Citations

TPS610 Background: Several studies demonstrated worsening disease-free survival in patients who failed to achieve complete pathological response after neoadjuvant chemotherapy (NAC), particularly in HER2-positive (HER2+) breast cancer. Despite the recent approval of trastuzumab emtansine (T-DM1) in patients with residual disease after NAC approximately 12% of patients still develop recurrent and metastatic disease. TPIV100 is a multi-epitope vaccine that includes a pool of 4 degenerate HER2-derived HLA-DR epitopes, which activate CD4 helper T cells, admixed with GM-CSF. In our previous phase I trial this vaccine was shown to be safe in combination with trastuzumab in stage II-III HER2+ breast cancer after completion of standard of care chemotherapy. Furthermore, this vaccine also generated robust long-lasting T-cell immune responses and antibody immunity against HER2. Methods: This trial is a multi-center, randomized, placebo-controlled, phase II trial of TPIV100 in combination with T-DM1 in stage II-III HER2+ breast cancer patients with residual disease after NAC. This trial is currently opened through the ACCRU consortium. Eligible patients include those with stage II-III HER2+ with residual disease, in the breast and/or lymph nodes, after trastuzumab ± pertuzumab-based NAC, with ECOG PS ≤ 2 and adequate organ function. Patients with baseline left ventricular ejection fraction < 50%, history of trastuzumab-related cardiac toxicity, myocardial infarction or stroke < 6 months, history of congestive heart failure, autoimmune disease, immunocompromised patients with known HIV or those on chronic steroid, hypersensitivity to GM-CSF, and other active malignancy < 3 years are excluded. TPIV100 or placebo, in combination with GM-CSF, will be given concurrently with T-DM1. To ensure that TPIV100 in combination with T-DM1 is safe, there is a run-in phase with 20 patients treated with the combination. If there is no significant dose-limiting toxicity observed in the run-in phase, the trial will be expanded to the randomized phase II portion, which will include 240 patients. Eligible patients will be randomized in a 2:1 fashion with ER/PR as a stratification factor. The primary endpoint is invasive disease-free survival, and the secondary endpoint includes immunogenicity of TPIV100 as assessed by IFN-g ELIspot analysis. Correlative studies include assessment of helper T-cell response distribution (including Th1, Th2, Th17, Tfh), HER2-specific antibody immunity, and HLA genotype. Currently, 20 patients in the run-in phase have been enrolled. Enrollment to the randomized phase II portion is expected to begin in March 2022. Clinical trial information: NCT04197687.

Abstract Purpose Selective IgA deficiency (IgAD) is the most common primary immunodeficiency and may be associated with autoimmune diseases such as celiac disease (CeD). Although IgAD is thought to precede CeD and autoimmunity, the association between the two conditions has not been clarified. Methods Routine techniques were used to measure serum IgA and TG2-IgA and for immunohistochemistry. Results We report two childhood cases of IgA deficiency that evolved after the diagnosis of CeD and the start of a gluten-free diet. Histology showed persistence of IgA in the intestinal mucosa. Conclusion Both children with CeD showed IgA deficiency that developed after the initiation of a gluten-free diet. This supports IgA deficiency as being an autoimmune process that develops gradually and occurs due to specific defects in immunoregulation.

Abstract Background: Cyclin-dependent kinase 4/6 inhibitors (CKD4/6i) have demonstrated clinical utility extending progression-free survival (PFS) and overall survival (OS) for advanced hormone receptor positive and HER2 negative (HR+/HER2-) breast cancer patients. The efficacy in early-stage breast cancer (eBC) is unclear, with conflicting results from adjuvant CDK4/6i trials on invasive disease-free survival. Thus, there is a critical need to identify biomarkers of response (BoR) to determine which, if any, eBC patients could benefit from this treatment. This BoR could also stratify advanced BC patients for likelihood to respond to CDK4/6i. Metabolism is influenced by both genome and environment, and changes in the metabolome can be correlated with drug responsiveness. Thus, metabolite BoRs may serve to identify eBC patients for which CDK4/6i would offer a therapeutic benefit.Methods: Plasma and serum samples from 50 early-stage ER+/HER2- breast cancer patients, treated with neoadjuvant CDK4/6 inhibitor palbociclib (palbo) and aromatase inhibitor (AI) anastrozole on NeoPalAna trial (ClinicalTrials.gov identifier NCT01723774), were collected from treatment-naïve patients (BL) and 3 consecutive time points: anastrozole,1 mg daily for 4 weeks (C1D1), anastrozole plus palbo,125 mg daily, for 15 days (C1D15), and for 4-5 months before surgery (SURG). Metabolites were extracted from all samples via methanol and chloroform precipitation and quantified using an unbiased, non-destructive, nuclear magnetic resonance (NMR)-based profiling platform (Olaris®, Inc., Waltham, MA). Statistical analysis and machine learning was used to identify differential metabolites and generate predictive models. A separate validation set of samples was collected from a subset of patients (N=6) who received an additional cycle of palbo treatment prior to surgery to assess model accuracy. Results: Non-parametric differential expression analysis of BL/C1D1, BL/C1D15, and C1D1/C1D15 identified 53 ,97, and 90 differential NMR resonances in plasma (p&lt;0.05) and 36, 34, and 25 differential NMR resonances in serum (p&lt;0.05), respectively. Based on the proliferative marker Ki67 levels at C1D15, 37 patients were classified as responders (Ki67≤2.7%) and 6 patients as non-responders (Ki67&gt;2.7%). Analysis of the responder (R) and non-responder (NR) groups identified that 13 plasma and 14 serum resonances (21 unique resonances and 6 overlapping) were differentially expressed (p&lt;0.05) at C1D1. Many of the differential resonances could be mapped back to amino acid metabolites including several branched chain amino acids such as leucine, valine, and isoleucine, and positively charged amino acids such as lysine. A Olaris® BoR score was generated using 5 differential resonances that had an AUC of 0.931 (training set) and 100% accuracy when predicting palbo-response in a blinded test set (N=6).Conclusion: The differential metabolites identified from matching plasma and serum samples suggest that, compared to serum, plasma has a better representation of the metabolic changes associated with palbo treatment-response. While comparing samples from R and NR patients, amino acids were found to be consistently altered in both serum and plasma before palbo treatment. In addition, a BoR model based on select metabolites could precisely stratify palbo-response in a blinded dataset. A larger independent validation cohort is ongoing. Citation Format: Chen Dong, Shana Thomas, Chandrashekhar Honrao, Leonardo O. Rodrigues, Nathalie Tessier, Bo Zhang, Souzan Sanati, Kiran Vij, Brenda J. Ernst, Karen S. Anderson, Mateusz Opyrchal, Foluso Ademuyiwa, Lindsay L. Peterson, Matthew P. Goetz, Donald Northfelt, Elizabeth O'Day, Cynthia Ma. Identifying a metabolite signature that correlates with tumor proliferation in early-stage breast cancer patients treated with CDK4/6 inhibitors from matched plasma and serum samples [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-13-20.

Abstract Background: FGFR dysregulation is observed in multiple cancers and targeting FGFR is an emerging therapeutic strategy with FDA approved treatments in bladder and cholangiocarcinoma. Here we examined the prevalence of FGFR mutations, fusions, and high-level amplifications in breast cancer, stratified by receptor subtype and local/metastatic status, in both Foundation Medicine (FM) and institutional Mayo Clinic (MC) cohorts. Methods: For the FM cohort, comprehensive genomic profiling (CGP) examining at least 324 genes for all classes of alterations, including FGFR1-4 was carried out for 32,048 breast cancers during the course of routine clinical care in a Clinical Laboratory Improvement Amendments (CLIA)-certified lab (Foundation Medicine Inc., Cambridge, MA, USA). Tumor mutational burden (TMB) was determined on up to 1.1 Mb, microsatellite instability high (MSI-High) was determined on up to 114 loci and predicted ancestry from &gt;10,000 SNPs. Estrogen receptor (ER) and HER2 status were available for a subset of FM samples. Additionally, 131 patients with metastatic breast cancer from a subset of patients at three Mayo Clinic sites (MC cohort) with clinical characteristics and cancer-panel DNA sequencing data from a CLIA-certified lab (Tempus, Chicago, IL) were included. Results: In the FM cohort, the prevalence of FGFR1-4 high-level amplification (CN≥10) was 10.1%, while mutations (1.5%) and fusions (0.72%) were rare. Most amplifications occurred in FGFR1 (9.2%); most fusions and mutations occurred in FGFR2 (0.46%, 0.77%). FGFR alteration prevalence was highest in ER+/HER2- subtype (14.4%) and lowest in HER2+ disease (7.7%). FGFR alterations were more common in IDC (11.7%) than ILC (7.7%), p&lt;3E-08. FGFR alterations were more prevalent in the metastatic setting relative to breast-biopsied disease (13.6% v 10.1%; OR = 1.4; p=2E-17), especially in the HER2+ (OR =1.9, p=0.004) and ER-/HER2- (OR = 1.9, p = 0.05) disease; no enrichment was seen in the ER+/HER2- metastases (OR =1.0, p = 1). FGFR amplifications were observed at a higher prevalence in patients with predicted East Asian ancestry, relative to patients with European ancestry (12.1% v 10.0%; p = 0.03). Overall, the most common activating mutations in FGFR were FGFR2 N549K (n=85), FGFR1 N546K (n=78), FGFR4 V510M (n=28), FGFR2 K659E (n=28), FGFR4 V510L (n=20), and FGFR2 Y375C (n=15). The most common recurrent fusions were FGFR3:TACC3 (n=36), FGFR2:TACC2 (n=17), FGFR1:TACC1 (n=9), FGFR1:BAG4 (n=6), and FGFR2:ATE1 (n=5). In patients with FGFR amplifications, the most frequently co-occurring alterations were ZNF703 (78.4%), TP53 (51.5%), CCND1 (36.1%), FGF3/4/19 (32.9 - 34.4%), PIK3CA (30.7%), MYC (29.6%), ESR1 (17.2%), EMSY (16.3%), and PTEN (10.6%). Significant co-occurrence was observed for a number of genes including FGF3/4/19, CDK4, and CDK8 (all OR&gt;2, p&lt;1E-07); mutual exclusivity was observed with PIK3R1, BRCA1, and BRCA2 (all OR &lt;0.5, p&lt;4E-13), among other genes. In the 131 metastatic tumors from MC, the prevalence of FGFR1-4 high-level amplifications was 19.8% [FGFR1 (12.4%), FGFR2 (7.4%), and FGFR3 (0.8%)]. The prevalence of high-level FGFR amplifications did not differ by clinical subtypes: HR-/HER2- (7/31), HR+/HER2- (15/79), and HER2+ (2/11), p=0.68. Conclusions: High-level FGFR amplifications are observed in &gt;11% of breast cancers, especially the ER+/HER2- subtype, while mutations/fusions are rare. These data support the ongoing studies evaluating targeted therapies for FGFR amplified ER + breast cancer. Correlations with clinical information (MC cohort) and associations with actionable alterations are ongoing and may inform potential combination strategies. Citation Format: Karthik V Giridhar, Ethan S Sokol, Peter T Vedell, Jason P Sinnwell, Aakash Desai, Tufia C Haddad, Ciara C O’Sullivan, Roberto A Leon-Ferre, Siddhartha Yadav, Kostandinos Sideras, Brenda Ernst, Minetta C Liu, Abe Eyman Casey, Xiaojia Tang, Zoe Fleischmann, Karthikeyan Murugesan, Krishna R Kalari, Matthew P Goetz. The frequency and somatic mutation landscape of Fibroblast growth factor receptor (FGFR) alterations in breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-08-02.

Background: Perinatal factors including gestational age, birthweight, size for gestational age, delivery route, maternal parity, maternal age, maternal education, socioeconomic status, race, and sex, are associated with the future risk of obesity and co-morbid conditions. This study evaluated the relationship of birthweight for gestational age and perinatal factors with severe obesity and dyslipidemia in adulthood. Methods: We conducted a population-based, retrospective birth cohort study of infants born to residents of Olmsted County, MN between 1976 and 1982. Outcomes were assessed after age 18 years until October 2020, including severe obesity (BMI ≥ 40 kg/m 2 ) and dyslipidemia (total cholesterol ≥200 mg/dL, non-high density lipoprotein [non-HDL] cholesterol ≥145 mg/dL or HDL cholesterol <40 mg/dL). We obtained mother’s age, education level, and parity as well as newborn sex, race, type of delivery, single/multiple birth, gestational age, and birthweight from birth certificate data. Individual-level socioeconomic status (SES) of the household at birth was determined with the HOUSES index. Results: Of 10 938 birth cohort subjects, 7394 had clinic visits after age 18 years and were included, with 2630 having severe obesity (n = 798) or dyslipidemia (n = 2357) as adults. In multivariable models, female sex, singleton birth, less maternal education, and lower SES defined by HOUSES were independently associated with an increased risk of severe obesity in adulthood. Non-white race, singleton birth, and lower birthweight were independently associated with adult dyslipidemia. Birthweight for gestational age was not associated with severe obesity or dyslipidemia. Conclusion: Perinatal factors were associated with both severe obesity and dyslipidemia in adulthood. Lower SES at birth was predictive of severe obesity in adulthood, highlighting the opportunity to investigate modifiable perinatal social determinants to reduce the risk of severe obesity.

132 Background: Enhancing equitable oncologic care is an increasingly emphasized priority. Our study aims to identify aspects of breast cancer (BC) care in which differences exist based on insurance coverage. Methods: We performed a retrospective, case control study, (from 2014-2020); 39 Hispanic ethnicity uninsured patients (UP) from underserved communities with newly diagnosed BC and 119 insured patients (IP) diagnosed at Mayo Clinic Arizona (MCA). Patients were matched 3:1 for age, stage, year of diagnosis, estrogen receptors and HER-2 status. Demographic information, clinical variables, and zip code level specific socioeconomic information were compared. Continuous variables were compared by Wilcoxon rank-sum test and categorical variables by chi-square test. All patients were treated at MCA. Results: Similar treatment patterns with radiotherapy, chemotherapy and surgery were observed between groups. Primary language was Spanish for 94% of UP and English for 97.5% of IP. The majority of UP were of Hispanic ethnicity (97.4%); IP were 83.2% non-Hispanic White, 9.2% Hispanic, 3.4% African American. Zip code level information reflected more unemployment with a median of 10.6% versus 6.9% p < 0.001, percent of high school or lower (53.0 % v 23.2 %, p < 0.001), and lower income for UP (33733.5 v 64728.0 p values < 0.001).BMI was significantly higher for UP (30.6 V 24.7, p = 0.005), with presence of more co-morbidities; diabetes (28.2% v 5.0%, p < 0.001), hypertension (35.9 % v 20.2%, p = 0.046), dyslipidemia (28.2% v 12.6%, p = 0.023), metabolic syndrome (p 23.7% v 8.5, p = 0.013), and tobacco use (17.9% v 2.5%, p < 0.001). Genetics consultation was performed for 62.2% IP versus 35.9% UP (p = 0.004), lower acceptance of nutrition consultation for UP (29.4% vs 7.4%, p = 0.024). Median time from mammogram to biopsy (25.5 days vs. 14 days, p = 0.056), and interval from diagnosis to treatment (62 days vs. 39 days) (p = 0.001) were less favorable for UP compared to IP. Conclusions: In comparing the status of UP and IP with newly diagnosed BC, we identified greater prevalence of co-morbidities and adverse social determinants of health in the former group. We identified access to genetic counseling, nutrition consultation, and timeliness of diagnostic biopsy and initiation of treatment as disparate features in the care pathway. These observations allowed development of tailored interventions to achieve greater equity in delivery of BC care at Mayo Clinic.

Cloning of the sodium iodide symporter (NIS) 25 years ago has opened an exciting chapter in molecular thyroidology with the characterization of NIS as one of the most powerful theranostic genes and the development of a promising gene therapy strategy based on image-guided selective NIS gene transfer in non-thyroidal tumors followed by application of 131 I or alternative radionuclides, such as 188 Re and 211 At. Over the past two decades, significant progress has been made in the development of the NIS gene therapy concept, from local NIS gene delivery towards promising new applications in disseminated disease, in particular through the use of oncolytic viruses, non-viral polyplexes, and genetically engineered MSCs as highly effective, highly selective and flexible gene delivery vehicles. In addition to allowing the robust therapeutic application of radioiodine in non-thyroid cancer settings, these studies have also been able to take advantage of NIS as a sensitive reporter gene that allows temporal and spatial monitoring of vector biodistribution, replication, and elimination – critically important issues for preclinical development and clinical translation.

10541 Background: Biomechanical tissue properties may vary in the breasts of patients at elevated risk for breast cancer. We aim to quantify in vivo biomechanical tissue properties in various breast densities and in both normal risk and high risk women using Magnetic Resonance Imaging (MRI)/MRE and examine the association of biomechanical properties of the breast with cancer risk. Methods: In this IRB–approved prospective single-institution study, we recruited two groups of women differing by breast cancer risk to undergo a 3.0 T dynamic contrast enhanced MRI/MRE of the breast. Low-average risk women were defined as having no personal or significant family history of breast cancer, no prior high risk breast biopsies and a negative mammography within 12 months. High-risk breast cancer patients were recruited from those patients who underwent standard of care breast MR. Within each breast density group (non-dense versus dense), two-sample t-tests were used to compare breast stiffness, elasticity, and viscosity across risk groups (low-average vs high). Results: There were 50 low-average risk and 86 high-risk patients recruited to the study. The risk groups were similar on age (mean age = 55.6 and 53.6 years), density (68% vs. 64% dense breasts) and menopausal status (66.0% vs. 69.8%). Among patients with dense breasts, mean stiffness, elasticity, and viscosity were significantly higher in high risk patients ( N = 55) compared to low-average risk patients ( N = 34; all p < 0.001). In the multivariate logistic regression model, breast stiffness remained a significant predictor of risk status (OR=4.26, 95% CI [1.96, 9.25]) even after controlling for breast density, MRI BPE, age, and menopausal status. Similar results were seen for breast elasticity (OR=4.88, 95% CI [2.08, 11.43]) and viscosity (OR=11.49, 95% CI [1.15, 114.89]). Conclusions: Structurally-based, quantitative biomarker of tissue stiffness obtained from global 3D breast MRE is associated with differences in breast cancer risk in dense breasts. As such, tissue stiffness could provide a novel prognostic marker to help identify the subset of high-risk women with dense breasts who would benefit from increased surveillance.[Table: see text]