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548 Background: TNBC is associated with higher risk of recurrence and poorer survival rates than other breast cancer subtypes. For node-positive TNBC or tumors larger than 0.5 cm, chemotherapy is generally recommended. For stage I TNBC, the benefit from chemotherapy, the optimal regimen, and whether to administer it in the neoadjuvant versus adjuvant setting remain controversial. Here, we report the treatment patterns and clinical outcomes of patients with stage I TNBC treated at Mayo Clinic. Methods: Using the Mayo Clinic Tumor Registry data, we identified patients with stage I TNBC treated between 2010 and 2021. We used the pathologic tumor (T) category for patients treated with upfront surgery and the clinical T category for patients receiving neoadjuvant chemotherapy. We used the Kaplan-Meier method and log-rank test to compare recurrence-free survival (RFS) according to treatment groups, measured from the day of surgery. RFS was reported at a median follow-up of 3.9, 6.2, and 7.3 years for patients who received chemotherapy neoadjuvantly, adjuvantly, and surgery alone with no chemotherapy, respectively. Results: A total of 602 patients with Stage I TNBC were included, with a median age of 62 years. 290 (48%) underwent upfront surgery followed by adjuvant chemotherapy (pT1a: 2%, pT1b: 25%, pT1c: 74%), 127 (21%) received neoadjuvant chemotherapy followed by surgery (cT1a: 2%, cT1b: 11%, cT1c: 87%), and 185 (31%) underwent primary surgery without any chemotherapy (pT1mi/T1a: 33%, pT1b: 32%, pT1c: 35%). Most patients treated with neoadjuvant therapy received anthracycline/cyclophosphamide + taxane (70%), while most patients treated in the adjuvant setting received a non-anthracycline containing regimen (60%). The 5-year RFS was 96% (95% CI: 93-100%) for patients who received chemotherapy neoadjuvantly, 95% (95% CI: 92-98%) for those who received chemotherapy adjuvantly, and 85% (95% CI: 80-91%) for those treated with surgery alone and no chemotherapy ( P < 0.0001). 71 (56%) of the 127 patients who received neoadjuvant therapy achieved a pCR, with only 1 RFS event (at 14 months) in that group, compared to 4 RFS events among those not achieving pCR (at 12, 20, 28 and 75 months, respectively). Among patients not receiving chemotherapy (either adjuvantly or neoadjuvantly), the 5-year RFS rates were 94% for pT1mi/T1a, 92% for pT1b and 72% for pT1c (T1mi/a/b vs T1c, P = 0.009). Conclusions: In this large cohort of stage I TNBC, patients who received chemotherapy (adjuvantly or neoadjuvantly) had better 5-year RFS compared with those treated with locoregional therapy only. Among patients receiving chemotherapy, 5-year RFS was nearly identical regardless of whether chemotherapy was administered before or after surgery. Interestingly, patients undergoing upfront surgery were more likely to receive an anthracycline-sparing chemotherapy regimen.

10582 Background: Breast cancer is the most common cancer in young women, with an increasing incidence over the past two decades. This study aims to evaluate the characteristics of young-onset breast cancers among patients aged ≤50 and compare tumor characteristics by germline mutation carrier status. Methods: Patients with breast cancer diagnosis ≤50 years old and evaluated across the Mayo Clinic enterprise between 2000 and 2024 were identified through the prospective Mayo Clinic Breast Cancer Study and the institutional tumor registry. Demographics, tumor characteristics, and clinical outcomes were obtained and described using summary statistics. Germline pathogenic or likely pathogenic variant (PV) carrier status for 5 established breast cancer predisposition genes (BRCA1, BRCA2, ATM, CHEK2 and PALB2) was available in a subset of unselected patients who consented to participation in sequencing studies at Mayo Clinic. Clinical characteristics were compared between PV carriers in each gene and non-carriers utilizing Chi-square test. All tests were two-sided and p-value less than 0.05 was considered statistically significant. Results: Among 8,462 patients (8435 women, 27 men) with breast cancer diagnosis at age ≤50 in the study, the median age of diagnosis of breast cancer was 44 years (range 18 – 49). At diagnosis, 84% had invasive disease, 43% of the tumors were high-grade, 15.8% had triple-negative breast cancer (TNBC), more than two-thirds (67.5%) presented with stage I or II breast cancer, and 3.7% had bilateral breast cancer. Among the 2,527 patients who consented to germline sequencing, 10.1% were found to be carriers of PVs; these included BRCA1 (3.3%), BRCA2 (2.7%), CHEK2 (2.3%), ATM (1.3%), and PALB2 (0.6%). Compared to non-carriers, a significant enrichment (p<0.05) of invasive breast cancer (92.6% vs. 83.3%) and high grade tumors (61.7% vs. 31.4%) were noted in BRCA1 PV carriers, and of bilateral breast cancer (13.4% vs. 3.8%) and high grade tumors (46.4% vs. 31.4%) in BRCA2 PV carriers. After exclusion of in-situ disease, proportion of TNBC was observed to be significantly higher in BRCA1 (61.3%), BRCA2 (15.5%) and PALB2 (30.7%) PV carriers compared to non-carriers (11.2%), whereas >90% of ATM or CHEK2 PV carriers had ER+ breast cancer and none had TNBC. A significant difference in stage at presentation was not observed by germline PV carrier status. Conclusions: The high frequency (>10%) of PVs in young-onset breast cancer underscores the importance for genetic testing in this population. The observed differences in breast cancer phenotypes based on germline PV carrier status among young-women may have significant implications for clinical outcomes and needs to be further explored.

10510 Background: The impact of germline pathogenic or likely pathogenic variants (PVs) in cancer predisposition genes on overall survival (OS) after breast cancer diagnosis is not well defined. In particular, unbiased OS estimates from population-based studies accounting for clinical subtypes of breast cancer (based on ER, PR, and HER2 status) and for genes other than BRCA1/2 are lacking. Methods: The study included 25,168 prospectively followed women with locoregional invasive breast cancer within the population-based CARRIERS study. Germline sequencing using a custom multigene amplicon-based panel was performed to identify PVs. OS was compared between germline PV carriers in ATM, BRCA1, BRCA2, CHEK2 and PALB2 and non-carriers (negative for germline PVs in 13 known breast cancer predisposition genes) for each clinical subtype of breast cancer from the time of breast cancer diagnosis to death or last follow up in a multivariable Cox proportional hazard regression analysis adjusting for age at diagnosis, race/ethnicity, histology, TNM stage, type of surgery, use of adjuvant radiation, chemotherapy and endocrine agents. Results: Among 25,168 women with breast cancer, germline PVs in one of the five breast cancer predisposition genes were detected in 5.8% of the women [ ATM : 0.8%, BRCA1 : 1.3%, BRCA2: 1.6%, CHEK2 : 1.5%, and PALB2 : 0.6%]. Among women with ER+ breast cancer, compared to non-carriers, a significantly worse OS was noted for BRCA1 (Hazard Ratio (HR): 1.8, 95% Confidence Interval (CI): 1.1 – 3.0, p=0.02) and BRCA2 (HR: 1.8, 95%CI: 1.4 – 2.4, p<0.001), but not for ATM (HR: 1.2, 95%CI: 0.8 – 1.7, p=0.40) or CHEK2 (HR:1.0, 95%CI: 0.8 – 1.3, p=1.0) PV carriers. Worse OS was noted in PALB2 PV carriers with ER+ breast cancer (HR:1.5, 95%CI: 0.9 – 2.2, p=0.09), although it did not reach statistical significance. Similar HR estimates for OS as with ER+ breast cancer were observed in women with ER+/HER2- breast cancer for BRCA1 , BRCA2 and PALB2 PV carriers, but only BRCA2 results were statistically significant. Among women with ER-negative breast cancer, compared to non-carriers, a significant difference in OS was not observed for PV carriers in ATM (HR:0.8, 95%CI: 0.4 – 1.8, p=0.63), BRCA1 (HR:1.2, 95%CI: 0.8 – 1.7, p=0.35), BRCA2 (HR: 0.8, 95%CI: 0.5 – 1.2, p=0.29), CHEK2 (HR: 0.7, 95%CI: 0.3 – 1.4), or PALB2 (HR: 0.9, 95%CI: 0.5 -1.7, p=0.78). Conclusions: The suggestive differences in OS by ER status of the tumor in BRCA1 and BRCA2 PV carriers warrant further investigation of underlying tumor biology and assessment of endocrine sensitivity of breast cancer in germline PV carriers.

10544 Background: Incorporation of Polygenic Risk Scores (PRS) can refine traditional breast cancer risk assessment models to provide precise estimates of breast cancer risk. However, the impact of such an integrated model on clinical decision-making related to breast cancer surveillance and preventive strategies is not fully understood. Methods: The GENRE-2 is a prospective single-arm multisite clinical trial (NCT04474834) incorporating PRS into standard breast cancer risk assessment models to determine the impact of PRS on clinical decisions on breast cancer prevention and surveillance. Women at high risk of breast cancer due to NCI-BCRAT 5-year risk of ≥ 3%, or IBIS (Tyrer-Cuzik) 10-year breast cancer risk of ≥5%, biopsy-proven high-risk breast lesion, or a pathogenic variant (PV) in ATM , BRCA1, BRCA2, CHEK2 or PALB2 , were enrolled from five sites in the United States. All women were invited to complete surveys on their breast surveillance and cancer prevention decisions based on pre-PRS standard risk models and post-PRS risk estimation, and further annual surveys are planned for 10 years. Results: Among 902 women enrolled in the study, 605 (median age: 52 years) received PRS results and completed a survey to date. Of those who received PRS results,195 (32.2%) were PV carriers. Among non-carriers, the median 10-year and lifetime pre-PRS IBIS-based risk was 10.0% and 28.7%, respectively. Among PV carriers, the CanRisk-based 10-year and lifetime pre-PRS risk estimates were 6.3% and 25.2% for ATM , 22.3% and 77.6% for BRCA1 , 18.5% and 77.7% for BRCA2 , 7.1% and 25.7% for CHEK2 , and 16.8% and 38.0% for PALB2 PV carriers, respectively. After the incorporation of PRS, the lifetime risk of breast cancer increased by at least 10% in 31% of non-carriers and 7.7% of PV carriers and decreased by at least 10% in 10.7% of non-carriers and 7.7% of PV carriers. The proportion of non-carriers with lifetime risk < 20% or > 40% changed from 17.3% and 22.0%, respectively, in the pre-PRS evaluation to 24.4% and 32.9%, in the post-PRS evaluation. A higher lifetime post-PRS score was associated with intent to take preventive action (surgery or endocrine agents). In non-carriers, the proportion of women with a lifetime risk < 20% with intent to take preventive action was 11%, compared to 36.8% of those with a lifetime risk > 40% (p < 0.001). Similarly, in PV carriers, the proportion of women with lifetime risk < 20% with intent to take preventive action was 20.8% compared to 41.1% of those with lifetime risk > 40% (p = 0.015). Conclusions: The GENRE-2 trial demonstrates that the incorporation of PRS into breast cancer risk assessment models in high-risk women is feasible and leads to clinically meaningful changes in breast cancer risk estimates and decision-making regarding preventive strategies. Evaluation of the implementation of breast cancer risk management strategies in study participants is ongoing and will be reported. Clinical trial information: NCT04474834 .

Purpose: To develop and validate an explainable machine learning (ML) tool to help clinicians predict the risk of propofol-associated hypertriglyceridemia in critically ill patients receiving propofol sedation. Methods: Patients from 11 intensive care units (ICUs) across five Mayo Clinic hospitals were included if they met the following criteria: a) ≥ 18 years of age, b) received propofol infusion while on invasive mechanical ventilation for ≥24 h, and c) had a triglyceride level measured. The primary outcome was hypertriglyceridemia (triglyceride >400 mg/dL) onset within 10 days of propofol initiation. Both COVID-inclusive and COVID-independent modeling pipelines were developed to ensure applicability post-pandemic. Decision thresholds were chosen to maintain model sensitivity >80%. Nested leave-one-site-out cross-validation (LOSO-CV) was used to externally evaluate pipeline performance. Model explainability was assessed using permutation importance and SHapley Additive exPlanations (SHAP). Results: Among 3922 included patients, 769 (19.6%) developed propofol-associated hypertriglyceridemia, and 879 (22.4%) had COVID-19 at ICU admission. During nested LOSO-CV, the COVID-inclusive pipeline achieved an average AUC-ROC of 0.71 (95% confidence interval [CI] 0.70–0.72), while the COVID-independent pipeline achieved an average AUC-ROC of 0.69 (95% CI 0.68–0.70). Age, initial propofol dose, and BMI were the top three most important features in both models. Conclusion: We developed an explainable ML-based tool with acceptable predictive performance for assessing the risk of propofol-associated hypertriglyceridemia in ICU patients. This tool can aid clinicians in identifying at-risk patients to guide triglyceride monitoring and optimize sedative selection.

Abstract Rationale: Propofol can increase the risk of hypertriglyceridemia and subsequent pancreatitis in critically ill patients. It is unclear whether modifying or continuing sedation regimens in patients experiencing hypertriglyceridemia while on propofol infusion influences the development of adverse events such as acute pancreatitis. This study compared the clinical outcomes of patients receiving invasive mechanical ventilation (IMV) who had their propofol regimen modified versus continued following the detection of hypertriglyceridemia. Methods: A targeted trial emulation was conducted using retrospective data from 5 Mayo Clinic hospitals between 05/05/2018 and 06/30/2023. Inclusion criteria included: 1) receiving IMV and continuous propofol infusion for &gt;24 hours, 2) experiencing triglyceride level &gt;400 mg/dL while on propofol, and 3) still requiring IMV at 24-hours after hypertriglyceridemia onset. Patients were then categorized based on whether they had their propofol regimen modified (i.e., dose reduction by ≥50% or any reduction with alternative sedatives started) versus continued (no reduction or &lt;50% reduction without alternative sedative initiation). Outcomes included 30-day ventilator-free days, successful extubation, acute pancreatitis (determined by chart review, in-duplicate), ICU and hospital length of stay, 30- and 90-days alive and at home, as well as all-cause mortality. Analyses were conducted using stabilized inverse probability of treatment weights with adjustments for covariates selected a priori. Sensitivity analyses, where only benzodiazepines or benzodiazepines and ketamine were considered to be eligible alternative sedatives, were done. Results: During the study period, 728 patients were included, of whom 422 had their propofol regimen modified (Image). The two groups had similar demographics, comorbidities, and illness severity. We identified 14 cases of acute pancreatitis possibly attributable to propofol, with 9 cases in the modified and 5 cases in the continued regimen group (2.1% versus 1.6%; P=0.63). Following adjustment for covariates, there were no significant differences in any outcomes of interest. After censoring for mortality, there was no significant difference in the 30-day cumulative incidence of successful extubation when comparing those with their regimen modified versus continued (Hazard ratio [HR] 0.95; 95% confidence intervals [CI] 0.77 to 1.18; P=0.70). There was also no significant difference in the 90-day survival rate between the two groups (HR 0.89; 95% CI 0.71 to 1.11; P=0.34). These findings remained consistent upon sensitivity analyses. Conclusion: There were no differences in outcomes among patients who had their propofol regimens modified versus continued following the detection of hypertriglyceridemia. Further prospective investigations are needed to identify the optimal strategy for managing sedative regimens in this patient population.

Abstract Rationale: Hematopoietic cell transplantation (HCT) risk scores have seen minimal updates over the past 20 years, despite advancements in clinical practice. Pulmonary function test (PFT) thresholds, initially based on NHANES reference equations, now have alternative reference standards from the Global Lung Function Initiative (GLI) 2012 and GLI-Global, which may reclassify patients and affect outcomes. This study investigates the impact of GLI reclassification on outcomes in HCT, comparing traditional fixed thresholds with continuous (z-score) risk assessment models. Methods: A retrospective review of 3,120 adult patients who underwent autologous HCT at MD Anderson Cancer Center from 1999 to 2015 was conducted. Primary endpoints were ICU admission, mechanical ventilation (IMV), and survival within 120 days post-transplant. PFT measures (FEV1, FVC, DLCO) were calculated using GLI-2012 and GLI-Global reference equations, analyzed both continuously (z-scores) and categorically by ATS/ERS guidelines. Cox proportional hazards and logistic regression models were employed, with AUROC comparisons to evaluate predictive performance. Results: The cohort had a mean age of 49 years (SD 14), with 41% female and 77% White. Of the 3,120 patients included in the study, the cohort consisted of 77% White, 5.4% Black, 3.3% Asian, and 14% identifying as other ethnicities. At 120 days, mortality was 1% (n=41), ICU admission 5% (n=169), and IMV 2% (n=70). Continuous DLCO was associated with a lower risk of mortality (HR: 0.75; p=0.03), ICU admission (OR: 0.83; p=0.01), and IMV (OR: 0.80; p=0.02). GLI-Global's FEV1 z-scores were also significant for mortality (HR: 0.70; p=0.01), ICU admission (OR: 0.74; p&lt;0.0001), and IMV (OR: 0.70; p=0.0003). Categorical analyses showed significant mortality reduction with normal DLCO (HR: 0.46; p=0.01) and ICU admission reduction with normal FEV1 GLI-2012 (OR: 0.63; p=0.02). Reclassification by race, as shown in Figure 1, indicated that race-specific equations overestimated PFT values in Black patients and underestimated them in Asian patients. Conclusion: Reclassification by GLI reference equations, particularly using continuous z-scores, significantly influences post-HCT outcomes, suggesting that continuous assessment may improve risk stratification. Including race does not improve the model's performance. These findings support integrating updated PFT references and continuous risk models into HCT prognostic tools for enhanced clinical decision-making.

Abstract RATIONALE: Long-term survival after lung transplantation is challenging, with limited research on risk and protective factors. Clinical factors such as younger age, female sex, fewer acute rejection hospitalizations, and double lung transplants are associated with better outcomes. However, the role of psychosocial health and socioeconomic status (SES) remains underexplored. This study aimed to assess the influence of pre-transplant psychosocial health and SES on long-term survival in adult lung transplant recipients. METHODS: We conducted a single-center, retrospective case-control study using the Mayo Clinic Rochester lung transplant registry. Cases (survivors ≥ 6 years) and controls (survivors &lt;6 years) were matched by transplant date (+/- 5 years) and indication for transplant, resulting in 190 subjects (63 cases, 127 controls). We assessed the impact of pre-transplant psychosocial health and SES on long-term survival using initial PACT scores (&lt;2), the HOUSES index, and the national/state area deprivation index (ADI). Additional factors included proximity to the transplant center, insurance type, marital status, primary caregiver status, and employment status. Statistical analyses used the paired Wilcoxon rank-sum test for continuous variables and McNemar's test for categorical variables, with results reported as median (IQR) or percentages. RESULTS: Donor characteristics (age, sex, smoking history, risk criteria, cause of death) and recipient characteristics (age at transplant, sex, BMI, medical condition, functional status, type of transplant) were similar between cases and controls, with no statistically significant differences (all p&gt;0.05). CMV mismatch, waitlist time, and transplant hospital length of stay were also comparable (all p&gt;0.05). Psychosocial health indicators, including proximity to the transplant center, pre-transplant initial PACT score, insurance type, marital status, primary caregiver, and employment status, did not differ significantly between groups (all p&gt;0.05). The HOUSES index was similar between cases and controls (p=0.179). However, long-term survivors had significantly higher national and state ADI scores than controls (national ADI: p=0.029; state ADI: p=0.019). CONCLUSIONS: Pre-transplant psychosocial health indicators, including proximity to the transplant center, initial PACT score, and caregiver support, did not differ significantly between long-term lung transplant survivors and those with shorter survival. Although SES measured by the HOUSES index was not associated with long-term survival, higher national and state ADI scores were linked to increased long-term survival, suggesting unique protective factors for patients from socioeconomically deprived areas. These findings highlight the complex role of socioeconomic factors in lung transplant outcomes and underscore the need for further research into how specific socioeconomic and environmental factors influence long-term survival.

Abstract RATIONALE: Allogeneic hematopoietic stem cell transplant (alloHSCT) is the only curative therapy for multiple hematological malignancies and bone marrow failure syndromes. Graft versus host disease (GvHD), remains one of the leading causes of morbidity and mortality. Bronchiolitis obliterans syndrome (BOS) is the canonical manifestation of chronic GvHD of the lungs, occurring in 3-10% of alloHSCT recipients and conferring poor prognosis. There has been a recent paradigm shift towards using post-transplant cyclophosphamide (PTCy) for GvHD prophylaxis resulting in dramatic decreases in both acute and chronic GvHD compared to traditional regimens using methotrexate and tacrolimus. The effect of PTCy on the development of BOS is not well-studied. METHODS: We performed a retrospective cohort study comparing the cumulative incidence of BOS between 93 patients receiving PTCy and 154 patients receiving non-PTCy containing regimens for GvHD prophylaxis between 2015 and 2023 at a single center (Mayo Clinic, Rochester, MN). Patients were included if they were ever diagnosed with BOS or if they survived and were followed for at least 1 year. BOS was diagnosed using 2014 National Institutes of Health criteria. Patients who met 3 of 4 diagnostic criteria were included if a clinical diagnosis of BOS was made. We performed a competing risks time-to-event analysis to compare the incidence of BOS (or death) between the two cohorts. Outcomes were not adjusted for HSCT type (related, unrelated, or haploidentical [HID]) due to a high degree of collinearity with GvHD prophylaxis strategy. RESULTS: Combined cohorts were median age 55 (40-63), 56% male, and 43% ever smokers. Transplants involved HID donors (59% of PTCy cohort, zero non-PTCy), matched related (10% of PTCy, 44% of non-PTCy), matched unrelated (20% of PTCy, 51% of non-PTCy), and mismatched unrelated donors (11% of PTCy, 5% of non-PTCy). Three-year cumulative incidences of BOS among PTCy and non-PTCy recipients were 7% and 14%, respectively (subdistribution HR 0.52 [95% CI 0.21-1.29], P=0.159). For those who received PTCy, incidence of GvHD was smaller (subdistribution HR 0.64 [95% CI 0.46-0.99], P=0.006) with fewer organs involved (1 versus 2, P=&lt;0.0001) and fewer immunosuppressive therapies employed for treatment (2.0 versus 2.5, P=0.01). CONCLUSION: PTCy may reduce risk of BOS among patients undergoing HSCT. Findings are limited by important differences between the cohorts, such as HCT type, and by small sample size. As PTCy is now increasingly used for non-HID transplants, future studies are needed to examine the effect of PTCy on the development of BOS.

Abstract There are limited prospective data on whether established risk factors modify breast cancer risk in women with pathogenic variants (PV) in BRCA1/2 and virtually no risk modification data for ATM, CHEK2, or PALB2. We conducted a nested case–control study in the Women’s Health Initiative (WHI), randomly selecting women with and without breast cancer for DNA sequencing. We evaluated breast cancer odds associated with obesity, family cancer history, smoking, alcohol, parity, breastfeeding, oophorectomy, tubal ligation, neighborhood socioeconomic status, and menopausal hormone therapy (MHT) with estrogen and progestin or estrogen only in PV carriers and noncarriers. In exploratory analyses, we grouped genes by established predisposition for estrogen receptor (ER)-positive (ATM and CHEK2) or ER-negative (BRCA1 and PALB2) disease. Multivariable models with interaction terms were used to assess differential risk modification by PVs. Among 12,957 WHI participants, 287 carried PVs. Breastfeeding was modestly associated with reduced risk for PALB2 [OR = 0.08; 95% confidence interval (CI), 0.00–0.92; P value = 0.042]. With one-sided 95% CI, power was sufficient to exclude OR ≥2.0 with obesity for ATM and BRCA2; smoking and alcohol for CHEK2; no breastfeeding for ATM; no oophorectomy for BRCA2 and CHEK2; no tubal ligation for CHEK2; and neighborhood socioeconomic status for all genes. Estrogen + progestin MHT was modestly associated with increased risk for ER-positive PVs (OR = 7.31; 95% CI, 1.14–64.20; P = 0.036). PVs did not modify risk (interaction P ≥ 0.05). BRCA1/2, ATM, CHEK2, and PALB2 PV carriers do not have breast cancer OR ≥2.0 with many established risk factors. However, MHT warrants additional study in PV carriers. Significance: There is limited information on whether established risk factors increase breast cancer risk from PVs. In the WHI, PV carriers had no substantial (≥2-fold) increase with most risk factors, except potentially MHT in ATM or CHEK2 carriers. The results may inform counseling and research on MHT.