Citations

262 Background: Inherited and somatic aberrations in DNA repair genes in castrate resistant prostate cancer (CRPC) are associated with poor prognosis, but respond well to poly ADP ribose polymerase (PARP) inhibitors. We evaluated the prevalence and prognostic impact of harboring germline DNA repair variants in hormone sensitive prostate cancer (HSPC). Methods: Germline DNA from buffy coat was sequenced on HiSeq4000 with a median coverage of 200X for DNA repair variants in 20 genes in HSPC and CRPC patients (pts) enrolled in a hospital registry. Pts were divided into two groups; Group A: pts enrolled at the time of CRPC stage; Group B: treatment naïve HSPC stage pts. The primary endpoints were to determine any impact of harboring DNA repair variants on time to progression from HSPC to CRPC and, from CRPC to death. Group A pts were retrospectively analyzed for time to progression from HSPC to CRPC while Group B patients were followed prospectively for outcomes. Statistical analysis included Cox proportional hazard models and Wilcoxon Rank sum test with significance at p≤0.05. Results: In Group A, 51/562 CRPC pts (9.07%) had variants in the 20 genes (most frequently in BRCA2; n = 15). 44/51 pts with variants and 399/511 without variants had died. Median time of progression from HSPC to CRPC with/without variants was 22.1 vs. 25.1 months (mths); p-value = 0.679. Median time from CRPC to death with/without variants was 32.2 Vs. 27.7 mths (p = 0.6). In HSPC Group B, 14/100 pts were identified with germline variants in ATM (n = 5), CHEK2 (n = 3), BRCA1 (n = 2), BRCA2 (n = 2), RAD50 (n = 1), and MSH2 (n = 1). 31/100 have died and median time to progression from HSPC to CRPC with/without variants was 15.6 vs.11.8 mths, p-value = 0.76. Conclusions: Pts with germline DNA repair variants detected in HSPC stage were not associated with poor prognosis. Presence of additional somatic DNA repair gene aberrations in cell-free DNA, not investigated in this cohort may add to the prevalence of DNA repair gene variations in HSPC and together impact prognosis adversely so as to provide a rationale for PARP inhibitor therapy in select HSPC stage pts.

5 Background: Triple-negative breast cancer (TNBC) is an immunogenic breast cancer subtype, with a greater percentage of tumors containing tumor-infiltrating lymphocytes (TILs) compared to non-TNBC. TILs are prognostic for recurrence and predictive for chemotherapy benefit in TNBC, but not in estrogen receptor (ER)-positive tumors. A subset of TNBC expresses the androgen receptor (AR), and resembles ER-positive breast cancer in terms of demographics (older age) and clinical course (later recurrences that tend to involve bone). However, little is known regarding the association between TILs and AR expression in TNBC. Methods: From a cohort of 9982 women with surgically-treated non-metastatic breast cancer, patients who met criteria for TNBC (ER/PR < 1% and HER2-negative) by centralized-pathology review were included as previously published [Leon-Ferre et al, Breast Cancer Res Treat 2017]. Stromal TILs in these tumors were quantified on full-face hematoxylin and eosin sections from the surgical specimen, following the 2014 TIL Working Group recommendations [Salgado et al, Ann Oncol 2014]. The expression of AR [EPR1535(2), Abcam] was scored as a continuous variable (1% increments), and categorized as absent (0%), low (1-25% ), low-moderate (26-50%) moderate (51-75%) and high (> 75%) and correlated with TIL density. Results: 605 patients met criteria for TNBC. The median age was 56 years. Most tumors were T1-2 (95%), N0-1 (86%), and high grade (88%). The median stromal TIL content was 20% (0-90%). Tumor tissue was available for AR staining in 509/605 patients. 165 (32%) tumors expressed AR as follows: low: 12%, low-moderate: 7%, moderate: 5%, and high: 8%. Apocrine tumors (n = 30) expressed AR most frequently (86%) and at higher levels (AR high: 50%). For all 509 tumors, the median stromal TIL content according to AR expression was AR absent: 20%, AR low: 20%, AR low-moderate: 15%, AR high: 10%. AR and stromal TILs (both as continuous variables) demonstrated a weak inverse correlation (correlation coefficient -0.1064, p = 0.017). Conclusions: AR expression in TNBC is associated with lower levels of stromal TILs. Additional data correlating the AR, stromal TILs and outcomes in this cohort will be presented at the meeting.

Abstract Introduction:Pathogenic and/or founder germline variants in the ataxia-telangiectasia mutated (ATM) gene confer an increased breast cancer (BC) risk. The protein kinase ATM plays a central role inDNA double-strand break-repair and in the activation of downstream targets such as p53 and BRCA1. We sought to define the repertoire of somatic genetic alterations of BCs from patients with pathogenic germline ATM mutations and whether somatic loss of heterozygosity (LOH) of ATM would be present in these cancers. Methods: 21 BCs from ATM germline mutation carriers were microdissected. Tumor and normal DNA samples were subjected to whole-exome sequencing (WES, n=12) or massively parallel sequencing targeting all coding regions and selected intronic and regulatory regions of 410 key cancer genes (n=9). Somatic mutations, copy number alterations, cancer cell fractions, large-scale state transitions (LSTs) and mutational signatures were defined using state-of-the-art bioinformatics algorithms. ABSOLUTE and FACETS were employed to assess LOH of the wild-type allele of ATM. Results: Of the patients included in this study, 71%, 24% and 5% of cases harbored ATM missense (all but one p.V2424G), frame-shift and nonsense germline mutations, respectively. All tumors were ER-positive and four (19%) were HER2-positive. The median age of the patients was 46 years (32–79 years). Our analyses revealed biallelic inactivation of ATM through LOH of the wild-type allele in 16 of 21 cases (76%), and second somatic ATM mutations were not found. The median number of non-synonymous somatic mutations was 38 (range 15-113) and 2 (range 0-8)in tumors subjected to WES and targeted sequencing, respectively. The repertoire of somatic genetic alterations of ATM-associated BCs was found to be heterogeneous, including clonal PIK3CA mutations (24%), GATA3 mutations (19%), FANCI amplifications (19%) and CCND1 amplifications (14%). Importantly, however, no somatic mutations affecting TP53 were found. Analysis of the WES data revealed that 5 (42%) ATM-associated BCs displayed high LST scores, all of which harbored bi-allelic ATM inactivation. In contrast to BRCA1- and BRCA2-associated BCs, which frequently display the mutational signature 3 associated with defective homologous recombination DNA repair, the ATM-associated BCs studied displayed the ageing mutational signature (i.e. signature 1). Comparison of the mutational profiles of the ATM--associated BCs subjected to WES (n=12) with those of BRCA1- (n=11) and BRCA2-associated (n=10) BCs from The Cancer Genome Atlas revealed that TP53 was more frequently mutated in BCs from BRCA1 germline mutation carriers (0% vs 72%, P&lt;0.001), while no differences with BRCA2-associated BCs were found. Conclusion: ATM-associated BCs frequently display bi-allelic ATM inactivation through LOH of the wild-type allele and a subset of these cases displayed high levels of LSTs. These findings suggest that at least in a subset of ATM-associated BCs, biallelic inactivation of ATM rather than a dominant negative effect of the germline mutation may be the mechanism of inactivation of this tumor suppressor gene. The repertoire of somatic genetic alterations of ATM-associated BCs is heterogeneous, with a noticeable lack of TP53 somatic mutations. Citation Format: Weigelt B, Bi R, Kumar R, James PA, Thorne H, Couch FJ, Eccles DM, Blows F, Geyer FC, Li A, Selenica P, Lim RS, Blecua P, Shen R, Wen H, Robson ME, Reis-Filho JS, Chenevix-Trench G. The landscape of somatic genetic alterations in breast cancers from ATM germline mutation carriers [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD1-15.

Abstract Background New treatment strategies for metastatic breast cancer (mBC) are mainly driven by therapies against specific targets. BRCA mutations are one of the few established actionable targets, with PARP-Inhibitors and Platinum showing high efficacy in mBC. Hereditary cancer testing panels are now broadly used for identification of individuals with BRCA1/2 mutations who may benefit from these therapies. Many of these panels also contain other predisposition genes involved in BRCA-related DNA repair pathways, but the clinical relevance of mutations in these genes remain unclear. The aim of this study was to describe the mutation rates of BRCA1/2 and panel-based predisposition genes, and the associated clinical characteristics of individuals with these mutations, in a prospective cohort of mBC patients. Methods The PRAEGNANT mBC registry (NCT02338167) is a prospective registry for metastatic breast cancer patients with a focus on molecular biomarkers. Patients receiving any therapeutic regimen are eligible for this registry. Germline DNA was collected at study entry and genotyped for 37 cancer predisposition genes including BRCA1 and BRCA2. The frequency of mutations in each gene was determined, and associations between mutations and patient and tumor characteristics, metastatic pattern, and overall survival were assessed. Results Mutations in established high (odds ratio (OR)&gt;5.0) and moderate risk (OR&gt;2.0) breast cancer genes (BRCA1/2, PALB2, CHEK2, ATM, RAD51D, BARD1, and MSH6) were seen in 123 of 1462 tested patients with mBC (8.4%). BRCA1 and BRCA2 mutations were seen in 1.4% and 2.9% of patients respectively. Most frequently mutated non-BRCA panel genes were CHEK2, PALB2 and ATM with 2.8%, 0.8% and 0.6% of patients. Mutation frequency varied with regard to patients who developed brain metastases, visceral metastases or bone only metastases. BRCA1 or BRCA2 mutations were seen frequently in patients with brain (5.3%) or visceral metastases (5.2%), but were present in only 2.5% patients with bone only metastases and 1.5% of patients with lesions in other locations. Panel genes were equally distributed among all metastatic patients. PALB2 mutations (n=11) were only seen in patients with brain (1.9%) and visceral metastases (0.9%), but not in patients with bone metastases or other locations. 36.4% (N=4) of all patients with PALB2 mutations developing a brain metastasis. When adjusted for other mBC prognostic factors, a mutation (all genes) was associated with an unfavorable prognosis (HR: 1.50; 95%CI: 1.04 to 2.30, p=0.03). Mutation frequencies were similar according to therapy lines. All other associations with molecular subtypes and risk factors were similar to primary breast cancer cases. Conclusion Mutations in high and moderate risk breast cancer genes were frequent in metastatic breast cancer patients. The frequency was substantially higher than the 4 to 5% mutation frequency observed among unselected primary breast cancer patients, but is consistent with recent results from studies of metastatic prostate cancer patients. Patients with brain and visceral metastases had the highest BRCA mutation rates. Results suggested that PALB2 mutations may be more frequent in patients with brain metastases. Citation Format: Fasching PA, Hu C, Hart SN, Polley EC, Lee KY, Gnanolivu RD, Lilyquist J, Hartkopf AD, Taran FA, Janni W, Hadji P, Tesch H, Haeberle L, Ettl J, Lux MP, Lueftner D, Wallwiener M, Mueller V, Beckmann MW, Belleville E, Wimberger P, Untch M, Kolberg H-C, Fehm TN, Overkamp F, Wallwiener D, Brucker SY, Schneeweiss A, Couch F. Cancer predisposition genes in metastatic breast cancer – Association with metastatic pattern, prognosis, patient and tumor characteristics [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD1-02.

Abstract Background: Germline cancer testing panels provide an effective method for identifying individuals at increased risk for breast cancer. However, estimates of risk for triple negative breast cancer (TNBC) (estrogen receptor-negative, progesterone receptor-negative, HER2-negative) associated with pathogenic mutations in panel genes have not been established. We sought to define the genes that contribute to TNBC. Methods:Germline hereditary cancer multigene panel testing results were obtained for 8,753 TNBCs evaluated by a clinical testing laboratory. Associations between pathogenic mutations in individual genes and TNBC were assessed by comparing mutation frequencies in TNBCs and in the Exome Aggregation Consortium, non-Finn European, non-Cancer Genome Atlas reference controls. Results: Inactivating mutations in 21 known cancer predisposition genes were identified in 14.6% of TNBCs. BRCA1, BRCA2, PALB2, BARD1, and RAD51D alterations were associated with high risks (odds ratio(OR)&gt;5.0) of TNBC and variants in BRIP1, RAD51C, MSH6, and TP53 were associated with moderate risks (OR&gt;2). In contrast, ATM, CHEK2, NBN, and RAD50 yielded no clinically relevant risks of TNBC. Pathogenic mutations in these established non-BRCA1/2 TNBC susceptibility genes were detected in 6.3% of TNBCs. Similar trends were observed among African American TNBCs. Overall, 5.5% of TNBCs with pathogenic mutations did not meet NCCN clinical testing criteria for BRCA1/2 due to a lack of significant family history and diagnosis over the age of 60. Conclusions: The identification of genes associated with elevated risk of TNBC will improve understanding of the etiology of this aggressive form of breast cancer and inform risk management of individuals receiving panel testing. The high frequency of pathogenic variants suggests that all patients with TNBC, regardless of age of diagnosis or family history of cancer, should be considered for multigene panel testing. Citation Format: Couch FJ, Shimelis H, LaDuca H, Hu C, Hart SN, Polley EC, Pesaran T, Tippin-Davis B, Goldgar DE, Dolinsky JS. Triple negative breast cancer predisposition genes [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD1-01.

Abstract Background: Clinical panel testing has become routine practice for patients that are diagnosed with breast cancer at a young age and/or have a personal or family history of cancer. Associations with known breast cancer genes and breast cancer subtypes have been previously identified, such as BRCA1 associations with estrogen receptor negative (ER-) and triple negative (ER-/PR-/HER2-) breast cancers. However, the cancer predisposition genes associated with each of the four clinical subtypes of breast cancer have not been fully defined. We evaluated 24,901 Caucasian female breast cancer cases receiving clinical panel testing for 23 cancer predisposition genes and assessed associations between mutations in each gene and breast cancer subtypes. Methods: Germline hereditary cancer multigene panel testing results for cancer predisposition genes were obtained for 24,901 Caucasian female breast cancer cases evaluated by a clinical testing laboratory. Information on tumor histology, personal and family history of cancer, age at diagnosis, and previous genetic testing was provided by clinical care providers of patients receiving clinical cancer genetic testing. Breast cancer cases were classified into clinical breast cancer subtypes based on estrogen/progesterone hormone receptor status (HR) and HER2 status: Luminal A (HR+/HER2-), Luminal B (HR+/HER2-), HER2 subtype (HR-/HER2+), and Triple Negative (HR-/HER2-). The frequency of pathogenic or likely pathogenic mutations observed in each subtype was compared against the Exome Aggregation Consortium (ExAC) non-TCGA non-Finnish European population to estimate risks. Results: ATM was associated with moderate risks (odds ratio (OR)&gt;2.0) of Luminal A, Luminal B, and HER2 subtypes of breast cancer, but was not associated with the Triple Negative subtype. PALB2 was associated with moderate risk for Luminal B subtype, but high risk (OR&gt;5.0) for Luminal A, HER2, and triple negative subtypes. TP53 was associated with high risks for Luminal B and HER2 tumors. NBN, MRE11A, and RAD50 were not associated with any subtype of breast cancer. Conclusions: Identifying associations between inherited mutations (odds ratio (OR)&gt;2.0) and breast cancer subtypes can inform clinical risk management, treatment options, and therapeutic development efforts. Citation Format: Lilyquist J, Laduca H, Hu C, Na J, Polley EC, Hart SN, Pesaran T, Tippin-Davis B, Goldgar DE, Dolinsky JS, Couch FJ. Associations between hereditary cancer panel predisposition genes and breast cancer histological subtypes [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P6-09-02.

Abstract Background: While TNBC remains the most aggressive type of breast cancer (BC), substantial heterogeneity in biology and outcomes exists among TNBC subtypes. Historically, risk stratification of TNBC has been based on anatomic factors such as tumor size, nodal involvement and presence of distant metastases. However, these features alone fail to accurately predict outcomes. Tumor immune infiltration (sTILs) and distribution of immune cell subsets in the perip heral blood (NLR) have emerged as variables reported to be associated with outcomes in TNBC. We sought to evaluate whether NLR and sTILs provided independent prognostic information in TNBC. Methods: From a cohort of 9,982 women who underwent BC surgery at Mayo Clinic, Rochester, MN between Jan 1985 and Dec 2012, we identified 605 centrally-confirmed TNBC tumors. Patients (pts) with prior BC, bilateral BC, non-invasive disease, stage IV, neoadjuvant therapy, endocrine therapy, or adenoid cystic histology were excluded. For eligible tumors, clinical and pathologic variables were evaluated, including peripheral blood NLR and central assessment of sTILs per the 2014 International TILs Working Group recommendations. We calculated the Pearson correlation coefficient (PCC) between NLR and sTILs and constructed Cox Proportional Hazards Models to evaluate their association with invasive-disease free (IDFS) and overall survival (OS). NLR and sTILs were both analyzed as continuous variables. Results: Most pts had T1-2 (95%) and N0-1 disease (86%). Median OS follow-up was 10.6yrs. Median IDFS was 12yrs (95%CI 10.2-16.7) and median OS was 18.8yrs (95%CI 15.6-20.8). NLR and sTILs were available in 408 and 599 pts, respectively. The median NLR and sTIL content were 2.29 (0.14-10.50) and 20% (0-90%), respectively. NLR and sTILs were poorly correlated (PCC 0.0237). On univariate analysis (UVA), a higher NLR was associated with worse IDFS (HR 1.13; 95%CI 1.02-1.26, p=0.02) and OS (HR 1.17; 95%CI 1.04-1.31, p=0.01). Each 1% increment in sTILs was associated with improved IDFS (HR 0.99; 95%CI 0.98-0.99, p&lt;0.001) and OS (HR 0.99, 95%CI 0.98-1.00, p&lt;0.001). Among pts with high sTILs (≥20%), a higher NLR remained significantly associated with worse IDFS (HR 1.21; 95%CI 1.05-1.38, p=0.007) and OS (HR 1.25; 95%CI 1.09-1.44, p=0.001). In contrast, among pts with low sTILs (&lt;20%), NLR was not associated with IDFS (HR 1.07; 95%CI 0.89-1.28, p=0.49) or OS (HR 1.07; 95%CI 0.88-1.30, p=0.49). The interaction test between NLR and sTILs did not reach statistical significance. A multivariate analysis (MVA; including age, menopausal status, histologic subtype, grade, tumor size, nodal stage, Ki-67, NLR, sTILs, adjuvant chemotherapy, type of surgery and adjuvant radiation) showed that sTILs remained independently associated with IDFS (HR 0.99, 95%CI 0.97-1.0, p=0.019) and OS (HR 0.99, 95% CI 0.97-1.0, p=0.044), whereas NLR did not. Conclusions: A lower NLR and a higher sTIL content were each associated with improved IDFS and OS among pts with nonmetastatic TNBC on UVA. However, when evaluated on a MVA, only sTILs remained independently associated with IDFS and OS. Our data suggest that the effect of sTILs on outcomes may not be modified by the NLR. Citation Format: Leon-Ferre RA, Polley M-Y, Liu H, Gilbert J, Cafourek V, Hillman D, Negron V, Boughey JC, Liu MC, Ingle JN, Kalari K, Couch FJ, Visscher DW, Goetz MP. Prognostic value of the neutrophil-to-lymphocyte ratio (NLR) and its relation to stromal tumor infiltrating lymphocytes (sTILs) in triple negative breast cancer (TNBC) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-05-06.

Abstract Purpose: Triple negative breast cancer (TNBC) is an aggressive breast cancer subtype with substantial risks of disease recurrence. While cytotoxic chemotherapy is commonly administered and reduces recurrence, disease outcomes vary considerably and few prognostic tools are available for risk stratification for TNBC patients. We constructed and validated clinical calculators for invasive-disease free survival (IDFS) and overall survival (OS) for TNBC and compared their performance against AJCC-based models which include only tumor size and nodal status. Methods: From a surgical cohort of 9,982 patients who underwent breast cancer surgery at Mayo Clinic between January 1985 and December 2012, 605 centrally reviewed TNBC patients were identified and used to construct Cox models for IDFS and OS. Patients treated with neoadjuvant chemotherapy were excluded. Variables considered included age, menopausal status, tumor size, nodal status, Nottingham grade, type of breast surgery (mastectomy vs. lumpectomy), adjuvant radiation therapy, adjuvant chemotherapy, Ki67, stromal tumor infiltrating lymphocytes (sTILs), and neutrophil-to-lymphocyte ratio (NLR). Missing values were imputed using single imputation with all variables (including outcomes) included in the imputation model. Backward step-down procedure was used for model selections. The final models were internally validated for calibration and discrimination using bootstrapping methods and compared with AJCC-based models. Results: For both IDFS and OS, higher sTIL's, less extensive nodal involvement, use of adjuvant chemotherapy, and lower NLR were significant predictors of improved clinical outcomes. Premenopausal status and younger age were additionally predictive of improved IDFS and OS, respectively. Models for IDFS and OS have good calibration and are associated with bias-corrected C-indices of 0.68 and 0.71, respectively, as compared with C-indices of 0.59 and 0.62 for AJCC-based models. Conclusions: Our data indicate that a clinical calculator that includes sTIL's, NLR, menopausal status, age, nodal involvement as well as chemotherapy use can provide significantly greater prediction of clinical risk than tumor size and nodal status alone. These tools may be used to identify TNBC patients at elevated risk of disease relapse and to aid physician's communication with patients regarding their long-term disease outlook and planning treatment strategies. External validation is required to further evaluate broader applicability of this tool, which was developed utilizing a single-institutional experience. Citation Format: Polley M-YC, Leon-Ferre RA, Liu H, Gilbert J, Cafourek V, Hillman DW, Negron V, Boughey JC, Liu MC, Ingle JN, Kalari K, Couch F, Visscher DW, Goetz MP. Mayo clinic TNBC outcome calculator: A clinical calculator to predict disease relapse and survival in women with triple-negative breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-06-07.

Abstract Background: Mammography (digital 2D or digital 3D/tomosynthesis) is the cornerstone of current screening strategies for breast cancer, but new approaches are needed to further reduce the proportion of cancers diagnosed at advanced stages and more effectively identify those women in need of additional testing and biopsies. Circulating cell-free nucleic acids (cfNAs) shed from tumors, isolated from peripheral blood, and analyzed with ultra-deep and broad sequencing of cancer-associated genes, have great potential for early cancer detection. The ultimate goal is to develop blood cfNA cancer screening tests for use in conjunction with established risk factors and/or radiographic features for improved cancer detection. Development of these tests requires large, well-annotated cohorts of asymptomatic participants with adequate volumes of prediagnostic blood. The STRIVE Study cohort was recently established to train and validate cfNA-based tests for early detection of breast cancer. Eligibility criteria and trial design: The STRIVE Study is a new prospective, multi-ethnic mammography cohort that will recruit 120,000 subjects from 15+ US breast cancer screening centers (including Mayo Clinic and Sutter Health sites). Eligibility criteria require only that a participant has a scheduled routine screening mammogram at a participating center and has not received a biopsy prior to the research blood draw. Participants are recruited within 28 days of screening mammography (digital or tomosynthesis), consent electronically, provide blood samples, and complete an on-line risk factor questionnaire. Participants will be followed for all cancer diagnoses, cancer recurrences, and death for at least 5 years. Pertinent medical record information, imaging findings (including breast density), and follow-up data will be transferred electronically to a central database throughout the study period. Additional blood samples will be collected from participants with abnormal mammogram results, or who are diagnosed with cancer, to document and better understand the evolution of cfNA signals. Recruitment began in February 2017. Primary Aims: To train and validate a cfNA blood-based test to identify breast cancer overall in a cohort of women undergoing screening mammography. Statistical Methods: The study will be divided into a training phase (1/3 of participants) and an independent clinical validation phase (remaining 2/3 of participants). In the training phase, statistical machine learning techniques will be used to develop algorithms incorporating cfNA signals, clinical characteristics, or radiological features. In the validation phase, the prespecified locked algorithm developed from the training phase will be clinically validated in an independent group of women. Contact information for people with a specific interest in the trial: Additional details regarding the STRIVE Study are available on the ClinicalTrials.gov website (NCT03085888). For site-specific questions, please call 844-366-9738 for the Mayo Clinic and 1-855-578-7483 for Sutter Health. Citation Format: Liu MC, Cummings S, Vachon CM, Kerlikowske K, Couch FJ, Morris EA, Olson JE, Polley EC, Conners AL, Ellis RL, Patel B, Maimone IV S, Zhang N, Hamilton S, Clarke CA, Allen BA, Maddala T, Hartman A-R. Development of cell-free nucleic acid-based tests for early detection of breast cancer: The STRIVE study [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT3-02-01.