights.org). Previous studies on Scientist Spotlight assignments showed significant shifts in how college-level biology students relate to and describe scientists and in their performance in biology courses. However, the outcomes of Scientist Spotlight assignments in secondary schools were yet to be explored. In collaboration with 18 science teachers from 12 schools, this study assessed the impacts of Scientist Spotlight assignments for secondary school students. We used published assessment tools: Relatability prompt; Stereotypes prompt; and Performance/Competence, Interest, and Recognition (PCIR) instrument. Statistical analyses compared students' responses before and after receiving at least three Scientist Spotlight assignments. We observed significant shifts in students' relatability to and descriptions of scientists as well as other science identity measures. Importantly, disaggregating classes by implementation strategies revealed that students' relatability shifts were significant for teachers reporting in-class discussions and not significant for teachers reporting no discussions. Our findings raise questions about contextual and pedagogical influences shaping student outcomes with Scientist Spotlight assignments, like how noncontent Instructor Talk might foster student shifts in aspects of science identity.

Long-Term Results of a Phase 3 Randomized Prospective Trial of Erectile Tissue-Sparing Intensity-Modulated Radiation Therapy for Men With Clinically Localized Prostate Cancer.

PURPOSE: The objective of this study was to determine whether limiting the doses delivered to the penile bulb (PB) and corporal bodies with intensity modulated radiation therapy (IMRT) preserves erectile function compared with standard IMRT in men with prostate cancer. METHODS AND MATERIALS: A total of 117 patients with low- to intermediate-risk, clinical T1a-T2c prostate adenocarcinoma were enrolled in a single-institution, prospective, single-blind, phase 3 randomized trial. All received definitive IMRT to 74 to 80 Gy in 37 to 40 fractions and standard IMRT (s-IMRT) or erectile tissue-sparing IMRT (ETS-IMRT), which placed additional planning constraints that limited the D90 to the penile bulb and corporal bodies to ≤15 Gy and ≤7 Gy, respectively. Erectile potency was assessed with components of the International Index of Erectile Function and phosphodiesterase type 5 inhibitor (PDE5) medication records. RESULTS: Sixty-two patients received ETS-IMRT, and 54 received s-IMRT; 1 patient did not receive radiation therapy. Before treatment, all patients reported erectile potency. No patients received androgen deprivation therapy. In the intention-to-treat analysis, treatment arms did not differ in potency preservation at 24 months (37.1% ETS-IMRT vs 31.5% s-IMRT, P = .53). Of 85 evaluable patients with International Index of Erectile Function and PDE5 medication follow-up, erectile potency was seen in 47.9% of patients in the ETS-IMRT arm and 46.0% of patients in the s-IMRT arm (P = .86). PDE5 inhibitors were initiated in 41.7% of ETS-IMRT patients and 35.1% of s-IMRT patients (P = .54). Among all patients enrolled, there was no difference in freedom from biochemical failure between those treated with ETS-IMRT and s-IMRT (5-year 91.8% vs 90.7%, respectively, P = .77), with a median follow-up of 7.4 years. There were no differences in acute or late gastrointestinal or genitourinary toxicity. An unplanned per-protocol analysis demonstrated no differences in potency preservation or secondary endpoints between patients who exceeded erectile tissue-sparing constraints and those who met constraints, although power was limited by attrition and unplanned dosimetric crossover. CONCLUSIONS: ETS-IMRT that strictly limits dose to the penile bulb and corporal bodies is safe and feasible. Use of this planning technique did not show an effect on potency preservation outcomes at 2 years, though power to detect a difference was limited.

Neoadjuvant Chemoradiation Impacts the Prognostic Effect of Surgical Margin Status in Pancreatic Adenocarcinoma.

BACKGROUND: Many studies show significantly improved survival after R0 resection compared with R1 resection in pancreatic adenocarcinoma (PAC); however, the effect of neoadjuvant chemoradiation (NACRT) on this association is unknown. OBJECTIVE: The aim of this study was to evaluate the prognostic significance of positive surgical margins (SMs) after NACRT compared with upfront surgery + adjuvant therapy in PAC. METHODS: All cases of surgically resected PAC at a single institution were reviewed from 1996 to 2014; patients treated with palliative intent, metastatic disease, and biliary/ampullary tumors were excluded. The primary endpoint was overall survival (OS). RESULTS: Overall, 300 patients were included; 134 patients received NACRT with concurrent 5-fluorouracil or gemcitabine followed by surgery, and 166 patients received upfront surgery (+ adjuvant chemotherapy in 72% of patients and RT in 65%); 31% of both groups had a positive SM (+SM). The median OS for patients with a +SM or negative SM (-SM) was 26.6 and 31.6 months, respectively for NACRT, and 12.0 and 24.5 months, respectively, for upfront surgery. OS was significantly improved with -SM compared with +SM in both groups (p = 0.006). When resection yielded +SM, NACRT patients had improved OS compared with upfront surgery patients (p < 0.001). On multivariable analysis, +SM in the upfront surgery group (hazard ratio [HR] 2.94, 95% confidence interval [CI] 2.04-4.24; p < 0.001) and older age (HR 1.01, 95% CI 1.00-1.03, per year; p = 0.007) predicted worse OS. +SM in the NACRT group was not associated with worse OS (HR 1.09, 95% CI 0.72-1.65; p = 0.70). CONCLUSION: Patients with a positive margin after NACRT and surgery had longer survival compared with patients with a positive margin after upfront surgery. NACRT should be strongly considered for patients at high risk of R1 resections.

Ten-Year Update of a Randomized, Prospective Trial of Conventional Fractionated Versus Moderate Hypofractionated Radiation Therapy for Localized Prostate Cancer.

PURPOSE: The previously published single institution randomized prospective trial failed to show superiority in the 5-year biochemical and/or clinical disease failure (BCDF) rate with moderate hypofractionated intensity-modulated radiation therapy (H-IMRT) versus conventionally fractionated IMRT (C-IMRT). We now present 10-year disease outcomes using updated risk groups and definitions of biochemical failure. METHODS: Men with protocol-defined intermediate- and high-risk prostate adenocarcinoma were randomly assigned to receive C-IMRT (76 Gy in 38 fractions) or H-IMRT (70.2 Gy in 26 fractions). Men with high-risk disease were all prescribed 24 months of androgen deprivation therapy (ADT) and had lymph node irradiation. Men with intermediate risk were prescribed 4 months of ADT at the discretion of the treating physician. The primary endpoint was cumulative incidence of BCDF. We compared disease outcomes and overall mortality by treatment arm, with sensitivity analyses for National Comprehensive Cancer Network (NCCN) risk group adjustment. RESULTS: Overall, 303 assessable men were randomly assigned to C-IMRT or H-IMRT. The median follow-up was 122.9 months. Per updated NCCN risk classification, there were 28 patients (9.2%) with low-risk, 189 (62.4%) with intermediate-risk, and 86 (28.4%) with high-risk prostate cancer. The arms were equally balanced for clinicopathologic factors, except that there were more black patients in the C-IMRT arm (17.8% v 7.3%; P = .02). There was no difference in ADT use (P = .56). The 10-year cumulative incidence of BCDF was 25.9% in the C-IMRT arm and was 30.6% in the H-IMRT arm (hazard ratio, 1.31; 95% CI, 0.82 to 2.11). The two arms also had similar cumulative 10-year rates of biochemical failure, prostate cancer-specific mortality, and overall mortality; however, the 10-year cumulative incidence of distant metastases was higher in the H-IMRT arm (rate difference, 7.8%; 95% CI, 0.7% to 15.1%). CONCLUSION: H-IMRT failed to demonstrate superiority compared with C-IMRT in long-term disease outcomes.

Predictors of Distant Recurrence Following Stereotactic Body Radiation Therapy for Stage I Non-Small Cell Lung Cancer.

OBJECTIVE: The objective of this study was to characterize patients at an increased risk of distant metastasis (DM) following stereotactic body radiation therapy (SBRT) for stage I non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: We identified patients undergoing SBRT for stage I NSCLC between 2005 and 2016. Patients with a prior lung cancer diagnosis, receiving a biological effective dose <100 Gy, or receiving chemotherapy were excluded. Patients underwent pretreatment staging and were classified according to the American Joint Committee for Cancer (AJCC) 8th edition staging. The primary endpoint was DM. The Kaplan-Meier method and the Cox proportional hazards model were used for survival analysis and to identify predictors of DM. RESULTS: A total of 174 patients were included, with a median age 75 years (range, 49 to 96 y) and a median follow-up of 24 months (range, 3 to 123 mo). The 2- and 4-year cumulative incidences of DM were 14.2% and 19.1%, respectively. Patients who developed DM had worse overall survival versus patients developing a locoregional recurrence (P=0.023). On multivariable analysis, having stage IB disease (hazard ratio: 2.95; 95% confidence interval: 1.06-8.23; P=0.039) or a lower/middle lobe tumor (hazard ratio: 2.67; 95% confidence interval: 1.07-6.69; P=0.036) was associated with increased risk of DM. The 2-year cumulative incidences of DM were 10.9% and 35.7% (P=0.002) for patients with stage IA versus IB tumors, respectively, and 11.3% and 19.7% (P=0.049) for patients with upper lobe versus lower/middle lobe tumors, respectively. CONCLUSIONS: Patients with stage IB disease or lower/middle lobe tumors may have an increased risk of DM following SBRT. Randomized controlled trials are needed to further identify patients who may benefit from adjuvant systemic therapy after SBRT for stage I NSCLC.

Skin CanceR Brachytherapy vs External beam radiation therapy (SCRiBE) meta-analysis.

BACKGROUND AND PURPOSE: To compare cosmesis and local recurrence (LR) of definitive external beam radiation therapy (EBRT) vs brachytherapy (BT) for indolent basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) of the skin. MATERIALS AND METHODS: Studies including patients with T1-2 N0 SCCs/BCCs treated with definitive EBRT/BT and ≥10 months follow-up were analyzed. The primary endpoint was post-treatment cosmesis, categorized as "good," "fair," or "poor." The secondary endpoint was LR. Mixed effects regression models were used to estimate weighted linear relationships between biologically equivalent doses with α/ß = 3 (BED3) and cosmetic outcomes. RESULTS: A total of 9965 patients received EBRT and 553 received BT across 24 studies. Mean age was 73 years, median follow-up was 36 months, and median dose was 45 Gy/10 fractions at 4.4 Gy/fraction. At BED3 of 100 Gy, "good" cosmesis was more frequently observed in patients receiving BT, 95% (95% CI: 88-100%) vs 79% (95% CI: 60-82%), p < 0.05. Similar results were found for "good" cosmesis at BED3 >100 Gy. No difference in "poor" cosmesis was noted at any BED3. LR was <7% for both at one year. CONCLUSION: BT has favorable cosmesis over EBRT for skin SCCs/BCCs at common fractionation regimens. Prospective studies comparing EBRT vs BT are warranted.

Hypofractionated radiation therapy for basal and squamous cell skin cancer: A meta-analysis.

PURPOSE: To characterize the cosmetic outcomes and local recurrence (LR) rates of various hypofractionated radiation therapy (RT) regimens for skin basal and squamous cell cancers (BCCs/SCCs). METHODS: A PICOS/PRISMA/MOOSE selection protocol was performed to identify 344 articles published between 1985-2016 evaluating patients with T1-2 N0 SCCs/BCCs treated with definitive RT. Biologically equivalent doses with α/ß=3 (BED3s) were calculated. The primary endpoint was post-treatment cosmesis. Mixed effects regression models were used to estimate weighted linear relationships between BED3 and cosmetic outcomes. RESULTS: A total of 21 studies were identified detailing the treatment of 9729 skin BCC/SCC patients, across seven countries, with external beam RT (n=9255) or brachytherapy (n=474). Median follow-up was 36months (range: 12-77). Median dose was 45Gy/11 fractions (interquartile range: 37.5Gy/6-55Gy/18) at 4Gy/fraction (interquartile range: 2.5-6Gy); most hypofractionated 18.75Gy/1. There was a trend to decreased "good" cosmesis with higher total dose: -3.4% "good" cosmesis/10Gy BED3, p=0.01. Similarly, there was a trend to increased "fair" cosmesis with higher dose: +3.8% "fair" cosmesis/10Gy BED3,p=0.006. At a BED3 of 100Gy, the expected rate of "good" cosmesis is 79% (95% confidence interval: 70%, 88%). Hypofractionated schedules produced similar cosmesis to conventionally fractionated schedules, at the same BED3. Fewer than 8% of patients experienced "poor" cosmesis, independent of dose or fractionation regimen. CONCLUSION: Hypofractionated RT has favorable cosmesis for patients with skin BCCs/SCCs. We recommend clinicians consider these commonly-used regimens, which all have BED3 of ∼100Gy: 50Gy/15 fractions, 36.75Gy/7 fractions, or 35Gy/5 fractions, as they result in "good" cosmesis in 80% of patients.