Citations

Abstract Introduction/Objective Non-mass enhancement (NME) in breast tissue is an area of enhancement on MRI that appears distinct from background breast parenchyma, but lacks definitive features of a mass. NME is characterized by its internal enhancement pattern and distribution, and can represent benign, high risk, or malignant pathology. Given this considerable overlap, a core biopsy is often necessary for diagnosis and management. We aimed to elucidate the most frequent histologic findings found on breast biopsies for MRI NME. Methods Using our institutional database we identified 70 female patients with high risk status for breast cancer with MRI screen detected NME (BIRADS-4-suspicious for malignancy) that underwent subsequent biopsy procedure during the period of 01/2016-12/2017. Primary pathologic diagnoses were subcategorized as follows: malignant, atypical, benign mass-like lesions, fibrocystic changes (proliferative, nonproliferative), or “other” primary diagnoses. Results The median age of patients was 48 years (range: 22-76 years). Of the 70 patients, 66 underwent MRI-guided core biopsy, 3 underwent ultrasound-guided core biopsy and 1 underwent excisional biopsy. The primary diagnosis was analyzed. Of these 70 cases, 8 (11.4%) were malignant (7 with ductal carcinoma in situ and 1 with invasive ductal carcinoma), 1 (1.4%) had atypical lobular hyperplasia, and the remaining 61 (87.1%) showed benign findings (36 with fibrocystic changes (FCC), 22 benign mass-like lesions, 3 with other non-specific findings). The FCC were subcategorized as proliferative (usual ductal hyperplasia, columnar cell change, incidental radial scar, incidental intraductal papilloma, sclerosing adenosis, focal pseudoangiomatous stromal hyperplasia (PASH)) or nonprolifeative (stromal fibrosis, duct ectasia, apocrine metaplasia). Majority (61.1%) of FCC were both proliferative and nonproliferative, 22.2% proliferative only and 16.7% nonproliferative only. Benign mass-like lesions included PASH (45.4%), fibroadenomatoid nodule (22.7%), fat necrosis (18.2 %) and remaining had the diagnosis of clustered apocrine cysts, papillomatosis, and radial sclerosing lesion. Conclusion Less than a third of cases showed malignant findings and more than two-third of cases showed benign findings with a high rate of detection of proliferative lesions and PASH.

Abstract Background: Biopsy diagnosis of benign breast disease (BBD) based on the most severe lesion in a sample predicts future breast cancer risk and has implications for screening and management. Lobules are the functional unit of the breast and the structures from which BBD arises. We developed and preliminarily validated an automated computational pathology algorithm to discriminate normal from BBD breast lobules as a step toward automated comprehensive characterization of benign biopsies. Methods: 152 BBD biopsies (27 training, 125 validation) from the Mayo Clinic were examined using scanned digital images of H&E stained sections. For each image, a pathologist annotated up to 10 representative lobules as normal or BBD using standard pathology criteria. A deep learning algorithm to quantify lobular features was developed using 129 lobules from 27 subjects. Nine features were identified that discriminate normal vs BBD lobules, expressing lobule size, acini size and number, acinar lumen size, proportion of lobular stroma, and capillaries. Here, we validate their performance to discriminate normal vs BBD lobules in a set of 1250 lobules from 125 subjects using area under the ROC curve (AUC) analysis. Random forest analysis was used for multivariable modeling; model performance was assessed with a tenfold cross-validation approach. Results: Median subject age was 52 years. Among the 125 validation subjects, BBD findings were nonproliferative in 39%, proliferative in 45%, and atypical hyperplasia in 16%. Sections included 552 (44%) normal lobules and 698 BBD (56%) lobules, with representation of both lobule types on each section. In univariate analyses, four individual features showed good discrimination between normal vs. BBD lobules, yielding the following AUCs: lobule size= 0.74, mean acini size= 0.75, epithelial area= 0.75, and number of acini with large lumens= 0.76. Lobule size and epithelial area were highly correlated (Spearman rank correlation r = 0.95), but both of these features showed lower correlation with mean acini size and number of acini with large lumens (each r < 0.5). With random forest modeling, number of acini with large lumens was the strongest discriminating feature, followed by mean acini size, lobule size, and epithelial area. With ten-fold cross validation of the multivariable random forest model, the overall AUC was 0.82 (95% CI: 0.79-0.85). Conclusion: Our validation showed that automated quantitative computational pathology assessment of breast lobules can discriminate normal versus BBD on a per lobule basis. This finding supports the feasibility of developing automated algorithms to classify every lesion in breast biopsies, expanding beyond visual assessment. Further studies using deep learning may reveal novel pathology features for classifying BBD biopsies with the potential to strengthen estimation of breast cancer risk. Citation Format: Amy C. Degnim, Thomas de Bel, Mark E. Sherman, Derek C. Radisky, Stacey J. Winham, Tanya L. Hoskin, Melody L. Stallings Mann, Marlene Frost, Robert A. Vierkant, Brendan T. Broderick, Ethan P. Heinzen, Rushin Brahmbhatt, Muhammad Arshad, Celine M. Vachon, Jodi M. Carter, Lori A. Denison, Daniel W. Visscher, Jeroen van der Laak. Discrimination of benign breast disease from normal lobules using an automated computational pathology algorithm [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2113.

Abstract Metastasis causes poor prognosis and yet remains the least understood aspect of cancer. To identify key regulators of ovarian cancer metastasis that drive early colonization and are also essential for advanced metastasis, we have applied a novel, comprehensive approach of combining the analysis of an organotypic 3D culture model of early metastasis with ovarian cancer patient tumors. Using matched primary and metastatic tumors from 42 OC patients, we have compared the fully formed metastatic tumors with the primary tumor of the same patient. Since this is an end-point analysis and reveals little about the intermediated regulatory steps, we have also studied the changes occurring during early metastatic colonization as a result of the interactions with the metastatic microenvironment by using an organotypic 3D culture model of omental metastasis. By combining these two approaches, we have identified key master regulators of metastasis that are essential for early metastatic colonization and remain important in the fully formed metastatic tumor. We specifically focused on microRNAs because of their pleotropic effects through translational inhibition of multiple targets, and also our previous studies have demonstrated their important role in metastasis. Using this approach, we identified a novel microRNA miR-4454, downregulated in the metastasizing ovarian cancer cells through their specific paracrine interactions with fibroblasts in the metastatic microenvironment. The downregulation of miR-4454 promoted high-grade serous ovarian cancer cell migration, invasion, proliferation, and clonogenic growth as well as metastasis in xenografts. The targets of miR-4454 were identified by RNA-seq in high-grade serous ovarian cancer cells overexpressing the microRNA. SPARC and BAG5 were found to be the functional effectors of miR-4454. SPARC activated FAK signaling and promoted metastasis, while BAG5 inhibited apoptosis and helped the metastasizing cancer cells tide over adverse conditions in the microenvironment. Since miR-4454 is essential for early metastatic colonization as well as in advanced metastasis, targeting it is a promising approach to treat metastatic ovarian cancer. Citation Format: Subramanyam Dasari, Taruni Pandhiri, Tommaso Grassi, Daniel W. Visscher, Francesco Multinu, Komal Agarwal, Andrea Mariani, Viji Shridhar, Anirban K. Mitra. Paracrine interactions with microenvironmental fibroblasts promote ovarian cancer metastasis through downregulation of miR-4454 [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr B66.

1061 Background: Benign breast disease (BBD) is a significant risk factor for breast cancer (BC); however little is known about the aggressiveness of the BCs these patients develop. Shared features between select atypias and low-grade DCIS have led some to speculate that a history of BBD portends the development of well-differentiated BCs. Methods: The Mayo BBD cohort includes 9,376 women who had benign breast biopsies from 1967–1991. Data on BC events were obtained from medical records and questionnaires. Tissue from the BCs was reviewed by a single breast pathologist (DWV). Results: Our cohort included 6,244 patients with nonproliferative disease (NP), 2,801 women with proliferative disease without atypia (PDWA), and 331 with atypical hyperplasias (AH). With a median of 18 years of follow-up, 799 patients with BBD have developed breast cancer, 416 initially had NP, 313 had PDWA, and 70 AH. BC tissue was available for 703 of the women. The cancers were invasive ductal in 76.1% (n = 535), invasive lobular in 9.4% (n = 66), and DCIS alone in 14.5% (n = 102) patients. Grade is currently available for 500 women, and is well differentiated in 29.4% (n = 150), moderately differentiated in 42.7% (n = 218) and poorly differentiated in 27.8% (n = 142). In 537 cases the malignant tissue had a concurrent benign component consisting of NP in 24% (n = 129), PDWA in 25.1% (n = 135), and AH in 50.8% (n = 273). In regards to tumor size, 69.6% had T1 tumors, 24.9% T2 tumors, and 5.5% T3 disease. Metastasis to lymph nodes occurred in 25% of patients. Median time to BC was 12.3 years and did not differ across the different benign entities. Breast cancer developed within 5 years from the initial BBD in 163 women (20%). In this group, tumor size was greater (p = 0.02), and there were more poorly differentiated tumors (p = 0.006) than in those who later developed BC. Conclusions: In the BCs that have developed in our BBD cohort, we do not see a preponderance of well-differentiated, good-risk BCs. Patients diagnosed within 5 years of BBD appear to have BCs with more aggressive features. No significant financial relationships to disclose.

Abstract Over one million women in the United States receive biopsy diagnoses of benign breast disease (BBD) each year, which confer a 1.5–4.0-fold increase in breast cancer risk. Studies in the general population suggest that nonsteroidal anti-inflammatory agents (NSAID) lower breast cancer risk; however, associations among women with BBD are unknown. We assessed whether NSAID use among women diagnosed with BBD is associated with lower breast cancer risk. Participants included 3,080 women (mean age = 50.3 ± 13.5 years) in the Mayo BBD surgical biopsy cohort diagnosed between January 1, 1992 and December 31, 2001 who completed breast cancer risk factor questionnaires that assessed NSAID use, and whose biopsies underwent detailed pathology review, masked to outcome. Women were followed from date of BBD biopsy to breast cancer diagnosis (main outcome) or censoring (death, prophylactic mastectomy, reduction mammoplasty, lobular carcinoma in situ or last contact). Median follow-up time was 16.4 ± 6.0 years. Incident breast cancer was diagnosed among 312 women over a median follow-up of 9.9 years. Regular non-aspirin NSAID use was associated with lower breast cancer risk [HR = 0.63; 95% confidence interval (CI) = 0.46–0.85; P = 0.002] with trends of lower risk (highest tertiles of use vs. nonuse) for greater number of years used [HR = 0.55; 95% CI = 0.31–0.97; Ptrend = 0.003), days used per month (HR = 0.51; 95% CI = 0.33–0.80; Ptrend = 0.001) and lifetime number of doses taken (HR = 0.53; 95% CI = 0.31–0.89; Ptrend = 0.003). We conclude that nonaspirin NSAID use is associated with statistically significant lower breast cancer risk after a BBD biopsy, including a dose–response effect, suggesting a potential role for NSAIDs in breast cancer prevention among patients with BBD.

Abstract Treatment of ovarian cancer is limited by extensive metastasis and yet it remains poorly understood. We have studied the critical step of metastatic colonization in the context of the productive interactions with the metastatic microenvironment with a goal of identifying key regulators. By combining miRNA expression analysis using an organotypic 3D culture model of early ovarian cancer metastasis with that of matched primary and metastatic tumors from 42 patients with ovarian cancer, we identified miR-4454 as a key regulator of both early colonization and advanced metastasis in patients with ovarian cancer. miR-4454 was downregulated in the metastasizing ovarian cancer cells through paracrine signals from microenvironmental fibroblasts, which promoted migration, invasion, proliferation, and clonogenic growth in ovarian cancer cells as well as their ability to penetrate through the outer layers of the omentum. Stable overexpression of miR-4454 decreased metastasis in ovarian cancer xenografts. Its mechanism of action was through the upregulation of its targets, secreted protein acidic and cysteine rich (SPARC) and BCL2 associated athanogene 5 (BAG5), which activated focal adhesion kinase (FAK) signaling, promoted mutant p53 gain of function by its stabilization, and inhibited apoptosis. Because microenvironment-induced downregulation of miR-4454 is essential for early and advanced metastasis, targeting it could be a promising therapeutic approach. Implications: This study identifies a miRNA, miR-4454, which is downregulated by signals from the microenvironment and promotes early and advanced ovarian cancer metastasis through its effects on FAK activation, mutant p53 stabilization, and apoptosis inhibition.

Abstract Our study aims to quantitate neuromuscular morbidity from radiotherapy in Hodgkin lymphoma including: (i) frequency and (ii) time of onsets for neurological localizations; (iii) degree of disabilities and (iv) number of clinical visits compared to cardiopulmonary Hodgkin lymphoma-radiation complications. Medical records from Mayo Health systems were retrieved; identifying neuromuscular radiation treated Hodgkin lymphoma-complications from 1 January 1994 to 31 December 2016. Of an estimated 4100 post-radiotherapy Hodgkin lymphoma patients, 4.6% (189) were identified with complications. Mean latency to physician visit for symptoms was 23.7 years (range: 1–50). Most commonly identified complications included: head drop 10% (19) with or without myopathy, myopathy 39% (73), plexopathy 29% (54), myelopathy 27% (51) and polyradiculopathy 13% (24). Other findings included benign and malignant nerve sheath tumours 5% (9), phrenic and long thoracic mononeuropathies 7% (14) and compressive spinal meningioma 2% (4). Patients frequently had multiple coexisting complications (single = 76% [144], double = 17% [33], triple = 4% [8], quadruple = 2% [4]). Cardiac 28% (53) and pulmonary 15% (29) complications were also seen in these patients. History of Hodgkin lymphoma was initially overlooked by neurologists (14.3%, 48/336 clinical notes). Hospital and outpatient visits for complications were frequent: neuromuscular 19% (77/411) versus cardiopulmonary 30% (125/411). Testing was largely exclusionary, except when imaging identified secondary malignancy. Modified Rankin score at diagnosis varied: 0–1 (55.8%), 2–3 (5.8%) and 4–5 (38.3%). Neuromuscular complications among post-radiation Hodgkin lymphoma are diverse, occurring in ∼1 of 20 having markedly delayed onsets often eluding diagnosis. Frequent care visits and major morbidity are common. Survivorship recommendations should recognize the diverse neurological complications.

Abstract Background: TNBC is the most aggressive sub-type of breast cancer and has limited targeted therapies. Atezolizumab was recently FDA-approved for patients with advanced PD-L1+ TNBC. In a well-characterized cohort of patients with early-stage TNBC, we used the FDA-approved PD-L1 SP142 companion assay for atezolizumab to score whole tumor sections for PD-L1 expression. We determined the frequency and scoring distribution of PD-L1 in these tumors and evaluated PD-L1 status for associations with clinicopathologic variables and outcomes. Methods: Whole tumor sections from 498 women with surgically-treated, non-(distant) metastatic TNBC (ER/PR <1% & HER2-negative by central review) were semi-quantitatively scored for % of PD-L1-staining tumor cells (TC) or tumor-associated immune cells (IC) (PD-L1 SP142, Ventana, performed in CAP/CLIA-certified clinical laboratory). Per FDA assay guidelines, PD-L1+ tumors were defined as ≥1% of tumor-associated immune cells (IC) staining per tumor area. Baseline clinical characteristics, histopathologic features, Ki-67 proliferative indices (PI), and stromal tumor infiltrating lymphocytes (TILs) were correlated with PD-L1 status. The impact of tumoral PD-L1 status on invasive disease-free survival (IDFS) and overall survival (OS) was assessed using Cox proportional hazards models. Results: The majority of tumors were pT1-T2 (95%), pN0-1 (85%), and grade 3 (90%) with Ki-67 >15% (80%). 228/498 (46%) tumors were PD-L1+, distributed as IC score 1-5%: 21%, 6-10%: 13%, 11-20%: 5% and >20%: 7%. 270/498 (54%) were PD-L1-. 43 (8.6%) of tumors had PD-L1 staining in TC (all but 1 were also IC+). PD-L1 IC expression was associated with larger tumor size (p = 0.005), higher nodal stage (≥pN1: 43% vs. 31%, p < 0.001), higher grade (grade 3: 95% vs. 86%, p< 0.001), higher Ki-67 PI (>15%: 88% vs. 69%, p <0.001), and stromal TILs (median score: 40% vs. 10%; p < 0.001). PD-L1 IC status was not associated with patient age. Among histologic subtypes, PD-L1+ tumors were more frequently medullary type (31% vs. 6%) and less frequently metaplastic type (4% vs 10%). At time of this analysis, median follow-up for IDFS and OS were 11 years and 7.2 years, respectively. By univariable analysis, absence of PD-L1 IC expression was associated with poorer IDFS (median: 15.5 vs. 20 years, p = 0.04) and OS (9.5 vs. 17.5 years, p < 0.05).By multivariable analysis, tumor size, stromal TILs, nodal status, and adjuvant chemotherapy (CTX) were significantly associated with IDFS. Age, stromal TILs, nodal status, and receipt of adjuvant CTX were associated with OS. PD-L1+ tumors trended toward improved IDFS (statistical significance not reached), HR: 0.68 (95% CI: 0.45-1.03, p= 0.068) but not OS: 0.90 (95% CI: 0.52-1.57, p= 0.32). Conclusion: Using the PD-L1 SP142 companion assay, almost half of early-stage TNBC were PD-L1+ (IC). However, PD-L1 expression correlated with increasing tumor size and nodal burden, as well as histologic grade, Ki-67 PI, stromal TILs and lymphocyte-enriched subtypes. PD-L1 was associated with improved IDFS and OS in univariable analysis but not multivariable analysis. The majority of the PD-L1+ tumors (73%) had IC scores ≤10%, with heterogeneous tumoral staining. Given the low (1%) assay threshold for positivity, these data emphasize the utility of evaluating PD-L1 in whole tumor sections rather than tissue cores. Citation Format: Jodi M Carter, Mei-Yin C Polley, Jason P Sinnwell, Roberto A Leon-Ferre, Fergus J Couch, Krishna R Kalari, Judy C Boughey, Minetta C Liu, Daniel W Visscher, Matthew P Goetz. Frequency, characteristics and prognostic factors of PD-L1+ triple negative breast cancer using the PD-L1 SP142 companion assay [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD1-08.

Abstract Background Prior epidemiologic studies have shown an inverse relationship of aspirin and NSAID use with breast cancer (BC) risk in the general population. Women with benign breast disease (BBD) are at an increased BC risk compared with women in the general population, and we have shown that BBD biopsies contain increased numbers of immune cells compared with normal breast tissues donated for research in the Komen Tissue Bank. We hypothesized that NSAID use among women with BBD is associated with reduced risk of BC. Methods We evaluated BC risk in relation to aspirin and NSAID use in a single institution retrospective cohort of 4,498 women who received a biopsy diagnosis of BBD between 1/1/1992 and 12/31/2001. Information on usual medication use, including average number of days used per month (0, 1-7, 8-28 and >28), was collected via questionnaires mailed after identification of participants. NSAIDs were categorized into three classes: 1) Aspirin, 2) Ibuprofen (plus other prostaglandin synthesis inhibitors), and 3) COX inhibitors. BC events were captured via medical record, questionnaires, and Tumor Registry records. Medication use was evaluated for associations with clinical and pathology features. Hazard ratios (HR) and 95% confidence intervals (CI) examining associations between medication use and BC risk were estimated using Cox regression analyses, with adjustment for age and BMI at biopsy, years between biopsy and questionnaire, and pathologic features related to BC risk (severity of BBD and degree of involution in background lobules). Tests for trend examining frequency of use were calculated from ordered values (lowest to highest) in Cox models with a one degree-of-freedom linear term. We assessed BC associations with any type of NSAID use, as well as the three subclasses. Results Information on NSAID use was available for 3,089 (69%) of the participants in the cohort; these women had a median age of 49 and did not differ in BC risk from women who did not provide data on NSAID use (p=0.46). Of the 3,089 respondents, 313 (10.1%) subsequently developed BC with median follow-up of 17 years. Age was significantly associated with use of all types of NSAIDs, with increasing use in older women. BMI at the time of biopsy, severity of BBD findings, and involution in background lobules were also associated with NSAID use; thus these factors and age were adjusted for in risk association analyses. Ever users of NSAIDs (any type) had a significantly lower risk of BC than never users (HR 0.76, CI 0.59-0.98, p=0.03), and increasing frequency of NSAID use was significantly associated with lower BC risk (HRs 0.81, 0.79, and 0.70 for regular use 1-7, 8-28, and >28 days/month), trend p=0.02. Analyses of drug classes revealed that ever use of ibuprofen (HR 0.61, CI 0.42-0.89, p=0.01) and ever use of COX inhibitors (HR 0.59, CI 0.39-0.89, p=0.01) were associated with decreased BC risk. COX inhibitors in particular showed a strong dose response effect with increasing use (HRs 0.97, 0.52, and 0.47 for regular use 1-7, 8-28, and >28 days/month), trend p<0.01. Use of aspirin was not associated with BC risk (HR 0.88, CI 0.64-1.21, p=0.44). Conclusions In this exploratory analysis, we found use of ibuprofen and other NSAIDs to be associated with decreased BC risk among women who had undergone a BBD biopsy. These findings suggest that anti-inflammatory approaches may have value in chemoprevention among women with BBD. Citation Format: Amy Degnim, Robert Vierkant, Stacey Winham, Marlene Frost, Daniel Visscher, Jodi Carter, Suneetha Kaggal, Julie Cunningham, Teresa Allers, Tanya Hoskin, Ethan Heinzen, Celine Vachon, Keith Knutson, Keith Knutson, Derek Radisky, Mark Sherman. NSAID use and breast cancer risk in a retrospective cohort of women with benign breast disease [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-08-06.

Abstract Background The Circulating Cell-free Genome Atlas (CCGA; NCT02889978) study is a prospective, multi-center, observational, case-control study with longitudinal follow-up to support the development of a plasma cfDNA-based multi-cancer early detection assay. We previously reported that the fraction of tumor-derived cfDNA fragments in plasma (estimated tumor fraction [TF]) is associated with detection of multiple cancer types using a prototype whole-genome bisulfite sequencing (WGBS) assay in a pre-specified substudy. In addition, detectability of breast cancer varied by hormone-receptor (HR) status: HR negative (HR-) breast cancer had a higher detection rate than the overall breast cancer cohort. Here, we performed a planned in-depth analysis of the breast cancer cohort to understand the main clinical and biological determinants of detectability using our WGBS assay. Methods Blood samples were prospectively collected from participants (pts) with newly-diagnosed, untreated breast cancer. In a pre-specified CCGA substudy, 511 (31.4%) of 1,628 pts had a clinicopathologic diagnosis of breast cancer (any stage, excluding stage 0) and a WGBS result. Pre-specified biological and clinical factors were assessed for correlation with TF: clinical stage, pathologic N stage, lesion size (by imaging), T stage, histologic grade, hormone receptor (HR) status, and proliferative rate (Ki-67 by IHC [MIB-1 clone]) via univariate and multivariate analyses. Ki-67 was obtained from pathology reports provided by enrollment sites and also assessed centrally (Mayo Clinic [Rochester, MN]). Stage-specific differences in detection rates between HR positive (HR+) and HR- breast cancers due to biological differences such as histologic grade and/or proliferative rate was also assessed. Results Of 511 pts, 94 (18.4%; 48.9% HR- and 12.3% in HR+) had WGBS-detected cancer. Higher TF was significantly associated with cancer detection (p<0.001). In univariate analyses, the variables significantly associated with TF were clinical stage, pathological N stage, and histologic grade (p<0.001 each). Primary lesion size was modestly correlated with TF (all stages combined: Spearman's correlation coefficient rs=0.4, p<0.001), and when grouped by early and late stages (stages I/II: rs=0.27, p<0.01; stages III/IV: rs=0.50, p<0.01); clinical T stage was significantly associated with TF only when all stages were combined (p<0.001). Proliferative rate (Ki-67) was positively correlated with TF at stages I/II (rs=0.29, p<0.05) but not III/IV (rs=-0.24, p=0.34); Ki-67 results obtained through Mayo were similar to that from enrollment sites (Pearson’s correlation coefficient rp=0.68, p<0.001). HR- breast cancers had significantly higher TF versus HR+ breast cancers only at stage II (p<0.001). In addition, compared to HR+ breast cancers, HR- breast cancers had a significantly higher proportion of high histologic grade (p<0.001 at stages I and II) and proliferative rate at earlier stages (p<0.05 at stages I, II, and III). In the multivariate analysis, clinical stage (stage III vs I and IV vs I) and HR status remained the most significantly associated with TF (p<0.001 each). Conclusions Using a prototype methylation-based plasma cfDNA cancer detection assay, TF was found to be associated with detection, and with clinical and biological features of breast cancer. Features routinely used to assess clinical aggressiveness (eg, HR- status and histologic grade) also demonstrated stage-specific associations with TF. Given the known relationship between TF and detection, these data suggest that clinical and biological cancer features may also provide insight into the variability of cancer detection using plasma-based cfDNA tests. Citation Format: Minetta C. Liu, Jodi M. Carter, Daniel W. Visscher, Karla Kopp, Rita Shaknovich, Xiaoji Chen, Kathryn N. Kurtzman, Shilpen Patel, Jacqueline D. Brooks, Carlo R. Cosenza, Jafi A. Lipson, Donald A. Richards, Fergus J. Couch, Zhao Dong, Hai Liu, Oliver Venn, Joerg Bredno, Eric T. Fung, Anne-Renee Hartman. Blood-based cancer detection in plasma cell-free DNA (cfDNA): Evaluating clinical and pathologic tumor characteristics in participants with breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-01-01.