Citations

e13036 Background: In January 2023, the FDA approved elacestrant for ESR1-mutated, ER+/HER2- MBC based on a companion diagnostic cell free (cf)DNA test (Guardant Health). In this study, we analyze the trends of liquid biopsy utilization at Mayo Clinic (MC) over a 3 year period to understand the impact of this drug approval on testing patterns and identify emergent alterations in patients (pts) with MBC. Methods: We extracted clinically performed Guardant 360 and Guardant 360 CDx ordered at MC sites in Rochester (MN), Florida (FL), Arizona (AZ), and across 9 additional Mayo Clinic Health System (MCHS) sites. Pts with MBC were identified using the EMR and analyzing visit diagnosis codes and staging information. Shifts in testing patterns were analyzed over a 3 year period from January 1, 2021 - December 31, 2023. Data was collected on the number of tests, serial testing, frequency of pathogenic mutations, and emergent mutations in ESR1 and PIK3CA. Chi-square test was used to compare the categorical values. Results: Between 2021-2023, 2,741 pts with MBC were seen across all sites. A total of 408 cfDNA tests were performed in 370 unique patients with MBC. Most pts (90%) had 1 test performed. The proportion of pts with MBC tested was 85/1350 (6.3%) in 2021, 77/1495 (5.2%) in 2022, and 208/1558 (13.4%) in 2023. The increased proportion of pts tested in 2023 was statistically significant compared to prior years (p<0.0001), while no difference was observed between 2021 and 2022 (p 0.19). Testing patterns varied by site, with FL ordering the highest number of tests, followed by MN and AZ. Of the 34 providers practicing during the entire period seeing more than 10 MBC pts, the number of providers ordering Guardant testing increased from 15/34 (2021) and 14/34 (2022) to 20/34 (2023), though not statistically significant (p 0.15). Of the 41% with EMR-documented staging available, testing was highest in the ER+/HER2- (81.3%) subtype, followed by TNBC (13.6%) and then HER2+ (5.2%). The most commonly identified mutations identified in the first testing were PIK3CA (41.1%), TP53 (40.5%), ESR1 (30.5%), and ATM (13.2%). D538G (8.0%), Y537N (4.4%), and Y537S (3.5%) were frequent emergent mutations seen in ESR1. Conclusions: We observed an increase in cfDNA testing at the start of 2023 which aligns with the FDA approval of elacestrant. We observed variation by site and individual providers that warrants further exploration to improve cfDNA testing in MBC pts at Mayo Clinic.

TPS11588 Background: Imatinib is the worldwide standard for first-line therapy of advanced KIT-mutant GIST. However, secondary resistance mutations in the KIT ATP-binding domain (exons 13, 14), activation loop (exons 17, 18), or both develop and result in loss of imatinib-sensitivity. Bezuclastinib has a highly selective inhibition profile, leading to minimal off-target toxicities and allowing for combination with sunitinib. While no single tyrosine kinase inhibitor (TKI) inhibits all KIT mutations, the combination of bezuclastinib + sunitinib targets commonly occurring primary (exons 9, 11) and secondary (exons 13, 14, 17, and 18) KIT mutations and may provide more durable responses. The early signs of clinical activity, tolerability, and safety observed with the combination thus far in Peak Part 1 (Somaiah et al. [presentation] CTOS 2023. Paper 62) are consistent with the completed Phase 1/2 study (PLX121-01). Methods: Peak (NCT05208047) is a global, randomized, open-label, multi-part Phase 3 study evaluating the efficacy and safety of bezuclastinib + sunitinib versus sunitinib as second-line treatment in adult pts who were intolerant to imatinib or whose tumors had imatinib-resistance. Current Peak study sites are located in North America (3 countries), South America (3 countries), Europe (12 countries), and Asia-Pacific (4 countries). The lead-in portion to test a new formulation of bezuclastinib, (Part 1) completed enrollment in April 2023. Based upon PK and safety, a dose of bezuclastinib 600 mg QD + sunitinib 37.5 mg QD was determined for Part 2 of the Peak study. Part 2 will enroll ~388 pts to be randomized (1:1) to bezuclastinib 600 mg QD + sunitinib 37.5 mg QD or sunitinib 37.5 mg QD alone. Key inclusion: >1 measurable lesion per modified Response Evaluation Criteria in Solid Tumors (mRECIST) v1.1, Eastern Cooperative Oncology Group Performance Status 0-2, adequate organ function, and prior imatinib therapy (no other prior therapy). Key exclusion: known PDGFR mutations or succinate dehydrogenase deficiency, clinically significant cardiac disease, and use of strong CYP3A4 inhibitors or inducers. The primary endpoint is progression-free survival (PFS) confirmed by blinded independent central review per mRECIST v1.1. Additional efficacy (including overall survival and objective response rate) and safety endpoints will be evaluated and circulating tumor DNA (ctDNA) will be collected and assessed. Clinical trial information: NCT05208047 .

11135 Background: Cancer screening programs can improve outcomes and may reduce treatment cost and utilization by shifting cancers to earlier, more curable stages at diagnosis (Dx). Few studies have evaluated the impact of screening on outcomes prior to diagnosis. Such information is needed to better understand the potential impact of newer blood-based multicancer early detection technologies. Methods: We conducted a retrospective cohort study using SEER cancer registry data linked with Medicare claims. Patients with a breast cancer (BC) or colorectal cancer (CRC) Dx between 2010-2019 were included if they were 65-74 years old at Dx, continuously enrolled in Medicare Parts A&B, had a Charlson Comorbidity Index of ≤2, and no cancer for ≥12 months prior to Dx. Those enrolled in an HMO or with high genetic risk for BC (in BC cohort) were excluded. Patients were assigned to screening groups prior to Dx; screening was defined as ≥1 screening procedure in the 6 months prior to Dx using CPT/HCPCS codes. Screening included FIT/FOBT, sigmoidoscopy, colonoscopy, CT colonography, mt-sDNA (CRC), and mammography (BC). Screened and not screened groups were compared for statistical significance using chi-squared for categorical variables, Wilcoxon rank-sum test for continuous variables. Results: Screening procedures were more prevalent in the BC cohort (68%) than the CRC cohort (44%) (table). Both screened subgroups (vs non-screened subgroups) had significantly lower proportions of patients diagnosed at stage 4 (2% vs 10% BC, 16% vs 27% CRC) and shorter times from first screening or imaging procedure to confirmed diagnosis (BC: 33 vs 227 days, CRC: 14 vs 29 days). Screened patients in both cancer cohorts had a similar number of average procedures prior to treatment initiation as non-screened (BC: 4.8 vs 4.2, CRC: 3.3 vs 3.3 respectively, including screening procedures). Conclusions: Individuals diagnosed with BC and CRC through screening exhibit earlier stage diagnoses and shorter intervals to diagnosis. Novel screening technologies such as MCED tests can potentially improve peri-diagnostic outcomes in cancers lacking existing or widely adopted screening methods. [Table: see text]

11079 Background: Phase 3 randomized clinical trials (RCTs) inform the standard of care in cancer treatment yet have a mixed track record of success. In this study, we sought to 1) determine the overall success rate of phase 3 RCTs; 2) assess whether authorship patterns differ between successful (positive) and unsuccessful (negative) trials; and 3) explore if individual authors have distinct track records of success. Methods: The HemOnc knowledgebase (KB) was queried for initial publications of phase 3 RCTs of systemic anticancer therapy; those without primary outcome described were excluded. RCTs were labeled positive if the primary endpoint was met per HemOnc standard criteria (P value ≤ 0.05 or hazard ratio upper bound ≤ 1 for any experimental arm[s]) and negative if they did not meet these criteria or if the experimental arm was statistically inferior. Trial metadata and author information were extracted from the HemOnc KB. Author positive publication rate (PPR) was defined as % of publications reporting a positive result divided by total number of eligible publications. Prolific authors were defined as those with 6+ eligible publications. Author count for manuscripts reporting positive vs negative results was evaluated with the Mann-Whitney U test; other statistics were descriptive. Results: 3328 studies met criteria as of February 5, 2024; these were associated with 3305 initial publications between 1960-2023, involving 25,412 unique authors. 1474 (44.3%) of the studies were positive. Publications reporting positive trial results had, on average, 3 more authors, median (interquartile range) of 18 (12-23) vs 15 (11-20), p<0.0001. The mean (±SD) PPR for n=1967 prolific authors was 47.7% (±22.3%). The PPR was not related to individual author output; mean PPR for non-prolific authors was 48.0% (SD not reported). Differences in PPR were apparent by the disease under study and the years of publication (Table). Among the 46 prolific authors who had a PPR 2+ SD above the mean, 26 (55%) were from China followed by Italy with 3 (6%). Conclusions: Despite known positive publication bias, the success rate of published phase 3 RCTs remains <50%. Publications reporting positive results had significantly more authors; this finding requires further study including adjustment for trial sample size. Significant variation in PPR amongst fields could be due to watershed therapeutic advances, differential selection of primary endpoints, and/or selective reporting of results. Finally, a signal for geographic association of outlier PPRs suggests the need for further investigation. [Table: see text]

11030 Background: Drug regulators operate on their own timelines to assess the safety and efficacy of new drugs and/or extensions to existing indications, such that there are delays between regulators. During such a gap, patients in the “early” domain have access to the approved drug, while those in the “late” domain do not, outside of compassionate use. Our study aimed to quantify the “opportunity lost” for new therapies approved by FDA and EMA, assuming patients in the late domain receive standard-of-care (SOC) therapy – which is presumably inferior to the new drug – during the gap. Methods: Anticancer drugs approved by both FDA and EMA were identified through the HemOnc knowledgebase. Inclusion criteria included: 1) drugs approved in both domains based on the same randomized clinical trial (RCTs) for the same indication; 2) a primary time-to-event endpoint; and 3) a quantitated median time-to-event for the primary endpoint. For each included trial, the approval gap between FDA and EMA in days and the ratio of approval gap to median control arm time-to-event duration was calculated. A ratio ≥2 implies that, on average, no late domain patients starting treatment in the first half of the gap would be expected to have access to the new drug prior to an event. Results: Of 60 eligible RCTs, 59 had calculable median event durations. 25 (42%) had a primary overall survival endpoint; the most common surrogate endpoint was progression-free survival (PFS; 29/59; 49%). The median (interquartile range [IQR]) approval gap was 186 (124-271) days, with FDA being the first approver in 56/59 (95%) cases. The median (IQR) ratio of approval gap to median control arm event duration was 0.63 (0.35-1.11). Drugs with ratio ≥2 (Table) were targeted or immunotherapies; 7/8 (88%) were approved with PFS endpoint; 5/8 (62.5%) were approved for second line or later. Conclusions: Our study shows that FDA approves most drugs prior to EMA and a nontrivial number of patients may experience progression or death events while awaiting access to anticancer therapies already approved in another domain. The analysis does not take into consideration scenarios in which the new therapy is inferior to SOC or delays in patient access (due to slow uptake; regulatory barriers [in Europe/UK]; or patient affordability [in US]). Further regulatory collaboration (e.g., Project Orbis) between FDA and EMA could help to reduce and potentially ameliorate this differential in access to new cancer drugs in the future. [Table: see text]

10026 Background: Childhood cancer survivors are at high risk for developing subsequent breast cancer with higher mortality than females in the general population with primary breast cancer. Whether therapeutic tradeoffs in treating primary versus subsequent breast cancer alter survival is unknown. Methods: Breast cancer treatment data were abstracted from medical records for female survivors from the CCSS and a multi-institutional sample of females with primary breast cancer matched one-to-one by demographics, diagnosis age/year, and breast cancer characteristics. Survivors’ excess mortality risk was evaluated as hazard ratios (HRs), adjusting for receipt of historically-appropriate guideline-concordant treatment established for primary breast cancer. Results: Subsequent breast cancers were diagnosed between 1981-2016 among 431 survivors, with a median diagnosis age of 40 years (IQR: 35-44). Most subsequent breast cancers were invasive (77%), with hormone receptor profiles similar to the general population (78% ER-positive; 26% HER2-positive). Guideline-concordant breast cancer treatment did not differ between survivors and controls (N = 688; 94% versus 93%), but treatment selection differed, reflecting survivors’ complex clinical history and guidelines’ multiple treatment options. Anthracyclines were used in 47% of survivors (controls 66%), mastectomy in 81% of survivors (controls 60%), and radiotherapy in 18% of survivors (controls 61%). In the subgroup treated with surgery and chemotherapy (survivors 31%, controls 26%), survivors did not have greater likelihood of dose reductions or omissions, treatment delays, or hospitalization for fever and neutropenia, but they were more likely to experience hematological toxicities (21% vs. 9%, p = 0.033) and other organ system-specific toxicities (36% vs. 11%, p < 0.001). Over one-third (38%) of survivors died during follow-up (median follow-up 9 years, IQR 6-14) after breast cancer. Strikingly higher all-cause mortality was observed among survivors than controls (HR = 3.5, 95% CI 2.2-5.6), especially after in situ disease (HR = 9.9, 95% CI 2.2-44.2). Among survivors with invasive disease, breast cancer accounted for most deaths (51%), followed by other subsequent malignancies (15%) and cardiovascular diseases (15%). Other health conditions accounted for 67% of deaths following in situ disease. Conclusions: Childhood cancer survivors with subsequent breast cancer generally receive guideline-concordant breast cancer treatment. While the treatments survivors receive differ from females with primary breast cancer, they do not experience higher rates of on-therapy treatment modifications. Despite this, they face excess mortality, primarily driven by other health conditions. Managing comorbidities is critical to enhancing long-term survival for this high-risk population.

Introduction: There are minimal data to guide antibiotic management of patients undergoing holmium laser enucleation of the prostate (HoLEP) for benign prostatic hyperplasia. Specifically, management of high-risk patients who are catheter dependent or have positive preoperative urine cultures varies widely. We aimed to evaluate the effect of preoperative antibiotic duration on infectious complications in high-risk patients undergoing HoLEP. Methods: A multi-institutional retrospective review of patients undergoing HoLEP between 2018 and 2023 at five institutions was performed. Patients were defined as high risk if they were catheter-dependent (indwelling urethral catheter, self-catheterization, or suprapubic tube) or had a positive preoperative urine culture. These patients were categorized into long course (>3 days) or short course (≤3 days) of preoperative antibiotics. The primary outcome was 30-day infectious complications defined as a positive urine culture with symptoms. A t -test or Wilcoxon rank-sum test was used for continuous variables and Fisher's exact test was used for categorical variables. Logistic regression analysis was conducted to identify associations with infectious complications. Results: Our cohort included 407 patients, of which 146 (36%) and 261 (64%) were categorized as short course and long course of preoperative antibiotics, respectively. Median preoperative antibiotic duration was 1 day (interquartile range [IQR]: 0, 3 days) and 7 days (IQR: 5, 7 days) in the short and long cohorts, respectively. Thirty-day postoperative infectious complications occurred in 11 (7.6%) patients who received a short course of antibiotics and 5 (1.9%) patients who received a long course of antibiotics (odds ratio 0.24, 95% confidence interval 0.07–0.67; p = 0.009). Variables such as age, positive urine culture, and postoperative antibiotic duration were not significantly associated with postoperative infection after propensity score weighting. Conclusion: In high-risk patients undergoing HoLEP, infectious complications were significantly lower with a long course vs short course of antibiotics. Further prospective trials are needed to identify optimal preoperative antibiotic regimens.

OBJECTIVE Deficiency in patient education has been correlated with increased disease-related morbidity and decreased access to care. However, the associations between educational level, preoperative disease severity, and postoperative outcomes in patients with lumbar spondylolisthesis have yet to be explored. METHODS The spondylolisthesis dataset of the Quality Outcomes Database (QOD)—a cohort with prospectively collected data by the SpineCORe study team of the 12 highest enrolling sites with an 81% follow-up at 5 years —was utilized and stratified for educational level. Patients were classified into three categories (high school or less, graduate, or postgraduate). Patient-reported outcome measures (PROMs) documented at baseline and follow-up included Oswestry Disability Index (ODI) score, EQ-5D in quality-adjusted life years, and numeric rating scale (NRS) scores for back and leg pain. Disease severity was measured with PROMs. Postoperatively, patients also completed the North American Spine Society assessment to measure their satisfaction with surgery. Multivariable regression analysis was used to compare education level with disease severity and postoperative outcomes. RESULTS A total of 608 patients underwent analysis, with 260 individuals (42.8%) at an educational level of high school or less. On univariate analysis, baseline disease severity was worse among patients with lower levels of education. On multivariable regression analysis, patients with postgraduate level of education had significantly lower ODI scores (β = −3.75, 95% CI −7.31 to −0.2, p = 0.039) compared to graduates, while the other PROMs were not associated with significant differences at baseline. Five years postoperatively, patients from various educational backgrounds exhibited similar rates of minimal clinically important differences in PROMs. Nevertheless, patients with the lowest educational level had higher ODI scores (27.1, p < 0.01), lower EQ-5D scores (0.701, p < 0.01), and higher NRS leg pain (3.0, p < 0.01) and back pain (4.0, p < 0.01) scores compared to those with graduate or postgraduate levels of education. The odds for postoperative satisfaction were also comparable between cohorts at 5 years (reference, graduate level; high school or less, OR 0.87, 95% CI 0.46–1.64, p = 0.659; postgraduate, OR 1.6, 95% CI 0.7–3.65, p = 0.262). CONCLUSIONS Lower patient education level was associated with a greater baseline disease severity in patients with lumbar spondylolisthesis. Surgery demonstrated similar benefits irrespective of educational background; however, individuals with lower educational level reported lower outcomes overall. This emphasizes the need for enhanced health literacy to mitigate disparities for reported outcomes.

538 Background: The phase 3 PALLAS trial compared 2 years of the CDK4/6 inhibitor palbociclib with endocrine therapy of provider choice, versus endocrine therapy alone, as adjuvant treatment for patients (pts) with Stage II-III hormone receptor-positive HER2-negative (HR+/HER2-) breast cancer. The SET2,3 index adjusts the measurement of SETER/PR index of endocrine receptor-related transcriptional activity with a baseline prognostic index (BPI) derived from tumor size (T), number of involved lymph nodes (N) and gene expression levels of ESR1, PGR, ERBB2 and AURKA (RNA4 subtype score). High SET2,3 (index ≥ 2.10) represents high endocrine sensitivity with favorable prognosis. Clinical outcome results from PALLAS were previously published, and the trial now has 5-year median follow-up. Methods: Participants in PALLAS provided a tumor tissue block prior to randomization. RNA was extracted from samples with sufficient tumor tissue and cellularity (>25mm2 with ≥20% cancer nuclei). SET2,3 index was measured from 300ng total RNA using the QuantiGene Plex platform (ThermoFisher, Waltham, MA) following the manufacturer’s protocol and using pre-defined quality control (QC) parameters and cut point. Results from primary tumor samples prior to systemic therapy were analyzed. Invasive disease-free survival (iDFS) was summarized with Kaplan-Meier plots using log-rank test. Cox models were adjusted for treatment arm assignment, with a treatment arm by SET index value interaction term to test for prediction of palbociclib benefit. The pre-defined level of significance was a two-sided 0.05. Results: There were 4075 pts from the total PALLAS population (N=5796) who provided a primary tumor sample that met pre-analytical requirements to perform the SET assay, from which 3388 (83%) results passed quality control, including 3093 from a sample obtained prior to receiving systemic therapy (1559 in palbociclib arm and 1534 in the control arm). SET2,3 index could not be calculated for 12 pts due to missing tumor or nodal information. There was no evidence of an interaction between treatment arm and SET indices (continuous) for iDFS: SET2,3 index interaction p=0.12 and SETER/PR index interaction p=0.92. Estimated 5-year iDFS was superior for those with high SET2,3: iDFS was 91.4% (95%CI 89.9–92.8) in 1719 (55.8%) pts with high SET2,3, versus 78.5% (95%CI 76.0–80.8) in 1362 (44.2%) pts with low SET2,3 (HR 0.38, 95%CI 0.31–0.47, p<0.0001). The SETER/PR index was also significantly associated with iDFS (HR 0.70 per 0.5 units, 95%CI 0.65–0.77, p<0.0001). Conclusions: There was no evidence that the SET2,3 or SETER/PR index of endocrine-related transcriptional activity predicts benefit from palbociclib treatment. SET2,3 index was strongly prognostic for pts with Stage II-III breast cancer, with excellent 5-year IDFS for pts classified as SET2,3 high. Clinical trial information: NCT02513394 .