Citations

536 Background: Folate receptor alpha (FRα) is overexpressed in ~80% of triple-negative breast cancers (TNBC). We previously demonstrated that patients (pts) with breast cancer naturally mount immune responses to FRα. In prior Phase I and II studies, a GM-CSF-adjuvanted FRα peptide vaccine (FRPV) was safe and induced durable FRα-specific T-cell immunity in 83–90% of pts with breast and ovarian cancer. Methods: Eligible pts were women ≥18 years with TNBC (ER/PR ≤10%) with 1+ of the following: stage ≥T1c disease, node-positivity, or residual disease after neoadjuvant chemotherapy. Pts were randomized 2:1 to receive FRPV or placebo (GM-CSF alone) every 28 days for cycles 2-7 and then every six months for 7 booster doses, with cycle 1 consisting of cyclophosphamide 50mg orally twice daily for days 1-7 and 15-21 (in both arms). Randomization was stratified by chemotherapy setting (adjuvant only vs neoadjuvant) and stage (I/II vs III). FRα expression was evaluated by immunohistochemistry. The study was designed to detect (at 30 months after the last pt enrolled) a disease-free survival (DFS) difference of 14% assuming a 3.5-year DFS rate of 70% in the control group and with 78% power. Results: 280 pts were enrolled (median age 52). The majority had stage I or II tumors (n = 219, 78%). There were numerically more node-positive tumors in the vaccine arm, 78 (41%) vs 27 (32%), p = 0.15. Median follow-up was 3.5 years, and 33 (FRPV: 25, placebo: 8) DFS events were observed; 3.5-year DFS rate was 88% with FRPV and 90% with placebo (HR 1.42, 95% CI 0.64–3.15; p = 0.39). Overall survival (OS) also did not differ by arm (HR 2.48, 95% CI 0.55–11.20; p = 0.22). Among node-positive pts (n = 105), DFS did not differ between arms (HR 0.95, 95% CI 0.34–2.66; p = 0.92). However, a numerical DFS event rate improvement (14% for vaccine vs. 26% for placebo) was observed in 61 patients with stage III disease (HR 0.51, 95% CI 0.16–1.68; p = 0.26). DFS did not differ by chemotherapy setting or by receipt of anthracycline, capecitabine, and/or an immune checkpoint inhibitor. FRPV was well tolerated, with predominantly grade 1–2 adverse events (AEs) and no vaccine-related grade ≥4 AEs. FRα expression was available from tumor in 230 pts, with 72% expressing > 0. Overall, DFS was not significantly associated with FRα expression (0 vs > 0; HR 0.55, 95% CI 0.21–1.44; p = 0.21), and no significant differences in DFS by FRα expression were observed between treatment arms. Conclusions: FRPV following oral cyclophosphamide was safe, with no vaccine-related high-grade AEs. While no significant improvement in DFS or OS was observed overall, a numeric trend toward improved DFS was observed in pts with stage III TNBC. This finding is hypothesis-generating and supports further evaluation of FRα-targeted vaccination in higher-risk TNBC. Immune correlative analyses are ongoing to better define vaccine immunogenicity and its relationship to clinical outcomes. Clinical trial information: W81XWH-15-1-0293.

3525 Background: Tumor microenvironment (TME) features of colorectal cancer (CRC) may influence detection of circulating tumor DNA (ctDNA) and further refine prognosis. We applied a deep learning histopathologic algorithm to quantify TME features in stage III colon cancers and evaluated their association with postoperative ctDNA status among participants in a phase III FOLFOX-based adjuvant trial (NCCTG N0147). Methods: QuantCRC (Aiforia Technologies) was applied to digitized hematoxylin and eosin-stained whole-slide images of stage III colon adenocarcinomas to extract quantitative histopathologic features. Among cases where data met quality control (N=1817), associations between 15 distinct pathologist-defined features and clinical outcomes—time to recurrence (TTR), disease-free survival (DFS), and overall survival (OS)—were evaluated, stratified by postoperative ctDNA status assessed by a tissue-free assay (Guardant Reveal). Relationships were analyzed using univariate and multivariable Cox proportional hazards models that were adjusted for clinicopathologic and molecular features ( KRAS , BRAF V600E , MMR status). Interaction testing was performed. Results: We found statistically significant quantitative differences for histopathological features by ctDNA status. Features associated with ctDNA positivity(+) included lymphovascular invasion (LVI), and increased %high grade, %tumor budding, %necrosis, and %stroma. ctDNA+ cases had lower %inflammatory stroma and fewer %signet ring cells (all p< 0.006). Multivariable analyses, irrespective of ctDNA status, identified %tumor budding, %mucin, %signet ring cells, %inflammatory tumor bed, and %inflammatory stroma as significantly associated with adverse outcomes (TTR, DFS, OS). Within ctDNA+ cases, higher %immature tumor bed was associated with adverse outcome for all 3 variables. Among ctDNA-negative cases, significantly poorer outcomes (TTR, DFS, OS) were observed for tumors with lower tumor infiltrating lymphocyte (TIL) density and reduced %necrosis. After adjustment, significant interactions with ctDNA status were observed for LVI (p< 0.006) and %signet ring cells (p< 0.035) across all outcome variables, for %necrosis with DFS, OS (p<0.040), and for TILs with TTR (p<0.015). Analysis is ongoing for ctDNA tumor fraction as well as tumor genotyping data (739 genes; Guardant360). Conclusions: QuantCRC identifies TME features associated with postoperative ctDNA status that enable risk-stratification within ctDNA groups. Among ctDNA-negative patients, reduced intratumoral TIL density and reduced tumor necrosis identify high-risk subgroups with inferior clinical outcomes, and may have clinical utility.

10578 Background: Multicancer detection (MCD) testing using cell-free DNA methylation patterns is a novel blood-based approach to cancer screening. In 2022, Mayo Clinic implemented offering MCD testing into routine clinical practice. Prior real-world reports have been limited to single-site experiences. We evaluated enterprise-wide implementation of MCD testing across all three Mayo Clinic sites using the Mayo Clinic Platform. Methods: We performed a retrospective analysis of de-identified clinical data from Mayo Clinic Platform Discover, including GRAIL Galleri tests performed at Mayo Clinic sites in Rochester, MN; Scottsdale, AZ; and Jacksonville, FL. This activity did not require IRB review per 45 CFR 46.102. Demographics, test results, cancer diagnoses, and prior cancer history were extracted using a privacy-preserving protocol, with data de-identified by expert determination. ICD-10 diagnostic codes were used to identify subsequent cancer diagnoses. Results: A total of 8,201 Galleri tests were performed in 7,300 patients; some patients underwent repeat testing. Fifty-seven tests (0.7%) were positive. Among MCD-positive patients, cancer diagnostic codes were identified in 32 patients, yielding a positive predictive value (PPV) of 58.7%. The most common cancers identified were oropharyngeal (34.4%), lymphoid and hematopoietic (34.4%), and gastrointestinal malignancies (18.8%).Among 8,144 MCD-negative tests (99.3% of all testing performed), 423 patients (5.2%) subsequently received a cancer diagnostic code, yielding a negative predictive value of 92.5%. The most commonly identified cancers in this group were male genital organs (36.6%), urinary tract (10.6%), and thyroid or other endocrine glands (7.3%). Overall, 10.1% of patients had a prior cancer history, which was more common in MCD-positive than MCD-negative patients (22.6% vs 10.0%). Patients with positive tests were older (mean age 68.4 vs 61.5 years) and more often male (67% vs 62%). Race distribution was similar. Conclusions: Enterprise-wide implementation of MCD testing across diverse clinical settings is feasible within routine workflows. Over half of positive tests were associated with cancer diagnostic codes, supporting the clinical promise of MCD testing. Limitations include incomplete capture of externally diagnosed cancers and lack of cancer signal-of-origin data. The Mayo Clinic Platform enables scalable, secure analytics to support future cancer interception strategies.

Introduction: Evidence suggests that the distal radioulnar joint injury associated with an operatively treated displaced fracture of the distal radius does not benefit from specific treatment after the radius is realigned. To better understand variation in treatment of the distal radioulnar joint we performed a scenario-based experiment presenting radiographs of displaced distal radial fractures accompanied by clinical scenarios with randomized aspects. Methods: In a survey-based experiment, participants of the Science of Variation Group viewed a random subset of five of 10 sets of radiographs showing displaced fractures of the distal radius before and after anterior plate fixation. Each was accompanied by a clinical scenario with trauma energy level, age and gender randomized. Participants indicated their preferred distal radioulnar joint treatment: none, cast immobilization, operative reattachment of ligaments or ulnar styloid fixation, or distal radioulnar joint pinning. Factors associated with any treatment and with reattachment were sought in multivariable regression. Results: Surgeons recommended distal radioulnar joint treatment in 67% (404 of 607) of the scenarios, most commonly cast immobilization in 41% (247 of 607). Recommendation for any distal radioulnar joint treatment was associated with younger patient age, and for reattachment specifically, was associated with younger patient age, high-energy trauma and fracture of the base of the ulnar styloid. Conclusions: The observation of frequent recommendation for distal radioulnar joint treatment, relatively more so for younger patients with higher energy injuries, and some tendency to repair an aligned ulnar styloid base fracture may diverge from existing evidence.

Abstract Background Whether outcomes of germline BRCA1/2 (gBRCA1/2)-associated breast cancer differ compared with sporadic tumors is controversial. We explored the impact of gBRCA1/2 pathogenic variant (PV) status beyond established prognostic features. Methods We conducted 2 retrospective, matched cohort studies comparing gBRCA1/2 PV carriers and noncarriers with HER2-negative, stage I-III breast cancer (Clinical Outcomes Quality Database [COQD] cohort: 185 carriers, 555 noncarriers; Young Women’s Breast Cancer Study [YWS] cohort: 113 carriers, 226 noncarriers). Matching factors were age, stage, hormone receptor status, and year of diagnosis. Clinicopathological features, treatments, and survival outcomes were compared between carriers and noncarriers. Results Most patients in COQD had stage I-II disease (87.2%), and more carriers than noncarriers had genetic testing before diagnosis (33% vs 5.6%, P &lt; .001). In YWS, 22.7% of patients had stage III tumors, and few were tested before diagnosis (14.8% of carriers vs 1.7% of noncarriers; P &lt; .001). Carriers in COQD received chemotherapy more often than noncarriers (81.1 vs 67.0%, P &lt; .001), including platinum (P = .010); the proportion was similar for carriers and noncarriers in YWS. After adjusting for chemotherapy, relapse-free survival was longer in carriers than noncarriers in COQD (adjusted hazard ratio = 0.48 [95% CI = 0.26 to 0.87], P = .016), and a favorable trend was observed for other survival outcomes in both cohorts. Triple-negative tumors appeared to drive the differences. Conclusions We observed a trend toward improved outcomes in gBRCA1/2 PV carriers compared with noncarriers. These findings suggest that carriers should not receive more aggressive treatment solely based on their germline mutation status. Prospective clinical trials in this population are warranted.

Background: Hypoplastic left heart syndrome (HLHS) is defined as “a spectrum of congenital cardiovascular malformations with normally aligned great arteries without a common atrioventricular junction, characterized by underdevelopment of the left heart with significant hypoplasia of the left ventricle including atresia, stenosis, or hypoplasia of the aortic or mitral valve, or both valves, and hypoplasia of the ascending aorta and aortic arch”. Without treatment, HLHS is usually lethal in the neonate. Many hypotheses have been advanced to explain the etiology of HLHS; however, no single theory appears to fully explain the phenotypic variability seen in HLHS. Furthermore, many of these theories offer no explanations regarding the precipitating events which lead to the development of HLHS. Objective: This review considers and critically evaluates the strengths and weaknesses of the leading theories proposed to explain the pathogenesis of HLHS—including hemodynamic disturbances, primary myocardial structural defects, valvar malformations, and genetic or epigenetic alterations that may provoke developmental and anatomic abnormalities. After presenting each model, we propose a novel, comprehensive, and data-driven framework which may assist researchers in developing models for the pathogenesis of the various subtypes of HLHS. Methods: Key findings from human fetal imaging, histopathology, genetic studies, and animal models were considered, as well as the hypothetical contribution of each in observed HLHS phenotypes. The rationales for these findings as causal factors initiating individual HLHS patterns, as well as how they might contribute to HLHS in general, were critically analyzed. Results: The flow theory is strongly supported by animal models and in utero interventions that demonstrate the impact of altered hemodynamics on cardiac morphogenesis. However, the flow theory fails to identify initial causes of disturbed flow or related histological features of HLHS like endocardial fibroelastosis. The myocardial and valve-first models suggest an important role in developmental defects, but do not necessarily have a strong experimental basis that provides explanations for how they mediate HLHS. Genetic studies in patients with HLHS have identified several candidate causal mutations. However, such genetic causes of HLHS exhibit incomplete phenotypic penetrance and clinical impact. A multifactorial framework attempts to integrate these diverse mechanisms and may provide the most coherent explanation that can accommodate the heterogeneity and variable presentation of HLHS. Such a framework may identify multiple forces that drive disease but does not provide useful pathways for future research about HLHS. Conclusions: No single hypothesis has fully explained how HLHS is initiated, progresses, and presents with the clinical conditions that are encountered by cardiac surgeons and cardiologists. The most current models suggest that the spectrum of HLHS reflects acomplex interaction between genetic susceptibility, flow-dependent cardiac remodeling, and environmental factors in utero. A multifactorial model integrates these diverse mechanisms and may provide the most coherent explanation for the various phenotypic variations in HLHS. Based on our analysis of the most current data and the strengths and weaknesses of the current theoretical frameworks, we propose a novel research strategy aimed at identifying specific cardiac progenitor cell populations whose dysregulation may represent a unifying explanation for the etiology of the various phenotypes of HLHS. Based on the arguments made throughout this manuscript that evaluate the various genetic, structural, and hemodynamic models of initiation of disease, we believe that the significant phenotypic variability across the spectrum of HLHS (i.e., the different anatomic subtypes for “classic” HLHS) most likely reflects different underlying etiologies and mechanisms. At the very least, it is very likely that the timing of the insult is critical in determining anatomic subtype. Based on the published data and the arguments within this manuscript, it seems naive to think that there is a single unifying mechanism explain all forms of HLHLS.

Introduction Proton dose driven continuous scanning (DDCS) is a form of proton pencil beam scanning (PBS) in which the beam may remain on during transitions between successive spots. Mayo Clinic Florida (MCF) is preparing to commission a synchrotron-based proton therapy system designed for DDCS, incorporating novel irradiation control features. Given the novelty and complexity of this system, a systematic risk-based analysis was performed to inform upcoming commissioning strategies. Methods A prospective risk analysis was conducted using the American Association of Physicists in Medicine (AAPM) Task Group 100 (TG 100) framework. A comprehensive process map of the DDCS irradiation control workflow was developed. Failure modes and effects analysis (FMEA) was performed to identify potential delivery system failure modes and to score each failure mode based on occurrence, severity, and lack of detectability. Targeted mitigation and commissioning strategies were then developed to address the highest-risk items. Results Twenty-nine delivery system failure modes were identified. The highest-risk failure modes were specific to DDCS operation. Targeted commissioning strategies were defined, including scan path measurement and modeling, validation of move and flap dose, dose monitor collection efficiency testing, spot position monitor performance evaluation, and verification of control system intervention behavior. Incorporation of these strategies into the commissioning plan reduced the mean RPN by more than 50%. Discussion This work provides a detailed description of the MCF proton DDCS irradiation control system and uses a TG 100 based approach for identifying system-specific risks. As new systems incorporate technologies for which limited guidance exists, institutions must perform their own risk analyses to determine appropriate quality management strategies.

Abstract Introduction Solid tumors modify local angiogenesis and co-opt surrounding vasculature to maintain energy supply required for ongoing growth. This process is often complicated by metastasis and hemorrhage. Pulmonary tumors can rarely create intrapulmonary shunt physiology and hypoxemia in this manner; this has been described most often in bronchoalveolar carcinoma. We present a case of malignant intrapulmonary shunt occurring with spindle cell sarcoma, which resolved with arterial embolization. Case Presentation A 72-year-old male with a history of stage IV spindle cell sarcoma with abdominal, vertebral, and pulmonary metastases presented to an outpatient appointment with three weeks of fatigue and decreased exercise tolerance. He had no history of parenchymal lung disease nor any home oxygen requirement. In clinic, he was found to require 6L per minute of supplemental oxygen to maintain saturation of 88%. He was directly admitted to the oncology service. Initial laboratory evaluation was unremarkable. CT imaging demonstrated normal lung parenchyma, no pulmonary embolism, and an 11cm vascular tumor involving proximal branches of the local pulmonary artery (Figure). Transthoracic echocardiography (TTE) with agitated saline revealed a large intrapulmonary shunt. As the patient had limited response to oxygen therapy, this intra-tumoral shunt was deemed the most likely cause of his hypoxemia. Surgical resection was considered but was deemed to confer limited clinical benefit in the setting of multiple metastases. Embolization of the local pulmonary artery was therefore pursued with Interventional Radiology. The patient tolerated the procedure well with complete resolution of hypoxemia post-procedure. His energy and mobility improved, and he was discharged home. Three months later, he continued to require no supplemental oxygen. Discussion While shunt physiology is commonly part of the differential for hypoxemia, it is rarely described as an oncologic complication. This appears to be the first report of such pathology in a sarcoma patient, and the first to report shunt resolution through arterial embolization rather than surgical resection or systemic anti-tumor therapy. In addition, previous cases typically describe shunt detection via selective pulmonary arterial occlusion by Swan-Ganz catheter, whereas here the noninvasive TTE with agitated saline was sufficient. While the few existing reports highlight good response to lobectomy or pneumonectomy, this case highlights the potential for minimally invasive vascular intervention. Despite the metastatic nature of this patient’s disease, he received significant, rapid physiologic and functional benefit from a procedure with less morbidity. Maintaining suspicion of intra-tumoral shunt physiology is appropriate for patients with vascular pulmonary masses and hypoxemia. This abstract is funded by: None

OBJECTIVE The aim of this study was to evaluate freedom from tumor progression and clinical outcomes in older adults with small- to medium-sized vestibular schwannoma (VS) managed by observation versus stereotactic radiosurgery (SRS) to better inform optimal management in this patient population. METHODS In this international multicenter study, patients aged ≥ 60 years with Koos grade I or II VS managed by observation or SRS were retrospectively reviewed. Propensity score matching was conducted using patient characteristics, tumor size, and hearing assessments. Outcome measures of freedom from tumor progression, serviceable hearing preservation (SHP), and neurological function (tinnitus, vestibulopathy, House-Brackmann grade, and trigeminal nerve function) were assessed for both groups. RESULTS The observation and SRS groups each comprised 51 matched patients (median age 68 years for both). Ipsilateral serviceable hearing was observed at presentation for 35 patients in each group. The median follow-up duration was 39 months in the observation group versus 27 months in the SRS group (p = 0.5). Tumor progression was significantly lower with SRS than with observation (2% vs 52.9%, p < 0.001). The rate of 5-year freedom from tumor progression was 100% in the SRS group versus 43% (95% CI 29%–64%) in the observation group. The rate of 10-year freedom from tumor progression was 90% (95% CI 73%–100%) in the SRS group versus 20% (95% CI 8.5%–49%) in the observation group. At the last follow-up, hearing loss occurred in 42.9% of the observation group and 51.4% of those who underwent SRS (p = 0.5). The 3-year SHP rate was 68% (95% CI 53%–88%) versus 65% (95% CI 49%–85%) (p = 0.8), and the 5-year SHP rate was 53% in both groups (95% CI 36%–78% in the observation group and 95% CI 35%–79% in the SRS group, p = 0.8). The composite endpoint of tumor progression and/or worsened neurological outcome, including hearing loss, tinnitus, vestibulopathy, facial nerve dysfunction (House-Brackmann grade), or trigeminal dysfunction, demonstrated a significantly lower rate in the SRS group (17.6%) compared with the observation group (66.7%) (p < 0.001). CONCLUSIONS SRS in older patients for management of Koos grade I or II VS resulted in significantly superior rates of freedom from tumor progression, comparable hearing preservation rates, and significantly higher rates of favorable overall radiographic and neurological outcomes than observation alone. Compared with observation, SRS might be the preferred management option in this patient population.