Citations

Abstract Introduction: The utilization of self reported chemotherapy treatment data is common in epidemiologic research but there is little understanding of its accuracy and limitations. Methods: The Mayo Clinic Breast Disease Registry (MCBDR) has over 9,600 participants enrolled within one year of a first breast cancer diagnosis. Participants receive annual follow up surveys through the mail to capture data on breast cancer treatments and outcomes. We compared nurse abstracted medical record chemotherapy data to self reported chemotherapy data from women diagnosed with stage 0 to 3 breast cancer that completed five consecutive annual follow up surveys. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) statistics were assessed for the report of broad chemotherapy receipt (yes, no, DK) within each yearly survey compared to the gold standard medical record data. To assess the accuracy of the self reported use of specific chemotherapy regimens, a sub cohort known as the “congruent sub cohort” was created for each survey year that included subjects that agreed with the nurse abstractors report of their broad chemotherapy usage. Sensitivity, specificity, PPV, NPV, and concordance statistics were calculated for the congruent sub cohorts followed by an assessment of the proportion of subjects providing correct responses for all chemotherapy regimens queried compared to those that had at least one discrepancy with the nurse abstracted data and the proportion of subjects with 0, 1, 2 and 3 or more discrepancies within each survey year. Results: For the 430 survey respondents, the average age was 59.5 years (SD 11.7) with a range of 29 to 94. The mean time between diagnosis and the year 1 follow up survey was 13.5 months, with an average of 61.2 months between diagnosis and the year 5 survey. The respondents were 97% white, 100% female, and 53.5% had a bachelor’s degree or higher. The self-reported receipt of chemotherapy had substantial agreement across all 5 follow up surveys with the nurse abstracted treatment data from the medical record with kappa values ranging from 0.70 (0.63 to 0.76) to 0.64 (0.57 to 0.71). For subjects in the congruent sub cohort (N=125, 120, 122, 121, and 121 subjects across the 5 survey years, respectively), self reported use of specific chemotherapy regimens were reported with an average concordance of 90% across the 5 annual surveys, however only 23% had perfect agreement with nurse abstracted data. The average number of discrepant responses provided by subjects was 1.2, with at least 12% of subjects reporting 3 or more erroneous responses for the specific chemotherapy regimens each survey year. Discussion: This study supports previous findings that self-reported chemotherapy usage may be utilized when resources are unavailable for medical record abstraction, but may have less utility when analyzing specific chemotherapy regimens. Citation Format: Nicole L. Larson, Kathryn J. Ruddy, Feven Abraha, Denise M. Herman, Fergus J. Couch, Janet E. Olson. Accuracy of self reported chemotherapy usage in annual follow up surveys for a breast cancer registry [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 748.

Abstract Two recent studies have defined population-based risk of breast cancer (BC) due to pathogenic variants (PVs) in well-established BC susceptibility genes. Prior studies in high-risk BC cohorts identified variable BC risks based on the position and type of mutation in BRCA1 and BRCA2, and based on the type of mutation in ATM, CHEK2, and PALB2. Whether this variability holds true in the general population has not been evaluated. To determine the BC risks associated with mutations of different types and in different locations in BC susceptibility genes in the general population, we carried out case-control analyses of 32247 cases and 32544 controls in the CARRIERS study, including 12 US population-based studies, and case-control analyses, subset to mutation carriers. We used age-adjusted logistic regression to estimate odds ratios (OR), relative OR (rOR), and 95% confidence intervals (CI) for PVs in BRCA1, BRCA2, ATM, CHEK2, and PALB2. ORs were estimated using the full population of mutation carriers and noncarriers while rORs were estimated within subsets of individual gene mutation carriers. We identified 273 BRCA1, 421 BRCA2, 253 ATM, 351 CHEK2, and 148 PALB2 in women with BC and 35 BRCA1, 84 BRCA2, 139 ATM, 139 CHEK2, and 38 PALB2 variant carriers in those without BC. For BRCA1, we did not find differences in risk by mutation type or location. However, variants leading to nonsense mediated decay (NMD) predicted to have re-initiation at p.M128 had a non-statistical 3-fold higher risk for BC compared to those leading to NMD without re-initiation (rOR 3.1, 0.99-13.52, p = 0.0826). BRCA2 loss of function (LoF) mutations in exons 1-10 had a higher BC risk compared to LoF mutations in the exon 11 (rOR 2.7, 1.1-7.9, p=0.048) ovarian cancer cluster region (OCCR). We did not detect any differences in risk by mutation type or location in ATM, CHEK2, or PALB2. CHEK2 missense variants p.I157T (rOR 0.5, 0.4-0.7, p <0.001) and p.T476M (rOR 0.5, 0.3 - 0.8, p=0.005) were associated with lower BC risk relative to CHEK2 c.1100delC (OR 2.5, 2.0-3.3, p<0.001). The CHEK2 c.444+1G>A splicing variant was associated with highest BC risk among common CHEK2 variants (OR 4.2, 1.9-10.5, p<0.001), but was not statistically significantly different from c.1100delC (rOR 1.7, 0.8-4.3, p=0.230). In summary, we identified a higher BC risk for LoF variants in BRCA2, lower risk for CHEK2 missense mutations, and non-statistical higher risk for NMD/re-initiation BRCA1 variants and CHEK2 c.444+1G>A in this population-based study. Despite the large numbers included in the overall CARRIERS study, the number of PV carriers was relatively small, which may have limited the detection of associations. Nonetheless, we were able to detect genotype-risk associations that have implications for counseling women about their BC risk, and certainly for the development of individualized risks. Citation Format: Mwangala P. Akamandisa, Nicholas Boddicker, Chunling Hu, Siddhartha Yadav, Jeffrey N. Weitzel, Peter Kraft, Susan M. Domchek, Fergus J. Couch, Katherine L. Nathanson, for the CARRIERS Consortium . Mutation type and location in breast cancer susceptibility genes are associated with differential risk in the general population [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1183.

Abstract Purpose: Young women’s breast cancers (YBCs), defined herein as breast cancer (BC) diagnosed at age ≤ 40 years, are etiologically and biologically distinct from postmenopausal BCs, demonstrating a higher proportion of estrogen receptor (ER) negative subtypes and a worse prognosis. Studies have not assessed whether risk factors such as recent parity and body mass index (BMI) are linked to protein expression profiles in YBCs. Accordingly, we examined protein expression assessed with GeoMx® Digital Spatial Profiling (DSP) in 640 YBCs prepared as tissue microarrays (TMAs) in the Young Women’s BC Study (YWBCS). Methods: The YWBCS is a multi-institutional cohort of 1,297 women with incident BC diagnosed at age <40 years identified through medical record review, with risk factor data collected via questionnaires. TMAs including 1,505 cores of 640 YBCs that were collected prior to therapy and were suitable for molecular analysis were evaluated for 72 markers with NanoString GeoMx DSP. Associations of log-transformed biomarker expression with BMI and time from last live birth to BC diagnosis were carried out using linear mixed modeling approaches, accounting for multiple tumor tissue cores per individual. Results: Mean age at BC was 35.5 years (range 17-40). Tumor subtypes based on clinical immunostaining were the following: luminal B 46%; luminal A 36%; triple negative 12% and HER2+ 6%. Of 72 biomarkers tested, 53 (74%) were evaluable after QC and normalization. GeoMx ER and PR protein levels were higher in luminal A and luminal B YBCs than in HER2+ and TNBC (p=2x10-94 and 2x10-52, respectively), supporting the accuracy of the GeoMx assay. Compared to nulliparas or those with most recent birth > 3 years before BC, those who gave birth ≤ 3 years prior to BC had tumors with higher expression of PR (8x10-6) and ER (p=0.006), and lower expression of BCL-2 (p=0.006). In contrast, women with last birth ≥ 6 years prior to BC had higher expression of CD8 (p=0.006) and PD-1 (p=0.001) than nulliparas and those with more recent births. Compared to women with BMI between 18.5 and 29.9, those with higher or lower BMIs had higher expression of CD34 (p=0.0003), CD4 (p=0.0009) and CD14 (p=0.001). BCL-2 expression was higher among women with BMI < 18.5 compared to those with higher values (p=0.005). Women with BMI of 30+ had higher β2-microglobulin levels than those with lower BMIs (p=0.003). Inverse dose-response associations (with higher BMI related to lower levels) were observed for expression of ER (p=0.01), pan cytokeratin (p=0.004) and four proteins in the p13K/AKT signaling pathway (p ≤ 0.01 for each). Conclusions: Preliminarily, we identify differences in hormonal and immune markers in YBCs in relation to timing of births and BMI, suggesting that these factors may contribute to etiologic heterogeneity. Multivariate modeling is ongoing to incorporate molecular subtype and other risk factors. Citation Format: Robert A. Vierkant, Laura M. Pacheco-Spann, Stacey J. Winham, Jennifer M. Kachergus, Ji Shi, Craig Snow, Fergus J. Couch, Janet E. Olson, Chen Wang, Derek C. Radisky, Amy C. Degnim, E. Aubrey Thompson, Laura C. Collins, Kathryn J. Ruddy, Ann H. Partridge, Mark E. Sherman. Associations of parity and body mass index with NanoString digital spatial protein profiling in early onset breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1000.

AbstractBackgroundMechanical accuracy should be verified before implementing a proton stereotactic radiosurgery (SRS) program. Linear accelerator (Linac)‐based SRS systems often use electronic portal imaging devices (EPIDs) to verify beam isocentricity. Because proton therapy systems do not have EPID, beam isocentricity tests of proton SRS may still rely on films, which are not efficient.PurposeTo validate that our proton SRS system meets mechanical precision requirements and to present an efficient method to evaluate the couch and gantry's rotational isocentricity for our proton SRS system.MethodsA dedicated applicator to hold brass aperture for proton SRS system was designed. The mechanical precision of the system was tested using a metal ball and film for 11 combinations of gantry and couch angles. A more efficient quality assurance (QA) procedure was developed, which used a scintillator device to replace the film. The couch rotational isocentricity tests were performed using orthogonal kV x‐rays with the couch rotated isocentrically to five positions (0°, 315°, 270°, 225°, and 180°). At each couch position, the distance between the metal ball in kV images and the imaging isocenter was measured. The gantry isocentricity tests were performed using a cone‐shaped scintillator and proton beams at five gantry angles (0°, 45°, 90°, 135°, and 180°), and the isocenter position and the distance of each beam path to the isocenter were obtained. Daily QA procedure was performed for 1 month to test the robustness and reproducibility of the procedure.ResultsThe gantry and couch rotational isocentricity exhibited sub‐mm precision, with most measurements within ±0.5 mm. The 1‐month QA results showed that the procedure was robust and highly reproducible to within ±0.2 mm. The gantry isocentricity test using the cone‐shaped scintillator was accurate and sensitive to variations of ±0.2 mm. The QA procedure was efficient enough to be completed within 30 min. The 1‐month isocentricity position variations were within 0.5 mm, which demonstrating that the overall proton SRS system was stable and precise.ConclusionThe proton SRS Winston–Lutz QA procedure using a cone‐shaped scintillator was efficient and robust. We were able to verify radiation delivery could be performed with sub‐mm mechanical precision.

Abstract Purpose: Triple-negative invasive lobular carcinoma (TN-ILC) of breast cancer is a rare disease and the clinical outcomes and prognostic factors are not well-defined. Methods: Women with stage I-III TN-ILC or triple-negative invasive ductal carcinoma (TN-IDC) of the breast undergoing mastectomy or breast-conserving surgery between 2010 and 2018 in the National Cancer Database were included. Kaplan-Meier curves and multivariate Cox proportional hazard regression were used to compare overall survival (OS) and evaluate prognostic factors. Multivariate logistic regression was performed to analyze the factors associated with pathological response to neoadjuvant chemotherapy. Results: The median age at diagnosis for women with TN-ILC was 67 years compared to 58 years in TN-IDC (p<0.001). There was no significant difference in the OS between TN-ILC and TN-IDC in multivariate analysis (HR 0.96, p=0.44). Black race and higher TNM stage were associated with worse OS, whereas receipt of chemotherapy or radiation was associated with better OS in TN-ILC. Among women with TN-ILC receiving neoadjuvant chemotherapy, the 5-year OS was 77.3% in women with a complete pathological response (pCR) compared to 39.8% in women without any response. The odds of achieving pCR following neoadjuvant chemotherapy were significantly lower in women with TN-ILC compared to TN-IDC (OR 0.53, p<0.001). Conclusion: Women with TN-ILC are older at diagnosis but have similar OS compared to TN-IDC after adjusting for tumor and demographic characteristics. Administration of chemotherapy was associated with improved OS in TN-ILC, but women with TN-ILC were less likely to achieve complete response to neoadjuvant therapy compared to TN-IDC.

Purpose: To present 5 cases of alemtuzumab-induced thyroid eye disease (AI-TED) and review the literature to highlight the natural history, severity, and outcomes as compared with conventional thyroid eye disease (TED). Methods: A multi-institutional retrospective case series of patients with AI-TED was compiled. Chart review evaluated for clinical characteristics, imaging findings, and treatment for AI-TED. Additionally, a comprehensive review of the literature identified all previously published cases of AI-TED. Results: Five new patients with AI-TED were included in this series. The average clinical activity score on presentation was 2.8 (range 1–4) and reached an average peak of 5.0 during the active phase of the disease (4–7). Patients were treated medically with selenium (40%) or monoclonal antibodies including teprotumumab or tocilizumab (40%). Surgical treatment with orbital decompression for compressive optic neuropathy was performed on 2 (40%) patients. Combined with 11 previously reported cases, these 16 patients with AI-TED had an average clinical activity score on presentation of 3.3. The average length of the AI-TED phase was 14.0 months, and all patients were treated with medical and/or surgical interventions for their disease. Conclusions: Clinical and imaging findings in AI-TED mirror that of conventional TED, however, AI-TED may present with greater severity. AI-TED may develop many months after Graves’ disease; therefore, providers should be aware of this association and monitor patients for the development of severe TED.

Abstract Background: Two poly (adenosine diphosphate-ribose) polymerase inhibitors (PARPi) are currently FDA-approved for the treatment of HER2-negative metastatic breast cancer (MBC) in carriers of germline pathogenic variants (PVs) in BRCA1 or BRCA2 (BRCA1/2). This study explores the clinical outcomes of MBC patients treated with a PARPi. Methods: In this retrospective study, we included MBC patients treated with a PARPi between January 2017 and February 2022 at Mayo Clinic (Minnesota, Arizona, Florida, and Mayo Clinic Health Systems). We used the Kaplan Meier method to estimate the time-to-treatment-failure (TTF) and the log-rank test to compare different subsets. In addition, predictors of TTF were identified in a multivariate cox-proportional hazard regression model, including age at PARPi initiation, race, ethnicity, histology, estrogen receptor (ER), progesterone receptor (PR), and HER2 expression of the tumor, the number of prior therapies, type of PARPi, and PV carrier status (germline BRCA1/2 or PALB2 vs. somatic BRCA1/2 vs. other). Results: Sixty-five patients treated with PARPi (olaparib: 51; talazoparib: 14) were included in the final analysis. Fifty-five patients were carriers of germline PVs in BRCA1 (n=24, 37%), BRCA2 (n=27, 42%) or PALB2 (n=4, 6%), whereas ten patients (15%) had no germline PVs but the tumor had a somatic mutation in the homologous recombination-related (HRR) genes (7 in BRCA1/2, 2 in ATM, and 1 in CDKN2A and CDH1). At the data cutoff, 48 (74%) patients had discontinued PARPi due to progression or death. Fifteen (23%) patients required a dose reduction due to side effects. Occurrence of grade ≥ 3 side effects: anemia in 8, fatigue in 4, neutropenia in 2, and thrombocytopenia in 2 patients. Eight (15.7%) patients in the olaparib group and seven (50%) patients in the talazoparib group required a dose reduction for side effects. No patient on olaparib required drug discontinuation due to side effects, whereas two patients on talazoparib were switched to olaparib due to cytopenias and could tolerate olaparib. Median TTF in the overall population was 8 months (95% confidence interval [CI]: 6.4 – 9.6), and there was no difference (p=0.64) in TTF between the olaparib and talazoparib groups. Median TTF in the germline BRCA1, BRCA2, and PALB2 PV carriers were 7, 8, and 11 months, respectively (p=0.57). Among patients with somatic BRCA1/2 mutations, the median TTF was 4 months. Numerically, patients with HER2-positive tumors (n=8) had a shorter TTF compared to HER2-negative tumors (Median TTF: 4 vs. 8 months, p=0.098). No significant difference in TTF was observed by ER or PR status of the tumor, age at initiation of PARPi, the number of prior therapies, and prior use of platinum-based chemotherapy or CDK4/6 inhibitors. In multivariate analysis, HER2 positivity (hazard ratio [HR]: 8.0, 95% CI: 2.2 – 29.4, p=0.002), somatic BRCA1/2 mutations (HR: 7.6, 95% CI: 1.2 – 50.0, p=0.03) and somatic mutations in other HRR genes (HR: 19.1, 95% CI: 3.1 – 118.6, p=0.002) were associated with worse TTF. Conclusions: In the real world, PARPi were well-tolerated with promising time-to-treatment-failure (TTF) benefits comparable to data from clinical trials. Notably, relatively shorter TTF was observed in patients with somatic BRCA1/2 and other HRR gene mutations and HER2-positive MBC. These findings improve our understanding of the role of PARPi in MBC and will help to guide treatment decisions with PARPi in the clinical setting. Citation Format: Nusrat Jahan, Jodi Taraba, Karthik V. Giridhar, Roberto A. Leon-Ferre, Amye J. Tevaarwerk, Elizabeth Cathcart-Rake, Ciara C. O’Sullivan, Prema Peethambaram, Timothy J. Hobday, Kathryn Ruddy, Lida A. Mina, Pooja Advani, Felipe Batalini, Matthew P. Goetz, Tufia C. Haddad, Fergus J. Couch, Siddhartha Yadav. Clinical outcomes of metastatic breast cancer patients treated with poly (adenosine diphosphate-ribose) polymerase inhibitors (PARPi): the Mayo Clinic experience [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-01-22.

Abstract Background: The high-level aims of the Advocate-BREAST study are to study and improve the overall experience of patients with breast cancer (BC) through education, shared decision making, and patient-centered clinical trials. Assessing areas of unmet need in care delivery and research as identified by patients with BC will direct future research and help us improve the patient experience. Methods: In April 2022, an electronic RedCap survey was circulated to 6,918 BC survivors (stage 0-4 disease) enrolled in the prospectively consented Mayo Clinic Breast Disease Registry (MCBDR), which includes rural-dwelling women often underrepresented in cancer care delivery research. The questionnaire asked about satisfaction with multiple aspects of cancer care delivery and the education and support patients receive(d) regarding practical, financial, emotional, societal and spiritual concerns linked to BC. Patients were also asked to rank potential Quality Improvement (QI) projects in order of the likelihood the proposal could improve quality of life for BC patients and their families. Questions regarding clinical trial participation, use of integrative medicine and perspectives on medical second opinions were also included. Responses were collected via anonymous local language questionnaires. Results: The survey received 2,451 responses from MCBDR enrollees. 13% of respondents had Ductal Carcinoma in Situ (DCIS), 83% had early breast cancer (EBC) (Stage 1-3) and 4% had metastatic breast cancer (MBC). Mean age was 64 (SD 11.9), and mean time in months since diagnosis was 93 (SD 1.42). 69.3 % of patients received all care at Mayo Clinic; 24.7% at Mayo and another healthcare organization, and 6% at a non-Mayo site. Although the overall experience of care was generally good/excellent (&gt; 90 %), gaps were perceived in terms of information provision, continuity of care (including survivorship care after 5 years), navigating care transitions, and timely access to mental health resources. The main severe symptoms patients recalled in year 1 were hair loss, eyebrow/eyelash thinning, hot flashes, sexual dysfunction and cognitive issues. The main concerns patients recalled in the first year following diagnosis were fear of BC recurrence and spread as well as of dying, practical and emotional concerns for family members if they were to die of BC, and their emotional health. Patients were most dissatisfied with information and support related to management of lymphedema, sexual dysfunction, eyebrow/eyelash thinning, and peripheral neuropathy. Respondents overwhelmingly voiced the need for the following QI projects: i) lifetime access to online patient educational resources: including summary “cheat sheets”; ii) educational, practical, emotional and holistic support programs for MBC patients, and iii) BC Wellness Programs for EBC and MBC patients (endorsed by 82.6%; 82.4% and 81.9% of respondents, respectively). Predictors in terms of age, time since diagnosis, and cancer stage that may account for satisfaction with care, concerns, or QI preferences will be reported at the meeting. Of 20% of patients who saw an Integrative Medicine provider, 85% were satisfied/very satisfied with the care received. Of ~40% of patients who received a second opinion regarding their BC diagnosis and treatment plan, 96% found this beneficial. 47% of respondents had participated in a clinical trial, which is higher than seen in the general population such that conclusions may not be generalizable. Of those who had not participated in a study, 30% reported that they were unsure if they would participate in a trial if offered, and 9% reported that they would decline same. Conclusion: Understanding the lived experiences of persons with BC is essential to improve quality of care. Patients with early and advanced BC desire holistic care, continuity of care, concise educational resources and early psychological support. Citation Format: Kathryn Ruddy, Ciara C. O’Sullivan, Nicole Larson, Robert A. Vierkant, Mary Lou Smith, Cynthia Chauhan, Fergus J. Couch, Janet Olson. Advocate-BREAST: Advocates and Patients’ Advice to Enhance Breast Cancer Care Delivery, Patient Experience and Patient Centered Research by 2025 [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-05-41.

Abstract Objective: Aberrantly methylated DNA may be used to detect minimal residual disease or early recurrence in breast cancer. As a 1st step, we aimed to develop an MDM panel to delineate between healthy women, stage I-III breast cancer in remission with no evidence of disease (NED), and metastatic breast cancer (MBC). Methods: We prospectively enrolled patients into 3 groups: healthy controls (adult females with a normal mammogram in past 12 months with no history of breast cancer), NED [stage I-III breast cancer with no clinical evidence of recurrence 6 months - 3 years post-treatment (adjuvant endocrine therapy allowed)], and MBC (collected either at initial diagnosis of untreated metastatic disease or radiographic progression). DNA was extracted from 6 mL of plasma derived from blood collected in LBgard tubes (Exact Sciences Corp., San Diego CA), and was bisulfite-treated and assayed by target enrichment long-probe quantitative amplified signal (TELQASTM) method for a panel of 15 previously identified MDMs [Table], normalized by the control gene, B3GALT6. Areas under the receiver operating characteristic curve (AUC) were calculated for each MDM to assess discrimination of MBC from other groups. With 60 patients per group, we had greater than 80% power to detect a difference of 0.20 from the null AUC of 0.7. Results: We tested samples from 60 MBC (10 untreated, 50 recurrent), 60 NED, and 60 healthy women. The median age was 63 (IQR, 55-72) and was not different between groups. The NED group was all hormone-receptor (HR) positive, with 47 (78%) being human epidermal growth factor receptor 2 negative (HER2-) and 13 (22%) HER2+; 48 (80%) were stage I and 9 (15%) were N+. The MBC group had 35 (58%) patients with HR+/HER2- tumors, 11 (18%) HR+/HER2+, and 6 (10%) HR-/HER2-, 4 (7%) HR-/HER2+, with 4 (7%) unknown. Of the 41 MBC whose original stage and nodal status were known 9 (22%) were stage I and 22 (54%) were N+. The markers were able to discriminate between MBC and NED patient samples with AUCs from 0.97 to 0.72. AUCs for 10/15 MDMs (ITPRIPL1, EMX1, C17orf64, OSR2, TRIM67, CHST2, IFFO1, TRH, FAM59B, and MPZ) were &gt;0.90. No difference in MDMs was observed between the healthy and NED groups. Conclusions: MDMs, assayed from plasma, appear highly discriminant for metastatic breast cancer cases in comparison to control patients with NED or healthy controls. Further clinical validation of this MDM panel in a larger cohort is warranted. Table 1. Plasma MDM discrimination of metastatic breast cancer (MBC) from healthy controls and previously treated breast cancer patients with no evidence of disease (NED) Citation Format: Karthik V. Giridhar, Fergus J. Couch, Jason P. Sinnwell, Seth W. Slettedahl, William R. Taylor, Douglas W. Mahoney, Patrick H. Foote, Maria C. O’Connell, Mariah J. Robran, Mary E. Devens, Anna M. Gonser, Nicole Larson, Karen A. Doering, Kelli N. Burger, Michael Kaiser, Hatim Allawi, Kathryn Ruddy, Janet Olson, John B. Kisiel. Plasma assay of methylated DNA markers (MDM) detects patients with metastatic breast cancer (MBC) compared to healthy controls and treated breast cancer patients with no evidence of disease [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-11-06.

Abstract PURPOSE To examine incremental values of estrogen receptor (ER) status, body mass index (BMI), menopausal status, and a previously reported multi-gene classifier over commonly used clinical factors (i.e. age, tumor grade, comedonecrosis, surgical margins, and treatment) in predicting risk of any ipsilateral recurrence (IR) event within five years after DCIS diagnosis. METHODS A derivation cohort consisted of participants in the Translational Breast Cancer Research Consortium (TBCRC) 038, a retrospective multicenter cohort study in women undergoing surgical resection for DCIS between 01/01/1998 and 02/29/2016 (n=216). The validation cohort, the Repository of Archival Human Breast Tissue (RAHBT) at Washington University School of Medicine, provided cases meeting the same eligibility criteria as TBCRC038 (n=97). Participants in both cohorts had RNA-seq data and either developed IR 1-5y after initial DCIS diagnosis or were free from subsequent breast events for at least five years. The previously reported 812-gene classifier had been developed from a subset of the TBCRC038 samples using a negative-binomial regression model to identify differentially expressed genes in the primary tumor associated with subsequent recurrence events. This classifier has been shown to be highly correlated with 5-year invasive, DCIS, and all breast cancer events, and validated in the RAHBT cohort. Cox proportional hazards regression was used to estimate hazard ratios (HRs) of IR in the TBCRC038 cohort (76 with IR). The clinical score was developed using clinical predictors (aforementioned clinical factors and ER) and their regression coefficients from the model with the maximum predictive accuracy (e.g. c-index) and the minimum number of predictors; the summary score integrated the clinical score and multi-gene classifier. Predictive performance of both clinical and summary scores was validated in the RAHBT cohort (20 with IR). RESULTS In the TBCRC cohort derivation set, we used a multivariable model based on clinical factors alone (clinical score) and found that ER status, but not BMI or menopausal status, was independently associated with a higher IR risk (HR=2.06, 95% CI 1.18-3.58). Adding the multi-gene classifier to the clinical factors-based model (summary score) in the TBCRC038 test set increased predictive accuracy (c-index 0.68 to 0.70), with the genomic classifier-adjusted HR of 14.96 (95% CI 8.64-25.91). The summary score had higher predictive performance for IR risk than clinical score alone (c-index 0.82 vs. 0.70). In the RAHBT validation samples, model performance was similarly improved using summary scores clinical factors-based model plus multigene classifier as compared to clinical scores along (c-index 0.74 vs. 0.58). CONCLUSION Combining clinical factors and a multigene classifier provided more accurate risk estimates of IR within five years after excision of DCIS than clinical factors alone. Figure 1. Observed and predicted recurrence-free survival in the first five years after initial DCIS diagnosis in the RAHBT validation cohort, by risk groups defined by clinical scores (left) and clinical score plus multigene classifier (right). Citation Format: Ying Liu, Siri H. Strand, Lorraine King, Bryan Harmon, Fergus J. Couch, Kristalyn Gallagher, Mark Kilgore, Shi Wei, Angela DeMichele, Tari King, Priscilla F. McAuliffe, Jeffrey Marks, Carlo Maley, Robert West, E Shelley Hwang, Graham A. Colditz. Using clinical characteristics and molecular markers to predict the risk of subsequent ipsilateral breast events after excision of DCIS [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-07-02.