Citations

Abstract Background Breast cancer (BC) survivors frequently experience sleep disturbances, which may persist for many years after treatment. This study aimed to describe trends in sleep-related symptoms over time and identify factors that may be associated with sleep disturbances in BC survivors. Patients and Methods Adult patients from the Mayo Clinic Breast Disease Registry were surveyed annually for up to 7 years post-diagnosis. Sleep disturbance severity was assessed using numeric rating scales for difficulty falling and staying asleep. Data from 3354 unique patients were analyzed, excluding those with metastatic disease or recurrence. Univariable and multivariable analyses were performed at the 1-year survey timepoint to evaluate disease and patient-related factors that were associated with increased sleep-related symptoms, and these factors were also assessed in relationship to sleep-related symptoms over time. Results In multivariable analyses, more trouble falling asleep was associated with financial insecurity, higher clinical stage, more cigarettes smoked per day, and less weekly exercise. More trouble staying asleep was associated with older age, race, advanced education, financial insecurity, and higher clinical stage. Over time, there was a nonsignificant trend toward increased trouble falling asleep and fluctuations in trouble staying asleep. Higher clinical stage and receipt of radiotherapy were associated with decreased severity in trouble falling asleep over time, while more cigarettes smoked per day was linked to increased severity in trouble staying asleep. Conclusions These findings highlight the complex interplay of clinical, lifestyle, and demographic factors in sleep disturbances among BC survivors, underscoring the need for tailored sleep management strategies.

Abstract PARP inhibitors (PARPis) are now a standard of care for high-grade serous ovarian cancer (HGSOC), but resistance to these drugs poses a significant concern, necessitating the exploration of novel treatment strategies. Here we investigated the mechanism underlying enhanced PARPi activity in HGSOC cells following treatment with brigatinib—a second-generation anaplastic lymphoma kinase (ALK) inhibitor approved for treating lung cancer. Our previous work has shown that brigatinib is a dual inhibitor of tyrosine kinases FAK and EPHA2 with subsequent additive reduction in downstream PI3K/AKT and MAPK/ERK cell survival signaling. Suppression of these pathways conferred PARPi sensitivity to HGSOC cell lines and patient-derived xenograft (PDX) models, particularly in those with high FAK and EPHA2. To dissect the mechanism linking the FAK/EPHA2 – AKT/ERK pathway to PARPi synergy, we focused on proteomics approaches which revealed that FRA1—an Activator Protein 1 (AP-1) transcription factor known to be downstream of AKT/ERK—and its targets were decreased by brigatinib treatment. In subsequent phosphoproteomics approaches and cell-based confirmatory studies, a phosphorylation crucial for FRA1 stability was found to be disrupted, leading to reduction in total FRA1 protein levels and synergy with PARPis. To explore how FRA1 mediates response to PARPis, immunoblotting analysis revealed that PARPis increased the abundance of FRA1 in HGSOC cells at early timepoints, indicating potential involvement in an adaptive survival response. Follow-up pharmacologic and gene silencing techniques demonstrated that brigatinib still reduces FRA1 in PARPi-treated cells, and FRA1 depletion induces apoptosis when combined with PARPi to levels comparable to brigatinib treatment. Overall, our studies unveil a beneficial ALK-independent effect of brigatinib that may offer new avenues for considering its repurposing as a HGSOC therapy through disruption of a PARPi-induced adaptive survival mechanism. Citation Format: Julie R. Duffield, Xiaonan Hou, Benjamin W. Wilson, Anjali Prasad, Iman K. McKeon-Makki, Amelia M. Huehls, Xinyan Wu, Cristina Correia, Melissa C. Larson, Fergus J. Couch, Ann L. Oberg, Scott H. Kaufmann, Larry M. Karnitz, Arun Kanakkanthara. A PARP-inhibitor-induced early adaptive survival response is tackled through depletion of FRA1 by brigatinib in high-grade serous ovarian carcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Ovarian Cancer Research; 2025 Sep 19-21; Denver, CO. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl):Abstract nr A024.

Background/Objectives: This study aims to evaluate the quality of life (QoL) and oncological outcomes in premenopausal women diagnosed with hormone receptor-positive breast cancer who are receiving either bilateral oophorectomy (BO) or gonadotropin-releasing hormone agonist (GnRH) therapy. Both methods serve to inhibit ovarian function, which is essential for the management of estrogen-dependent tumors; however, their effects on QoL have yet to be fully clarified. Methods: Data were analyzed from the Mayo Clinic Breast Disease Registry, focusing on women under 55 diagnosed with estrogen receptor-positive breast cancer who received either BO or GnRH within one year of diagnosis. QoL was assessed using the Patient-Reported Outcomes Measurement Information System Global-10 (PROMIS-10) at baseline and annually for five years. Results: A total of 181 patients were enrolled in the study; 40 into the BO group and 141 to the GnRH group. Both groups exhibited similar levels of sexual dysfunction after a one-year period; however, the BO group stated a higher frequency of hot flashes. PROMIS-10 scores improved in both mental and physical health over time, with no significant differences between the groups. Within the BO group, one recurrence was observed, in contrast to the GnRH group, which had six events. Nonetheless, the difference in recurrence rates did not reach statistical significance. Conclusions: The long-term QoL and oncologic outcomes for premenopausal women with hormone receptor-positive breast cancer were similar for BO and GnRH therapy. These findings emphasize the need for individualized treatment decisions, considering patient preferences and side effects.

Abstract Purpose: Germline pathogenic variants (PV) in ATM increase the risk of pancreatic ductal adenocarcinoma (PDAC), but the underlying tumor biology of PDAC associated with germline PV in ATM has not been adequately explored. Experimental Design: Whole-genome, whole-exome, and RNA sequencing were performed on PDAC tumors from 25 germline ATM PV carriers diagnosed at Mayo Clinic between 2007 and 2017. Somatic and copy-number alterations, mutational signatures, transcriptomic subtypes, and the immune landscape were evaluated. Results: High-quality whole-exome and whole-genome sequencing were obtained from 21 and 15 tumors, respectively. Biallelic inactivation of ATM was observed in 87%, KRAS PV in 90%, CDKN2A homozygous loss in 60%, and TP53 alterations in <10% of these tumors. A predominant clock-like mutational signature was present in all samples. Whole-transcriptome analysis identified that the aberrantly differentiated endocrine exocrine subtype accounted for 18% of PDAC and was consistently associated with >5-year overall survival. In addition, a 28-gene expression–based signature associated with overall survival was identified and further validated in The Cancer Genome Atlas cohort. Immune landscape analysis through CODEX identified enriched CD4 T-helper cell/tumor interactions and reduced B7H3-high cell/tumor interactions in ATM PV carriers compared with noncarriers. Conclusions: The observed absence of TP53 PV and enrichment for CDKN2A alterations in ATM tumors, along with differences in the mutational signatures, transcriptomic subtypes and immune landscape, improve our understanding of the mechanistic pathways involved in PDAC development in germline ATM PV carriers and help identify potential targeted therapeutic strategies.

Background: The U.S. Food and Drug Administration has approved a bupivacaine and meloxicam extended-release (ER) intra-articular injection for pain during total knee arthroplasty (TKA). However, the real-world evidence with regard to analgesic efficacy of that medication has been limited. This randomized clinical trial investigated the efficacy of this new medication compared with our standard periarticular injection for postoperative analgesia after primary TKA. Methods: Eligible patients undergoing primary, unilateral TKA for osteoarthritis at our academic center were enrolled. Patients were blinded and were randomized 1:1 to the bupivacaine-meloxicam ER (ZYNRELEF) injection group or the standard injection (ropivacaine, ketorolac, epinephrine) control group. A standardized, multimodal analgesic pathway was implemented. Numeric Rating Scale (NRS) pain scores and tallies of opioid consumption were collected. The primary outcome was the area under the curve (AUC) for NRS pain, adjusted for opioid consumption, over 72 hours. The minimal clinically important difference was considered to be 30%. Power analysis determined a minimum of 44 patients per group. The final groups included 53 patients in the experimental group and 48 patients in the control group. Results: Similar postoperative analgesia was observed, with an AUC for the adjusted NRS pain score up to 72 hours of 331 in the experimental group and 373 in the control group (p = 0.09). The mean maximum NRS pain scores were similar and reflected good, but not complete, analgesia. Scores were 3 to 5 on the day of the surgery, 4 to 6 on postoperative day (POD) 1, 5 to 6 on POD 2, and 4 to 5 on POD 3 (p > 0.05). One patient in the experimental group and 2 patients in the control group had early postoperative complications, none of which was deemed to be related to the analgesic choice. Conclusions: This randomized clinical trial demonstrated similar analgesia with a bupivacaine-meloxicam ER solution and a standard periarticular injection up to 72 hours after primary TKA. Cost, reimbursement, and convenience may ultimately prove to be more important than analgesic differences when choosing between these 2 effective options for managing postoperative pain. Level of Evidence: Therapeutic Level I . See Instructions for Authors for a complete description of levels of evidence.

PURPOSE Testing for germline BRCA1 and/or BRCA2 mutations (gBRCAm) is recommended for patients with human epidermal growth factor receptor 2–negative (HER2–) breast cancer (BC) to guide treatment selection with poly (ADP-ribose) polymerase inhibitors (PARPis). However, real-world data on germline BRCA1 and/or BRCA2 (gBRCA) testing and PARPi treatment patterns in metastatic BC (mBC) are limited. METHODS Deidentified patient data from adults diagnosed with HER2– mBC between 2014 and 2022 were captured from electronic health records in the US Flatiron Health database. gBRCA testing patterns and prevalence were examined by tumor subtype (hormone receptor–positive [HR+]/triple-negative) and disease stage at diagnosis. Demographic and clinical characteristics were described by receipt of gBRCA testing and PARPi. PARPi treatment patterns were assessed, and real-word overall survival (OS) was estimated in patients with gBRCAm diagnosed with mBC after January 1, 2018. RESULTS Of the 15,006 total patients, 4,654 (31.0%) received a gBRCA test. gBRCA testing rates mostly increased from 2014 to 2022 and were lower in patients with HR+ than triple-negative tumors. Of the patients who underwent gBRCA testing, 337 (7.2%) had gBRCAm. From 2018 to 2022, PARPi was initiated in 94 (45.6%) of 206 patients with gBRCAm. With a median follow-up of 22.8 months across patients with available first-line treatment start dates, real-world OS was numerically longer among 94 patients with gBRCAm who received PARPi (32.3 months [95% CI, 22.7 to 47.4]) than among 99 patients who did not (21.9 months [95% CI, 18.4 to not reached]). CONCLUSION Although gBRCA testing increased over time, testing and PARPi utilization rates remained suboptimal in potentially eligible patients with HER2– mBC. Exploratory analysis showed numerically longer OS in patients who received PARPi. Wider and timelier gBRCA testing is warranted to inform potentially optimal treatment decisions.

e14545 Background: Next generation sequencing (NGS) identifies genomic alterations in DNA obtained from tissue biopsies and/or blood [circulating tumor (ct)DNA]. We anticipate a lower rate of copy number loss (CNL) in ctDNA compared to tissue, as lower ctDNA tumor fraction may limit the ability to detect a deletion. However, we observed several instances of a CNL in ctDNA that was not identified in a tissue specimen, prompting this systematic evaluation of an institutional dataset. We focused on BRCA1/2 pathogenic variants (PVs) given their therapeutic implications and coverage across testing platforms. Methods: Using an IRB-approved protocol, we evaluated an institutional repository of NGS results performed across the Mayo Clinic Enterprise. We focused on patients (pts) who had both tissue and blood NGS testing performed. We further narrowed this cohort to those with a BRCA1/2 PVs, somatic and/or germline, as determined by testing performed at Guardant Health, Tempus, or Foundation Medicine. We abstracted information about each variant, including type of alteration classification and functional impact. Demographic information, cancer characteristics, and germline testing information was collected. Fisher’s exact test was used to compare alteration frequencies in ctDNA vs tissue using GraphPad Prism v 10.1. Results: From Dec 2015-Sept 2024, we identified 158 unique pts with BRCA1/2 PV who had NGS results for both tissue and ctDNA. The median age at first reporting BRCA1/2 variant was 67 years (range: 29-98 years). 48% of pts were female, and the most common cancer type sites were lung (23%), colorectal (20%), and pancreaticobiliary (20%). We identified 198 unique pathogenic genomic alterations; 71 in BRCA1 & 127 in BRCA2 . Most common alteration was an SNV or indel (127/198), followed by CNL (n = 63), splice site variants (n = 5), fusions (n = 2), and rearrangements (n = 1). Of the 126 SNV or indels, 50 (39.7%) were identified in both ctDNA and tissue, 40 (31.7%) were detected in blood only, 36 (28.6%) identified only in tissue (p < 0.0001). Amongst the 63 CNL, only 3 (4.8%) were identified in both ctDNA and tissue; 41(65.1%) were only identified in ctDNA, and 19 (30.2%) in tissue only (p < 0.0001). In the 19 tissue-only CNL tests, 12/19 noted one or more additional pathogenic SNV/Indel in BRCA1/2. In the 41 ctDNA-only CNL tests, 1/41 noted one or more additional pathogenic SNV/Indel in BRCA 1/2 . Germline testing was available in 41/63 pts with copy number loss. 3/41 deletions were identified in germline (2 in ctDNA, 1 in tissue). Conclusions: We observed a low degree of concordance in CNL between tissue and ctDNA for BRCA1/2 . CNL detection in ctDNA that could not be confirmed in germline or with a second alteration warrants further attention. In particular, clinicians should be cautioned when interpreting ctDNA reports noting BRCA1/2 CNL without clarity if this represents biallelic loss or a synchronous loss of function.

569 Background: Several studies established the prognostic role of both the amount and locations of tumor-infiltrating lymphocytes (TILs) in TNBC. Three distinct immunotypes were described based on the amount and locations of TILs: immune enriched (IN), immune excluded, and immune desert. Using single-cell spatial transcriptomic analysis in the Mayo Clinic TNBC cohort, our previous studies showed the central role of interferon (IFN) signaling in IN phenotype. Herein, we evaluated the association between IFN and outcomes in TNBC in 3 independent datasets. Methods: NanoString IO360 was performed in 114 samples from FinXX (NCT00114816) to generate 22-gene IFNα and 33-gene IFNγ signatures. RNA sequencing was performed in 388 samples from CALGB 40603 (NCT00861705). 3038 TNBC samples were tested by WTS (NovaSeq; Caris Life Sciences, Phoenix, AZ). Median values were used as cut-offs for high vs low IFNγ RNA expression and 18-gene IFNγ signature scores. Caris Life Science CODEai was used to evaluate real-world overall survival (OS) obtained from insurance claims and calculated from tissue collection to last contact using Kaplan-Meier estimates. Chi-square, Mann-Whitney U, ANOVA, and Cox regression were used. Results: A high 22-gene IFNα signature score was associated with significantly improved recurrence-free survival (RFS) in FinXX (hazard ratio [HR] 0.32, 95% confidence interval [CI] 0.14-0.74, p 0.007) and OS (HR 0.28, 95%CI 0.12-0.66, p 0.003). Similar findings were observed with 33-gene IFNγ signature with significant improvement in RFS (HR 0.21, 95%CI 0.09-0.51, p < 0.001) and OS (HR 0.18, 95%CI 0.08-0.44, p < 0.001). Furthermore, in CALGB 40603, both IFNα and IFNγ scores were positively associated with pathologic complete response (pCR: IFNα p 0.019 and IFNγ p 0.007) and residual cancer burden (RCB: IFNα p 0.044 and IFNγ p 0.013). Using the Caris data platform to further validate, we identified 2899 TNBC patients (pts) with genomic and clinical outcome data. High IFNγ expression was associated with significant improvement in OS (25.95 vs 17.43 months; HR 0.65, 95% CI 0.59 – 0.72, p < 0.001). Similarly, pts with high IFNγ signature scores had significant improvement in median OS (25.79 vs 16.22 months; HR 0.66, 95% CI 0.6 – 0.73, p < 0.001). Conclusions: This study underscores the pivotal role of IFN signaling in TNBC. High IFNα and IFNγ signatures were consistently associated with improved RFS, OS, higher pCR rates, and lower RCB across clinical trial cohorts and real-world data. These findings signify IFN signaling as a potential key biomarker and therapeutic target in TNBC. Support: U10CA180821, U10CA180882, U24CA196171; Breast Cancer Research Foundation, Mayo Clinic Breast Cancer SPORE (P50CA116201-17), Bankhead Coley, W81XWH-15-1-0292, P50CA015083, R35CA253187; https://acknowledgments.alliancefound.org . Genentech. Clinical trial information: NCT00114816 and NCT00861705 .

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.