Costello, Brian A.

Physician burnout is prevalent and contributes to the high number of physicians choosing to leave clinical practice. The field of hematology-oncology (HO) poses unique challenges for trainees and staff physicians who have to deliver bad news, manage complicated psychosocial situations, deal with the limited ability to prolong life, and juggle multiple time-sensitive demands from coworkers, patients, and families. Furthermore, they often face the death of their patients, along with its emotional toll on patients’ families and the physicians themselves. Burnout in HO is prevalent and increasing, with many physicians reporting in several studies that they plan to reduce working hours and/or retire early. The demand for hematologists and oncologists is rapidly rising, but in the setting of a worsening HO workforce shortage and an increasing number of patients with cancer. Therefore, it is imperative to develop strategies to mitigate or address burnout in HO physicians to improve well-being and prevent attrition. Herein, we describe risk factors and causes of physician burnout in HO trainees and practicing physicians in the United States, with a focus on institutional and individual strategies to address this issue. We also provide recommendations to address the burnout epidemic from the HO standpoint.

This cohort study examines the oncological, neurological, and serological profiles of adult male patients with testicular germ cell tumors and paraneoplastic neurologic syndromes.

Abstract Purpose: Germ cell tumors (GCTs) pose significant diagnostic challenges due to the limited sensitivity and specificity of current tumor markers. Hereby we utilize phage immunoprecipitation sequencing (PhIP-Seq) technique to develop a unique immunosignature panel (iSIGN) with high sensitivity and specificity to improve the diagnosis and differentiation of GCTs. Patients and Methods: Serum samples from patients with confirmed gonadal or extragonadal GCTs and controls were collected from Mayo Clinic repositories. Controls included benign testicular lesions, autoimmune diseases, neurodegenerative disorders, and other cancers. Samples were randomized into development and validation cohorts. PhIP-Seq identified antigen-autoantibody interactions, and enrichment scores were calculated to develop a biomarker panel distinguishing GCT from non-GCT cases. A second biomarker panel was developed to predict seminoma from nonseminoma cases. Results: A total of 427 serum samples were analyzed, including 150 from GCT patients and 277 controls. For our primary model to distinguish GCT cases (GCT-iSIGN), 24 peptides from 16 antigens were identified based on significant differential autoantibody binding enrichment in GCT patients (p < 0.05), ≥2 peptides per antigen, and enrichment scores ≥ 2.5-fold. GCT-iSIGN was highly sensitive (93%) and specific (99%) for identifying GCT cases from controls with an area under curve (AUC) of 0.93 and 9% Unknown Case Rate (UCR). The secondary panel (Sem-iSIGN) included 17 peptides corresponding to 5 unique proteins with high specificity (93%), moderate sensitivity (65%) and AUC of 0.77 to distinguish seminoma from nonseminoma GCT cases. Conclusion: This study demonstrates the potential use of PhIP-Seq to identify unique immunosignature panels that can serve as reliable biomarkers for GCT. These panels address the limitations of traditional markers and other proteomic techniques. This immunosignature model represents a cost-effective, stable, and scalable approach to enhancing GCT diagnosis and management. Citation Format: M Bakri Hammami, Andrew Knight, Haidara Kherbek, Brian Costello, Silvana De Lorenzo, Bradley C. Leibovich, John C. Cheville, Yong Guo, Jessica Sagen, Janet E. Olson, Alicia Algeciras-Schimnich, Sean J. Pittock, John R. Mills, Surendra Dasari, Divyanshu Dubey. iSIGN panel identifies germ cell tumors via whole-proteome phage immunoprecipitation sequencing [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Mechanisms of Cancer Immunity and Cancer-related Autoimmunity; 2025 Sep 24-27; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(9 Suppl):Abstract nr B027.

4558 Background: In the past 7 years, 4 immuno-oncology (IO) based combinations have been approved for mRCC. However, QOL data on these combinations are limited to trials in which collection and reporting was not standardized, which further limits cross trial comparisons. Real-world QOL data with multiple treatment regimens are needed to understand how these regimens are tolerated in practice. Methods: ODYSSEY is a multi-site, prospective observational study of 500 US pts with mRCC. Pts must have mRCC (any histology), no prior ST, and follow up at a PCORnet study site. Exclusion criteria include treatment for cancer except mRCC. The primary objective is to determine patterns of change in QOL and symptom burden of pts with mRCC. Minimally important differences (MID) are 3 points for FKSI-19 total score, 1 point for the FKSI-Disease Related Symptoms (DRS) subscale and 7 points for FACT-G. Results: As of 1/6/25, 392 pts were enrolled of whom 299 were managed with ST. Of pts on ST, 114 were treated with IO-IO, 108 with IO-TKI, 33 with IO alone, 27 with Other, and 18 with TKI alone. Median follow up for all pts is 8.8 months (IQR 2.9, 16.2). IO-IO pts are median age 64 yrs, 81% male, 84% white, 56% prior nephrectomy, 84% clear cell; IO-TKI pts median age 66 yrs, 76% male, 92% white, 43% prior nephrectomy, 66% clear cell; IMDC risk profiles are similar. IO-IO pts are more likely to be KPS 100; whereas, IO-TKI pts have a higher median number of metastatic sites and are more likely to have bone or liver metastasis. With median follow-up of 6.0 (IQR 1.8, 14.9) and 8.8 months (4.5, 17.8) in the IO-IO and IO-TKI cohorts, 17 (15%) and 21 (19%) pts had died with a median time to death of 5.4 (2.5, 6.4) and 5.7 months (4.4, 12.8), respectively. 20 (18%) and 16 (15%) pts on IO-IO and IO-TKI had discontinued therapy at a median of 3.0 (IQR 2.0, 4.0) and 6.4 months (2.4, 13.0), respectively. Rates of discontinuation for disease progression and toxicity are similar. Baseline PROs for pts on ST are shown in the Table (higher score indicates better QOL), with RCT data for reference (NA, not assessed). Conclusions: In our prospective multi-center ODYSSEY study, we demonstrate that real world pts treated with contemporary ST have worse baseline QOL than those enrolled on pivotal RCTs. One-third of IO-IO and IO-TKI pts died or discontinued therapy within 6 months of initiation. Our data on real world vs RCT differences in baseline QOL may partially explain the limitations of current IO combination regimens in practice and support development of alternative treatment approaches. Instrument, Mean (SD) ODYSSEYIO-IO(N=114) CheckMate214(N=425) ODYSSEYIO-TKI(N=108) KEYNOTE426(N=402) CheckMate9ER(N=323) CLEAR(N=351) FKSI-19 total 56.0 (12.5) 60.1 (9.8) 53.8 (11.8) NA 58.7 (10.6) NA FKSI-DRS 27.5 (6.3) 30.7 (4.5) 27.0 (5.8) 32 (4.2) 30.2 (5.2) 31.3 (4.4) FACT-G 82.4 (16.7) 82.6 (15.0) 78.5 (16.0) NA NA NA

4553 Background: AS is a recognized strategy in select pts with mRCC to maximize QOL and delay potential toxicity of systemic therapy (ST); however, only 2 prospective studies of AS in mRCC have been published: only 1 with patient-reported outcomes (PRO) and none in the IO-TKI era. Methods: ODYSSEY is a prospective observational study of 500 US pts with mRCC. Eligible pts must have mRCC (any histology), no prior ST, age ≥19. Pts were excluded if treated for non-mRCC cancers or if not followed at a PCORnet study site. Pts completed QOL surveys at baseline, by phone every 3 months for 2 years and then every 6 months until end of follow up. The primary objective is to determine patterns of change in QOL and symptom burden of pts with mRCC. Minimally important differences (MID) are 3 points for FKSI-19 total score, 1 point for the FKSI-Disease Related Symptoms (DRS) subscale and 7 points for FACT-G. Here we report baseline pt characteristics in AS pts compared to ST pts, and baseline QOL differences between these cohorts. Results: As of 1/6/25, 392 pts were enrolled of whom 299 were managed with ST, and 93 pts deferred ST; of these, 53 pts (57%) were classified as AS. Pts on AS are median age 68 yrs, 66% male, 94% white, 81% clear cell, 50% favorable risk, 44% intermediate risk. Compared with ST pts, AS pts were more likely to have undergone nephrectomy (91% vs 53%), favorable risk profile (50% vs 15%), pancreatic metastasis (15% vs 5%), and longer time since RCC diagnosis (median 58 vs 3.3 months); and less likely to have bone, brain, or liver metastasis. After median 8.8 months follow-up (IQR 2.9, 16.2), 2 pts (4%) on AS had died compared with 45 pts (15%) on ST. One pt (2%) on AS started first-line therapy and 45 pts (15%) discontinued ST. Mean baseline QOL (FKSI-19 total, DRS and FACT-G) for AS and ST ODYSSEY pts is shown in the Table (higher score indicates better QOL), with RCT data for reference (NA, not assessed). ODYSSEY pts on AS had higher QOL for all measures compared with ODYSSEY pts on ST. FSKI-DRS was the same or lower for pts on AS compared to the pivotal trials, while ODYSSEY pts on ST had both lower FKSI-19 total and DRS. Conclusions: In our large prospective cohort from ODYSSEY, pts on AS had higher median QOL scores than pts on ST, but similar to those included in RCTs. These results suggest that some RCT pts could have benefitted from AS. Further follow up is needed to determine long term outcomes in pts on AS and how they respond to deferred ST. Clinical trial information: NCT04919122 . Instrument, Mean (SD) ODYSSEY AS (N=53) ODYSSEY ST (N=299) ODYSSEY Difference, AS vs ST (95% CI) CheckMate 214 (N=425) KEYNOTE 426 (N=402) CheckMate 9ER (N=323) CLEAR (N=351) FKSI-19 total 63.4 (9.2) 56.3 (12.5) 7.0(4.0, 10.1) 60.1 (9.8) NA 58.7 (10.6) NA FKSI-DRS 30.8 (4.2) 27.9 (6.0) 2.9(1.5, 4.7) 30.7 (4.5) 32 (4.2) 30.2 (5.2) 31.3 (4.4) FACT-G 87.9 (14.0) 82.4 (16.7) 5.6(1.1, 10.0) 82.6 (15.0) NA NA NA

524 Background: Antiangiogenic tyrosine kinase inhibitors (TKIs) play a key role in treating renal cell carcinoma and other solid organ malignancies, but TKIs cause bothersome side effects that frequently necessitate dose reductions or treatment holds. Olanzapine has been useful for palliating symptoms from classical chemotherapies and advanced cancer, but its effect on TKI-related symptoms is largely unknown. This retrospective study aimed to estimate the efficacy of olanzapine for TKI-induced nausea, vomiting, anorexia, weight loss, and insomnia. Methods: All patients prescribed olanzapine with lenvatinib, cabozantinib, axitinib, or tivozanib at Mayo Clinic between January 1, 2018, and June 30, 2024 were assessed for inclusion. For baseline symptom assessment, clinical care team notes documenting the presence or absence of symptoms and indication(s) for starting olanzapine were reviewed. For response assessment, clinical notes and patient portal messages from the first three months after starting olanzapine were evaluated for qualitative descriptions of change in symptom burden. Relevant data were extracted as direct quotations, which were reviewed by the research team and categorized as “improved,” “worsened,” “stable,” or “missing data.” Each symptom domain was analyzed independently when olanzapine was prescribed for multiple interrelated symptoms. Results: A total of 60 patients who received olanzapine for the treatment of TKI-related adverse effects were included. The most common documented indication for olanzapine was nausea without vomiting (n=35), followed by anorexia (n=25), nausea with vomiting (n=16), weight loss (n=16), and insomnia (n=11). In 32 cases (53%), olanzapine was prescribed for multiple, simultaneous symptoms. Response rates for each symptom domain are shown in the table. In addition, prior to olanzapine, 34 patients (57%) had documented weight loss. Following olanzapine, 50% (n=17) gained weight (median increase: 6.1 kg; range: 2.0 - 10.7 kg), 26% (n=9) stabilized their weight (±1 kg), and 24% (n=8) continued to lose weight. Clinicians utilized a TKI dose reduction within one week of olanzapine initiation in 5 cases (8.3%), and 3 of these patients could resume the higher dose of TKI after starting olanzapine. Only 4 patients (7%) discontinued olanzapine within 3 months due to perceived side effects. Conclusions: Olanzapine appears to be effective in treating TKI-induced nausea, vomiting, anorexia, insomnia, and weight loss. Prospective randomized placebo-controlled studies are needed to confirm these findings. Improvedn (%) Worsened n (%) Stablen (%) Missing Datan (%) Nausea without emesis 32 (84) 3 (8) 1 (3) 2 (5) Nausea with emesis 13 (93) 0 (0) 0 (0) 1 (7) Anorexia 26 (74) 2 (6) 4 (11) 3 (9) Insomnia 11 (85) 0 (0) 2 (15) 0 (0)

Background Clonal hematopoiesis (CH) is defined by somatic mutations in hematopoietic stem cells, often conferring a selection advantage based on clonal selection pressures. CH in DNA Damage Response and Repair (DDR, e.g. TP53, PPM1D) genes are frequent in individuals exposed to chemotherapy and radiation (chemo/XRT). In metastatic prostate cancer (mPC) patients, the prevalence of CH is estimated at 57% and is increased among those with prior exposure to chemo or XRT. In these patients, the use of radiotheranostics is becoming more prevalent and are now being tested in earlier lines of therapy. We have identified an increase in DDR-somatic variants post lutetium-177-PSMA, raising concern for long term hematologic safety. Here, we evaluate the spectrum of CH and CCUS (clonal cytopenias of undetermined significance) in mPC patients, prior to receiving radioisotope therapies. Methods We performed error corrected next-generation sequencing (NGS) on peripheral blood samples from 67 mPC patients enrolled in the Prostate Cancer Medically Optimized Genome Enhanced Therapy Study (PROMOTE) study (NCT #01953640). All patients enrolled also had whole exome sequencing (WES) performed on initial metastatic biopsies and on whole blood for germline genotyping. Somatic variants with a variant allele fraction (VAF) ≥0.5% were considered as CH, using standard bioinformatic variant calling algorithms. Results The median age at NGS was 74.4 years (range, 58.4-92.3). While all patients received androgen deprivation therapy (ADT) +/- androgen receptor pathway inhibitor (ARPI), 67.2% (n=45, pelvic XRT- 35, palliative XRT- 10) received prior XRT and 3% (n=2) received prior docetaxel. No patients in this cohort received prior platinum or PARP inhibitor. Of those treated with XRT or chemo, the median time from first exposure to CH sample collection was 4.1yrs (range, 0.12-29.6) and 2.3yrs (range, 0.6-4.0), respectively. Of the 67 patients, we identified a total of 111 pathogenic variants in 59 (88.1%) patients. We compared our NGS data to the germline data and tumor for each patient (All samples obtained at the same time point; Wang et al 2018). Our analysis excluded 2 ATM variants likely to be germline, and 1 TP53 variant likely to be tumor-derived. Each patient had at least one somatic variant, with a median of 2 variants (range, 1-6The median CH VAF was 1.8% (range, 0.5-50.2) with 91.0% of alterations detected at a VAF of <10%. Specific somatic variants, presence/absence of CH, number of variants, nor VAF was associated with age, prior chemo, or XRT exposures. At time of NGS, 54% of patients were anemic (hgb <13g/dL), 7% were thrombocytopenic (platelets <135 x109), 6% were leukopenic (WBC <3 x 109), and no patients were neutropenic (ANC <1 x109). Persistent cytopenias, lasting >3months, were present in 25% (n=17) of patients; however, bone marrow biopsies (BMB) were performed only in 6% (n=4). Three (75%) of these 4 patients had mPC infiltration in the BM, and 1 (25%) had mild dysplasia not meeting criteria for MDS but meeting criteria for CCUS (CHEK2 somatic variant). At last follow-up, there were no patients formally diagnosed to have myeloid neoplasm (MN). Median overall survival (OS) from prostate cancer diagnosis was 8.6yrs (range, 1.4-28.4). With a median follow up of 2.2yrs (range 0.1-10.8) after CH testing, 3.0% (n=2) were alive, with most deaths occurring due to mPC. The presence of CH did not impact overall survival (OS), however, presence of cytopenias at the time of NGS testing was associated with worse outcomes (median OS 2.5yrs vs 1.2 yrs., p=0.025). Conclusions We define the landscape of CH mutations in mPC patients predominantly treated with ADT/ARPI and XRT, demonstrating that DNMT3A, TET2, PPM1D and ASXL1 are frequently mutated (88%) and largely subclonal (91% with VAF ≤10%). While 25% of these patients had cytopenias, with cytopenias negatively impacting survival, due to inadequate BM biopsy work up, the true prevalence of CCUS and MN could not be estimated. Given the advancement of genotoxic therapies and the high prevalence of subclonal CH in mPC, future studies investigating CH as a predictive biomarker of hematological dysfunction are much needed.

12079 Background: Many troublesome symptoms experienced by men with prostate cancer are not specific to a particular disease state or treatment modality. As such, these issues' scope is neither fully appreciated nor characterized in the reporting of clinical trial data. A modern accounting of poorly controlled symptoms is needed to better inform survivorship and supportive care efforts. Methods: Data are drawn from the Enhanced, EHR-facilitated Cancer Symptom Control (E2C2) study, a cluster-randomized stepped wedge trial examining the effectiveness of routine symptom assessment and management on patient-centered outcomes and healthcare utilization (NCT03892967). This is a population-level study supporting patients with cancer, who are cared for in medical oncology clinics across the Midwest United States. The trial utilizes an automated symptom monitoring system with EHR-enabled algorithms for symptom triage and intervention. The current analysis focuses on pre-intervention surveys. The cohort includes E2C2 participants with prostate cancer (as determined by the Mayo Clinic Cancer Registry) receiving curative or palliative-intent therapies, along with prostate cancer survivors who previously completed their treatment. The prevalence of SPPADE symptoms (sleep disturbance, pain, impaired physical function, anxiety, depression, fatigue [low energy]) was assessed using 0 to 10 numerical rating scales (NRS), with scores of 4-6 indicating moderate symptoms and 7-10 indicating severe symptoms. Results: A total of 1,388 men with prostate cancer completed a pre-intervention survey between March 2019 and January 2023. The median age at completion of first survey was 74 years. The cohort includes patients living in diverse settings, including urban (n=718, 52%), micropolitan (n=250, 18%), small town (n=218, 16%), and rural (n=200, 14%) environments. The proportion of patients experiencing moderate-to-severe symptoms (NRS score ≥4) was 47% for fatigue, 40% for impaired physical function, 32% for sleep disturbance, 27% for pain, 22% for anxiety, and 20% for depression/emotional distress. The three domains with the highest prevalence of severe symptoms (NRS score ≥7) were fatigue (17%), impaired physical function (12%), and sleep disturbance (10%). Conclusions: Proactive symptom monitoring identifies a high overall burden of moderate-to-severe symptoms, particularly fatigue and impaired physical function, among prostate cancer patients and survivors. Collaborative care approaches and symptom control trials are needed to mitigate and manage these burdensome symptoms. Clinical trial information: NCT03892967 . [Table: see text]

PURPOSE Patients with no evidence of disease (NED) after metastasectomy for renal cell carcinoma are at high risk of recurrence. Pazopanib is an inhibitor of vascular endothelial growth factor receptor and other kinases that improves progression-free survival in patients with metastatic RCC (mRCC). We conducted a randomized, double-blind, placebo-controlled multicenter study to test whether pazopanib would improve disease-free survival (DFS) in patients with mRCC rendered NED after metastasectomy. PATIENTS AND METHODS Patients with NED after metastasectomy were randomly assigned 1:1 to receive pazopanib 800 mg once daily versus placebo for 52 weeks. The study was designed to observe an improvement in DFS from 25% to 45% with pazopanib at 3 years, corresponding to 42% reduction in the DFS event rate. RESULTS From August 2012 to July 2017, 129 patients were enrolled. The study was unblinded after 83 DFS events (92% information). The study did not meet its primary end point. An updated analysis at 60.5-month median follow-up from random assignment (95% CI, 59.3 to 71.0) showed that the 3-year DFS was 27.4% (95% CI, 17.9 to 41.7) for pazopanib and 21.9% (95% CI, 13.3 to 36.2) for placebo. Hazard ratio (HR) for DFS was 0.90 ([95% CI, 0.60 to 1.34]; Pone-sided = .29) in favor of pazopanib. Three-year overall survival (OS) was 81.9% (95% CI, 72.7 to 92.2) for pazopanib and 91.4% (95% CI, 84.4 to 98.9) for placebo. The HR for OS was 2.55 (95% CI, 1.23 to 5.27) in favor of placebo ( Ptwo-sided = .012). Health-related quality-of-life measures deteriorated in the pazopanib group during the treatment period. CONCLUSION Pazopanib did not improve DFS as the primary end point compared with blinded placebo in patients with mRCC with NED after metastasectomy. In addition, there was a concerning trend favoring placebo in OS.