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With abundant information and interconnectedness among people, identifying knowledgeable individuals in specific domains has become crucial for organizations. Artificial intelligence (AI) algorithms have been employed to evaluate the knowledge and locate experts in specific areas, alleviating the manual burden of expert profiling and identification. However, there is a limited body of research exploring the application of AI algorithms for expert finding in the medical and biomedical fields. This study aims to conduct a scoping review of existing literature on utilizing AI algorithms for expert identification in medical domains. We systematically searched five platforms using a customized search string, and 21 studies were identified through other sources. The search spanned studies up to 2023, and study eligibility and selection adhered to the PRISMA 2020 statement. A total of 571 studies were assessed from the search. Out of these, we included six studies conducted between 2014 and 2020 that met our review criteria. Four studies used a machine learning algorithm as their model, while two utilized natural language processing. One study combined both approaches. All six studies demonstrated significant success in expert retrieval compared to baseline algorithms, as measured by various scoring metrics. AI enhances expert finding accuracy and effectiveness. However, more work is needed in intelligent medical expert retrieval.

Exercise-induced respiratory muscle fatigue contributes to limiting exercise tolerance. Accordingly, better understanding the exercise conditions under which respiratory muscle fatigue occurs is warranted. Although heavy-intensity as well as short- and long-duration severe-intensity exercise performed to intolerance elicit diaphragm and expiratory muscle fatigue, we find, for the first time, that the relationship between exercise intensity, exercise duration, and the magnitude of exercise-induced fatigue is different for the diaphragm compared with the expiratory muscles.

Objective: The purpose of this study was to implement a 2-phase approach to rapidly increase the number of annual wellness visits (AWVs) and build a sustainable model at 3 study units (Mayo Clinic in Rochester, Minnesota, and clinics in 2 regions of Mayo Clinic Health System), which collectively serve approximately 80 000 patients who qualify for an AWV annually. Methods: In the rapid improvement phase, beginning in July 2022, goals at the facilities were reoriented to prioritize AWVs, educate staff on existing AWV resources, and create low-effort workflows so that AWVs could be incorporated into existing patient appointments. Staff at all 3 study units worked independently and iterated quickly. In the second phase, all study units collaborated to design and implement a best-practice solution while they leveraged the engagement and lessons learned from the first phase and invested in additional system elements and change management to codify long-term success. Results: The number of AWVs completed monthly increased in each study unit. In the rapid improvement phase, the number of AWVs increased but then plateaued (or decreased at some study units). In April 2023, the final scheduled outreach automation and visit tools were implemented, and the number of AWVs was sustained or increased, while outreach and scheduling times were decreased. The number of completed AWVs increased from 1148 across all study units in the first 6 months of 2022 to 14 061 during the first 6 months of 2023. Conclusions: The lessons learned from this project can be applied to other health systems that want to provide more patients with AWVs while improving operational efficiency. The keys are to have a clear vision of a successful outcome, engage all stakeholders, and iterate quickly to find what works best for the organization.

Abstract Background: Breast cancer (BC) in males represents a rare clinical entity, accounting about 1% of all breast malignancies diagnosed every year. Emerging evidence suggest that a gender medicine approach is critical in the research and treatment of cancer, based on the possibility that sex hormones, molecular differences, immune system, and other factors might play a crucial role in disease management. Here, we characterized molecular and immune differences between male BC (MaBC) and female BC (FeBC) across BC subtypes. Methods: 10,728 BC samples (male, n=137; female, n=10591) were analysed by next-generation sequencing (592, NextSeq; WES, NovaSeq), Whole Transcriptome Sequencing (WTS; NovaSeq) (Caris Life Sciences, Phoenix, AZ). Tumor mutational burden (TMB) totaled somatic mutations per tumor (high ≥10 mt/MB). Microsatellite-instability (MSI) was tested by IHC and NGS. Immune cell fractions were calculated by deconvolution of WTS: Quantiseq. Real world treatment-associated survival was extracted from insurance claims and calculated from sample collection to last contact using Kaplan-Meier estimates. Statistical significance was determined using chi-square and Mann-Whitney U test with p-values adjusted for multiple comparisons (q < 0.05). Results: MaBC represented higher HR+/HER2+ (6.61% vs 4.76%), HR+/HER2- (80.17% vs 60.66%) and lower HR-/HER2+ (1.65% vs 3.5%), TNBC (11.57% vs 31.08%) molecular subtypes compared to FeBC. Compared to HR+/HER2+ FeBC, MaBC had higher frequency of CHEK2, RAD51B, TSC1 mutation (Table 1) and RARα (100% vs 13.61%), DAXX (10% vs 0.16%) copy number alteration (all p < 0.05). HR+/HER2- MaBC had higher frequency of BRCA2, FOXA1, CREBBP, FLCN mutation (Table 1), and FGF3 (21.62% vs 14.31%), MRE11 (1.75% vs 0.23%), MEN1 (1.75% vs 0.13%) copy number alteration, but lower frequency of TP53, CHD1, ESR1 and AKT1 mutation (Table 1) (all p < 0.05). HR-/HER2+ MaBC had higher frequency of BRCA1 (p < 0.05) mutation (Table 1). Male TNBC had higher frequency of CDKN2A, KMT2D, STK11, ASXL1, MYC, NF2, PPM1D, WT1, EPHA2, AMER1, ARHGAP35 mutation (Table 1) and BCL6 (4.35% vs 0.05%) copy number alteration, but lower frequency of TP53 mutation (all p < 0.05) (Table 1). MaBC had higher AR protein expression (82.5% vs 60%) but lower frequency of fusion variant-AR (0.7% vs 3.9%) (all p < 0.05) compared to FeBC. There was no difference in TMB high (7.1% vs 8.4%, p = 0.5) and dMMR/MSI-H (1.8% vs 0.8%, p = 0.1). Analysis of inferred immune cell infiltrates showed that MaBC had increased immune cell infiltration of B cells (5.8% vs 5.3%) and M2 Mφ (4.9% vs 4.3%), but decreased infiltration of DC (2% vs 2.6%) (all p < 0.05). MaBC had increased expression of MHC class II gene HLA-DQB2 (FC: 1.3), but decreased expression of immune-related genes CD274 (FC: 1.2), IDO (FC: 1.4), IL1A (FC: 1.3) and IL12A (FC: 1.5) (all p < 0.05). Correlative analyses with survival will be presented at the meeting. Conclusions: These data indicate that MaBC has a differential mutational frequency, copy number alteration, immune gene expression and immune cell infiltration and overall survival compared to their FeBC counterparts. A better understanding of these sex-based differences with additional research may help inform disease outcomes, provide a rationale for tailored therapeutic approaches and design future treatments. Table 1. Mutation frequency in male and female breast cancer Citation Format: Dario Trapani, Sachin Deshmukh, Sharon Wu, Joanne Xiu, Phil Walker, Pooja Advani, Nancy Lin, Giuseppe Curigliano, Stephanie Graff, Chadi Nabhan, George Sledge Jr, Sara Tolaney, Jose Leone. Molecular and immunological landscape of sex-based differences in breast cancer: a distinct disease in men [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS13-09.

Abstract Background: Multiple studies have confirmed the central role of preexisting immune response measured by stromal tumor-infiltrating lymphocytes (sTILs) in triple-negative breast cancer (TNBC). Emerging studies showed that not only the number of TILs but also the location of TILs is important. There are 3 distinct immune architectures described based on the amount and locations of TILs, namely immune enriched (IN), immune excluded (IE), and immune desert (ID). Here we evaluated outcomes and characteristics associated with each immune landscape. Methods: NanoString Digital Spatial Profiling (DSP) and CosMx, a spatial multi-omics single-cell imaging platform, were performed in 75 samples from the Mayo Clinic (MC) TNBC cohort (Leon-Ferre BCRT 2018). NanoString IO360 was performed in 114 samples from the FinXX trial ( NCT00114816) . Firstly, tumors with sTIL quantified by H&E ≤ 30% were classified as ID. The rest of the tumors with high sTIL > 30% were categorized according to the intratumoral CD8 protein expression by DSP, with IE having intratumoral CD8 in the lower median and IN having intratumoral CD8 in the upper median. Chi-square test, gene set enrichment, Cox regression, and Kaplan-Meier analysis were used. Differential expression listed as log 2-fold change (FC) was estimated from the linear mixed model with significance defined as two-sided p< 0.05. Results: ID is associated with low Ki67 < 5% (23.3% vs. 9.6% ID, p 0.02) as well as apocrine (11/13, 84.6%) and metaplastic histology (10/12, 83%). In both univariate and multivariate analysis, patients with IN had significantly improved recurrence-free survival (RFS) compared to those with ID (HR 0.37, 95%CI 0.18-0.74, p 0.005). Despite having high sTILs, IE had poor outcomes similar to ID (HR 0.84, 95%CI 0.36-1.98). Strikingly, we identified that IE patients had significantly lower plasmacytoid dendritic cells (pDCs) compared to IN (mean 0 vs. 0.26/100 tumor cells, 95%CI 0.08-0.43 , p 0.01). Using Gene Set Enrichment Analysis to evaluate differential hallmarks between IN and IE, we identified IF Nɑ and IFNγ (FDR < 0.001) responses as significantly enriched in IN group, consistent wi th the function of pDCs, which are a subset of dendritic cells specialized in secreting high levels of type I interferon. To validate this finding, we further evaluated the 11 leading edge gene IFNɑ signature in the FinXX trial. A high IFNɑ signature score was associated with significantly improved outcomes in the FinXX trial (HR 0.21, 95%CI 0.09-0.51 , p < 0.001). Similar findings were observed using Kaplan-Meier analysis in the FinXX trial with significantly improved RFS (p 0.0006) and overall survival (p 0.0001) in patients with high IFNɑ signature scores. Furthermore, we evaluated the differential gene expression unique to IN tumors in the Mayo cohort. Expressions of MHC class I and class II in tumor cells, including HLA-A, HLA-B, HLA-C, HLA-DRA, HLA-DRB1, HLA-DPA1, and HLA-E, were associated with IN and significantly improved outcomes (p < 0.05) compared to ID and IE. Conclusions: Highlighting the importance of spatial context, we identified that patients with IE tumors had poor outcomes despite having high TILs. Moreover, u sing an in-depth analysis with spatially defined context, we identified the central role of pDC and the significance of IF Nɑ in TNBC. Support: Breast Cancer Research Foundation, Mayo Clinic Breast Cancer SPORE (P50CA116201-17) W81XWH-15-1-0292, P50CA015083, R35CA253187 Citation Format: Saranya Chumsri, Yi Liu, Yaohua Ma, Jodi Carter, Mark Gregory, Sarah Church, Jason Reeves, Heather Ann Brauer, Sarah Warren, Heikki Joensuu, Edith Perez, Roberto Leon-Ferre, David Hillman, Judy Boughey, James Ingle, Krishna Kalari, Fergus Couch, Matthew Goetz, Keith Knutson, E. Thompson. The spatially resolved single-cell atlas of the tumor immune architecture revealed the central role of IFN-alpha and plasmacytoid dendritic cells in triple-negative breast cancer in the Mayo Clinic cohort and FinXX trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS03-03.

Abstract Background: PARP inhibitors (PARPi) have demonstrated progression-free survival benefits vs. chemotherapy in patients (pts) with metastatic breast cancer (mBC) and germline BRCA mutations (gBRCAm). NCCN guidelines recommend that all pts with mBC are offered gBRCAm testing to aid in systemic treatment decisions with PARPi. Understanding real-world gBRCAm testing patterns and PARPi use would be beneficial for improving clinical outcomes of pts with gBRCAm mBC. Methods: This retrospective cohort study identified pts ≥ 18 years old with HER2-negative mBC, diagnosed from 2014 to 2022 (US Flatiron Electronic Health Record database). gBRCAm testing patterns in mBC over time were examined by BC subtype (hormone receptor-positive [HR+] or triple-negative breast cancer [TNBC]) and disease stage at diagnosis [de novo or recurrent]). Timing of gBRCAm testing and subsequent initiation of first-line or later PARPi in pts with gBRCAm HR+ and TNBC mBC was assessed in pts diagnosed after 2018 when PARPi were approved in mBC. Prevalence of gBRCAm was calculated overall and by mBC subtype. Demographic and clinical characteristics were described by gBRCAm testing and PARPi initiation (yes/no). Real-world overall survival (OS) by PARPi use since mBC diagnosis was estimated using the Kaplan-Meier method and a log-rank test. Results: Of 15,006 total pts, 4654 (31.0%) had a gBRCAm test. Compared with pts who were not tested, gBRCAm-tested pts were younger at initial mBC diagnosis (median age: 53.5 vs. 62.0 years), had a shorter median disease-free interval before mBC diagnosis (821 vs. 959 days), and were less likely to have de novo mBC (28.0% vs. 31.2%). gBRCAm testing prevalence was 6.1% in the HR+ group (n=11,945) and 8.9% in the TNBC group (n=2430). gBRCAm testing rates mostly increased from 2014 to 2022 and were lowest in HR+ tumor subtypes; < 2/3 of all pts had a gBRCAm test from 2020 onwards (Table). Most pts with recurrent mBC (HR+: 68.3%; TNBC: 76.1%) were gBRCAm tested before diagnosis, whereas pts with de novo mBC were tested at a later timepoint ( > 60 days after mBC diagnosis – HR+: 48.3%; TNBC: 38.4%). Of all pts with gBRCAm diagnosed from 2018 onwards (n=187), 44.4% initiated PARPi. A higher proportion of pts with gBRCAm in the TNBC group initiated PARPi (52.9%) than in the HR+ group (42.4%). Pts with gBRCAm in the TNBC group received PARPi earlier than pts with gBRCAm in the HR+ group (mean days from mBC diagnosis to first PARPi use: 173 and 411 days, respectively). Fewer pts with de novo mBC (35.7%) initiated PARPi than pts with recurrent mBC (50.8%). With a median follow-up of 15.3 months, pts with gBRCAm initiated on PARPi had numerically longer median OS (32.3 months [95% CI: 24.2–47.4]) than PARPi non-initiators (21.4 months [95% CI:18.4–43.5]). OS results should be regarded with caution due to the small sample size (n=187). Conclusions: Despite NCCN guideline gBRCAm-testing recommendations, < 2/3 of pts with HER2-negative mBC in our study were gBRCAm tested from 2020 onwards. gBRCAm testing was lower in pts with HR+ disease and was performed at a later timepoint for pts with de novo disease. Wider and timelier implementation of gBRCAm testing to identify pts that could benefit from PARPi is warranted. Fewer pts with gBRCAm who had HR+ tumors or de novo disease received PARPi than pts with TNBC. Our data suggest that pts who initiated PARPi had numerically longer OS than PARPi non-initiators; further research into OS trends and PARPi use in gBRCAm mBC would be of interest. Editorial acknowledgment: Medical writing assistance was provided by Leigh-Ann Booth, Ph.D. from BOLDSCIENCE Inc., funded by AstraZeneca and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, US Legal entity responsible for the study: AstraZeneca. Funding: This study was supported by AstraZeneca and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, US, who are codeveloping olaparib. Table. gBRCAm testing rates over time in pts with HER2-negative mBC HER2-negative mBC is defined as IHC 0, or 1-positive, or IHC2-positive/ISH-negative. *Olaparib approved in mBC; †Olaparib approved in eBC. eBC, early breast cancer; gBRCAm, germline breast cancer gene mutation; HER2, human epidermal growth factor receptor 2; HR, hormone receptor; IHC, immunohistochemistry; ISH, in situ hybridization; mBC, metastatic breast cancer; pt, patient; TNBC, triple-negative breast cancer. Citation Format: Siddhartha Yadav, Sam Hillman, Linlin Luo, Weiyan Li, Jagadeswara Earla, Xiaoqing Xu. BRCA testing and PARP inhibitor utilization in real-world HER2-negative metastatic breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS04-02.

Abstract Introduction: Interstitial Lung Disease (ILD) is a known adverse event associated with Antibody Drug Conjugates (ADCs), causing fibrosis of the lung. In the DESTINY-Breast 04, TROPICS-02, and ASCENT trials the rate of ILD/Pneumonitis was 12.1%, 0.4%, and 0% respectively. In these studies, the time to first cross-sectional imaging after initiation of ADC was 6 weeks. However, prior treatment with a topoisomerase-1 inhibitor ADC was not permitted in these studies, so the influence of sequential ADC treatments remains unknown. Here, we aimed to characterize the frequency and management of ILD in sequential use of ADCs in a multi-institution retrospective analysis. Methods: We identified patients (pts) with HR+/HER2-low and HR-/HER2-low MBC who had received both Trastuzumab-deruxtecan (T-DXd) and Sacituzumab govitecan (SG) monotherapy (in either order, with or without intervening therapies) who were treated at five academic centers between 2020-2023. Patients had received treatment with the ADC in either routine clinical treatment or as a prior participant on a clinical trial with ADC monotherapy. Information regarding ILD diagnosis, imaging, timing of onset, peak and resolution along with management information was collected and analyzed. Retrospective assessment of ILD toxicity was graded using CTCAE v5.0, based on available clinical and radiographic reports. Results: 10/60 pts who received ADC therapy in this multi-institutional cohort were diagnosed with ILD (all grades). No differences in age or BMI were observed in those who developed ILD versus those who did not, and 9/10 pts were White, 1 was Asian, with a median age of 59 years (47-79 years). Pertinent history in these pts included 3/10 had a prior smoking history, 8/10 had a prior cardiac or pulmonary comorbidity (including sleep apnea, lung cancer, hypertension, hyperlipidemia, thrombosis, or stroke). Prior to receiving their first ADC, 7/10 patients had metastatic disease to the lung. All 10 patients were diagnosed with ILD during treatment with T-DXd. 4 pts initially received T-DXd, then developed ILD and then upon recovery, subsequently received SG. The remaining 6 pts initially received SG (with no reports of ILD), and then received T-DXd and subsequently developed ILD. In the entire cohort, the median time from ADC initiation to first CT scan was 8 weeks (range 1-22 weeks). Within the cohort that developed ILD, the median time from initiation of T-DXd to first CT scan was also 8 weeks (range 6-13 weeks). The median time to diagnoses of ILD was 3 months after initiation of T-DXd (range 0.4-14.5 months). Dyspnea was the most common presenting symptom in 9/10 pts and at diagnosis of ILD, dyspnea was graded as III in 6/10 pts, II in 3/10 pts, and I in 1/10 pts. Diagnostic evaluation included CT chest (9/10), pulmonary consultation (8/10), pulmonary function testing (2/10), and bronchoscopy (1/10). 4/10 patients presented at their highest-grade toxicity at diagnosis. All patients stopped T-DXd treatment, 7 were hospitalized, 7 required supplemental oxygen, and 8 were prescribed steroids for treatment. Of those receiving steroids, the most common starting dose was prednisone 1 mg/kg and doses ranged from 0.5 mg/kg to 9mg/kg prednisone equivalents. No patient received a secondary immunosuppressive agent. The steroid treatment duration ranged from 1-4 months. None of the 10 pts underwent re-challenge with T-DXd and 3/10 developed grade V ILD (death). Conclusion: We observed a 16.6% incidence of all grade ILD (5% grade V ILD) with T-DXd and 0% with SG. In this small cohort study, we did not observe a clear increased risk for ILD with sequential treatment of ADCs. Practice patterns were consistent with recommended diagnostic evaluation and steroid management. Additional strategies are needed to characterize pts most at risk for developing ILD and to identify situations where re-challenge may be safe. Citation Format: Sarah Premji, Laura Huppert, Reshma Mahtani, Samantha Fisch, Naomi Dempsey, Angelina Raimonde-Taylor, Saya Jacob, Laura Quintal, Jo Chien, Michelle Melisko, Ana Sandoval-Leon, Lauren Carcas, Manmeet Ahluwalia, Natasha Harpalani, Jenna Hoppenworth, Dame Idossa, Ruta Rao, Hope Rugo, Karthik Giridhar. Interstitial Lung Disease (ILD) in Sequential Antibody Drug Conjugate (ADC) use in patients with Metastatic Breast Cancer (MBC): A Multi-Institutional experience [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-12-06.

Abstract Background: Eyebrow and eyelash loss, known as madarosis, can occur secondary to breast cancer-directed therapy. However, the incidence and predictors of this phenomenon are not well-known. The purpose of this study is to ascertain the proportion of breast cancer survivors who experience madarosis, potential contributing factors to eyebrow and eyelash loss, and associations between this symptom and mental health. Methods: Breast cancer survivors were invited to participate in an ongoing longitudinal cohort study, the Mayo Clinic Breast Disease Registry (MCBDR), after having been seen at least once for breast cancer at Mayo Clinic in Rochester, MN. Those who consented were mailed a survey approximately one year after diagnosis. Respondents were asked to report their degree of eyebrow and eyelash loss experienced since their diagnosis on a 4-point scale of “no loss” (0) to “complete loss” (3). The proportions of participants who reported eyebrow and eyelash loss were evaluated overall and according to treatment type by descriptive statistics. Relationships between eyebrow and eyelash loss and mental health scores collected using the PROMIS-10 project scales (ranging from 0-20), with the poorest mental health indicated by scores under 8, were explored. Results: 838 registry participants responded to the year 1 survey’s alopecia questions. The median age of breast cancer survivors was 59.4 years (range 22-100 years). The majority were diagnosed at stage I-II (69%). 315 (37%) had received chemotherapy (+/- endocrine therapy), 415 (50%) had received endocrine therapy only, and 108 (13%) had received neither. Nearly half reported eyebrow loss (49%) or eyelash loss (49%). Eyebrow loss was reported by 89% of chemotherapy recipients, 27% of endocrine therapy only recipients, and 19% of those not treated with chemotherapy or endocrine therapy. 102 (32%) of those with chemotherapy-associated eyebrow loss reported that it was complete. Eyelash loss was reported by 274 (87%) of chemotherapy recipients, 112 (27%) of endocrine therapy only recipients, and 23 (21%) of those who received neither. Although no formal statistical testing was performed, there was a numerically higher proportion of patients with eyebrow and/or eyelash loss who reported poor mental health. Conclusions: Madarosis is a bothersome symptom in cancer survivors, particularly after chemotherapy. Future investigation into the incidence, predictors, and treatment of anti-neoplastic medication-related madarosis is needed. Table. Global mental health scores on PROMIS scale for eyebrow and eyelash loss Citation Format: Sarah Premji, Kathryn Ruddy, Nicole Larson, Charles Loprinzi, Brittany Dulmage, Maryam Lustberg, Fergus Couch, Janet Olson, Elizabeth Cathcart-Rake. Eyebrow and eyelash loss in breast cancer survivors [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-12-10.

Abstract Background Two years of adjuvant abemaciclib + endocrine therapy (ET) resulted in significant and clinically meaningful improvement in invasive disease-free survival (IDFS) and distant relapse-free survival (DRFS) in patients (pts) with HR+, HER2-, node-positive, high-risk early breast cancer (EBC) in the monarchE trial (NCT03155997). The benefit of abemaciclib was sustained beyond completion of treatment and deepened in magnitude at 4 years for IDFS and DRFS. This pilot study investigated the technical feasibility of ctDNA detection beginning prior to study treatment, as well as rates of persistence and clearance in a subset of EBC pts from monarchE using the clinically validated SignateraTM ctDNA assay. Methods Samples were analyzed from a selected subset of pts (n=178; 84 from abemaciclib+ET arm; 94 ET alone) who had blood collected both before initiating protocol directed therapy, Visit 1 (V1; randomization + ≤ 3 days) and near completion of the 2-year treatment period, Visit 27 (V27; 24 months +/- 5 days from V1). This cohort of pts was enriched for overall IDFS events compared to the total monarchE study population, however pts with relapses occurring prior to V27 were excluded. Primary tumors from selected pts were subjected to whole exome sequencing (WES). Selected samples included those from pts with a range of tumor mutation burden. Cell-free DNA was extracted from 356 plasma samples. A Signatera ctDNA assay was developed for each pt based on up to 16 variants detected by WES from each baseline tumor sample. Results The IDFS event rate for the selected subset (n=178) was 39.3% (abemaciclib+ET 34.5% [29/84] and ET alone 43.6% [41/94]). Ten pts (5.6%) were initially ctDNA+ and 42 pts (23.6%) were persistently (7 pts, 3.9%) or became (35 pts, 19.7%) ctDNA+ at V27. Notably, 70% of pts who were initially ctDNA+ and 100% of pts who were either persistently ctDNA+ or became ctDNA+ experienced recurrence (see Table 1). In contrast, none of the 3 pts that cleared ctDNA+ developed recurrence. In pts persistently ctDNA negative (neg), 28 (21.1%) experienced recurrence. Overall, 10% (7/70) of pts with IDFS events were initially ctDNA+ and 50% (35/70) had detectable ctDNA at V27. Conclusions Detection of ctDNA soon after completing neoadjuvant chemotherapy was infrequent, but also associated with a high-risk of recurrence. ctDNA positivity was common at the end of the 2-year treatment period and was highly prognostic with all pts subsequently developing disease recurrence. Importantly, ~30% of pts with early ctDNA detection ultimately dropped below detection limits during the 2-year treatment period and none developed recurrence. Although some pts remained persistently ctDNA neg during this study and experienced recurrence, the delay in recurrence may indicate longitudinal benefit from remaining ctDNA neg. Future planned analysis of an expanded cohort reflective of the intent to treat population including additional timepoints within the 2-year treatment period will further define how ctDNA dynamics may identify pts at high-risk of recurrence. Table 1. Summary of Subset Positivity Rates. + positive; - negative; NA, not applicable. Citation Format: Sherene Loi, Stephen Johnston, Carlos Arteaga, Stephanie Graff, Sarat Chandarlapaty, Matthew Goetz, Christine Desmedt, Jorge Reis-Filho, Hironobu Sasano, Vanessa Rodrik-Outmezguine, Anthony Sireci, Cynthia Sandoval Rubenstein, Helen Won, Deli Liu, Lacey M. Litchfield, Nicholas Turner. Results from a pilot study exploring ctDNA detection using a tumor-informed assay in the monarchE trial of adjuvant abemaciclib with endocrine therapy in HR+, HER2-, node-positive, high-risk early breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS06-01.

Abstract Introduction: CDK4/6 inhibitors (CDK4/6i), such as abemaciclib, ribociclib, and palbociclib, have significantly improved outcomes for patients with ER+/HER2− breast cancer. Nevertheless, they differ among each other in terms of chemical, biological, and pharmacological features, as well as toxicity profiles. Ribociclib causes concentration-dependent increases in the QTc interval, particularly in combination with tamoxifen. However, the pathogenesis of ribociclib-induced QTc prolongation remains unclear. We aim to determine whether QTc prolongation is caused by CDK4/6i in general or if it is associated with ribociclib only. Methods: We performed a systematic review and meta-analysis of randomized clinical trials (RCTs) to compare QTc prolongation in patients using CDK4/6i in combination with hormonal agents to patients that did not use CDK4/6i, including neoadjuvant, adjuvant, or metastatic scenarios in breast cancer. We searched Embase, PubMed and Cochrane Library databases from inception to June 2023. The outcomes evaluated were QTc prolongation of all grades. Statistical analysis was performed with R software version 2023.03.0+386. Results: We included 14 RCTs comprising 16,013 patients in the quantitative analysis, of whom 8,585 underwent therapy with CDK4/6i, and one more paper was included only in the qualitative analysis due to not reporting the exact number of events of QTc prolongation. An increased risk of QTc prolongation was associated with the use of CDK4/6i (RR 2.32; 95% CI 1.67–3.23; p=0.000001; I²=46%). Subgroup analyses revealed a significant increase in the QTc interval for the ribociclib and palbociclib cohorts. The ribociclib subgroup showed a risk ratio of 3.07 (RR 3.07; 95% CI 2.17-4.36; p< 0.000001; I² = 21%) while the palbociclib subgroup had a risk ratio of 1.52 (RR 1.51; 95% CI 1.05-2.16; p=0.025, I²=0%). Conclusion: Our findings suggest that QTc prolongation may be a common adverse effect of CDK4/6i, with ribociclib carrying greater risk. These results are important for guiding clinical decision-making, and further investigation is warranted to better understand the mechanisms and clinical implications of CDK4/6 i-induced QTc prolongation. Citation Format: Bruno Carvalho, Pedro Cotta Abrahão Reis, Alice Marinho, Ana Carolina Comini, Debora Xavier, Beatriz Mella S. Pessoa, Felipe Batalini. QTc prolongation as Adverse Effect of CDK4/6 inhibitors: A systematic review and meta-analysis of randomized controlled trials [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-12-08.