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Background: The Oncotype 21-gene Recurrence Score (RS) is the most commonly ordered genomic biomarker used to inform decisions on adjuvant chemotherapy for patients with estrogen receptor (ER)-positive, HER2-negative early breast cancer. Representation of racial/ethnic minority patients in the population used to develop the assay was poor, with only 5% of study participants identified as Black. This raises concern about the accuracy of the RS in underrepresented populations. In earlier work (Hoskins et al, JAMA Oncology 2021), we showed that the RS has less prognostic accuracy in Black compared with non-Hispanic White (NHW) women. This finding is concerning in light of persistent racial disparities in breast cancer mortality. Here we examine the predictive accuracy of the RS according to race/ethnicity for identifying patients with ER+, axillary node-negative breast cancer who benefit from adjuvant chemotherapy.Methods: We conducted a large, population-based retrospective cohort study of women 18+ years diagnosed with ER+, axillary node-negative breast cancer from 2004 to 2010 using Surveillance, Epidemiology and End Results Oncotype DX Database (2004-2015). This analysis included women with a minimum of 7 yrs follow-up and an RS of 11-25, since this is the group with the most uncertainty regarding the benefit of chemotherapy. Demographic and clinical characteristics were collected from cancer registry data. Propensity score weighted Cox models determined the association between chemotherapy use and breast cancer death. Age, insurance status, tumor grade, tumor size, progesterone receptor status, and RS were included as predictors of the propensity score. Associations between chemotherapy use and breast cancer death were determined using overall, race/ethnicity, and age stratum-specific hazard ratios (HR) and 95% confidence intervals (CI). Results: The analysis included 22,693 NHW, 5,657 Black, and 3,348 Hispanic women. The overall result is consistent with the prospective TAILORx trial, showing greater benefit from chemotherapy in women under age 50. There is a greater reduction in the hazard of breast cancer death associated with chemotherapy use for Black (HR 0.31, 95% CI, 0.15, 0.66) and Hispanic (HR 0.07, 95% CI, 0.02, 0.31) compared with NHW women under age 50 (HR 0.43, 95% CI,0.32, 0.59). In models combining Black and NHW patients, an interaction term for race*chemotherapy was significant (p=0.022), indicating a differential association between chemotherapy use and breast cancer death according to race/ethnicity. Visual comparison of breast cancer mortality curves that plot 7-year breast cancer death rate as a function of the continuous RS, stratified by chemotherapy administration (yes/no), shows that the curves begin to diverge at a lower RS for Black (RS 17) compared with NHW women (RS 24). Conclusions: This observational study found that Black women under age 50 with ER+, axillary node-negative breast cancer and an RS of 11-25 derive significantly more benefit from adjuvant chemotherapy than NHW women. National practice guidelines do not recommend routine use of adjuvant chemotherapy for patients in this risk category, indicating that many Black patients may be undertreated. Results need to be confirmed in prospective studies, but they suggest that RS cut-offs used to recommend adjuvant chemotherapy may need to be modified for racial/ethnic minority women. Hazard of Breast Cancer Death (95% Confidence Interval)Race/EthnicityChemotherapyAll AgesAge < 50Age 50+OverallYes0.71 (0.63, 0.81)0.32 (0.25, 0.41)1.01 (0.87, 1.18)NoRefRefRefNHWYes0.73 (0.62,0.84)0.43 (0.32, 0.59)0.87 (0.74, 1.04)NoRefRefRefBlackYes0.83 (0.60, 1.16)0.31 (0.15, 0.66)1.26 (0.84, 1.89)NoRefRefRefHispanicYes0.33 (0.20, 0.57)0.07 (0.02, 0.31)0.61 (0.33, 1.12)NoRefRefRef Citation Format: Hsiao- Ching Huang, Gregory S. Calip, Jennifer Weiss, Yael Simons, V.K. Gadi, Oana C. Danciu, Garth H. Rauscher, Kent F. Hoskins. Racial/ethnic differences in the benefit of adjuvant chemotherapy for breast cancer patients with an intermediate risk 21-gene recurrence score [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 P3-14-02.

Objective Approximately 24–68% of breast cancer survivors report co-occurring psychoneurological symptoms of pain, fatigue, sleep disturbance, depression, and anxiety during and after cancer treatment. This study aimed to assess the feasibility and acceptability of acupuncture for the treatment of multiple psychoneurological symptoms among breast cancer survivors and explore metabolomic changes before and after acupuncture. Methods We conducted a single-arm, prospective pilot study of breast cancer survivors with at least two moderate to severe psychoneurological symptoms (>3 on a 0–10 scale). Acupuncture was administered twice weekly for 5 weeks, for 30 minutes per session. Along with Patient-Reported Outcomes Measurement Information System (PROMIS) questionnaires, a fasting serum comprehensive hydrophilic metabolites panel was analyzed at baseline and after acupuncture. Results Eight participants (mean age 52.5 ± 10.9 years; 62.5% Black) were enrolled. Feasibility was supported, with 67% recruitment, 87.5% retention, and 98% acceptability. Post intervention, PROMIS T-scores were reduced for all psychoneurological symptoms. Significant differences in serum metabolites before and after acupuncture were F-1,6/2,6-DP, glutathione disulfide, phosphorylcholine, 6-methylnicotinamide, glutathione, and putrescine (variable importance of projection values larger than 1.5 and p values Conclusions Acupuncture to reduce multiple psychoneurological symptoms among breast cancer survivors was feasible and acceptable. Study findings also shed light on the metabolic pathways involved in the acupuncture response and will be tested in future studies.

ImportanceBlack women with hormone receptor–positive breast cancer experience the greatest racial disparity in survival of all breast cancer subtypes. The relative contributions of social determinants of health and tumor biology to this disparity are uncertain.ObjectiveTo determine the proportion of the Black-White disparity in breast cancer survival from estrogen receptor (ER)-positive, axillary node-negative breast cancer that is associated with adverse social determinants and high-risk tumor biology.Design, Setting, and ParticipantsA retrospective mediation analysis of factors associated with the racial disparity in breast cancer death for cases diagnosed between 2004 and 2015 with follow-up through 2016 was carried out using the Surveillance, Epidemiology, and End Results (SEER) Oncotype registry. The study included women in the SEER-18 registry who were aged 18 years or older at diagnosis of a first primary invasive breast cancer tumor that was axillary node-negative and ER-positive, who were Black (Black), non-Hispanic White (White), and for whom the 21-gene breast recurrence score was available. Data analysis took place between March 4, 2021, and November 15, 2022.ExposuresCensus tract socioeconomic disadvantage, insurance status, tumor characteristics including the recurrence score, and treatment variables.Main Outcomes and MeasuresDeath due to breast cancer.ResultsThe analysis with 60 137 women (mean [IQR] age 58.1 [50-66] years) included 5648 (9.4%) Black women and 54 489 (90.6%) White women. With a median (IQR) follow-up time of 56 (32-86) months, the age-adjusted hazard ratio (HR) for breast cancer death among Black compared with White women was 1.82 (95% CI, 1.51-2.20). Neighborhood disadvantage and insurance status together mediated 19% of the disparity (mediated HR, 1.62; 95% CI, 1.31-2.00; P P P P = .02).Conclusions and RelevanceIn this study, racial differences in social determinants of health and indicators of aggressive tumor biology including a genomic biomarker were equally associated with the survival disparity in early-stage, ER-positive breast cancer among US women. Future research should examine more comprehensive measures of socioecological disadvantage, molecular mechanisms underlying aggressive tumor biology among Black women, and the role of ancestry-related genetic variants.

Among breast cancer survivors, pain, fatigue, depression, anxiety, and sleep disturbance are common psychoneurological symptoms that cluster together. Inflammation-induced activation of the tryptophan-kynurenine metabolomic pathway may play an important role in these symptoms.This study investigated the relationship between the metabolites involved in the tryptophan-kynurenine pathway and psychoneurological symptoms among breast cancer survivors.Cross-sectional study.Participants were recruited at the oncology clinic at the University of Illinois HospitalHealth Sciences System.79 breast cancer survivors after major cancer treatment.We assessed psychoneurological symptoms with the PROMIS-29 and collected metabolites from fasting blood among breast cancer survivors after major cancer treatment, then analyzed four major metabolites involved in the tryptophankynurenine pathway (tryptophan, kynurenine, kynurenic acid, and quinolinic acid). Latent profile analysis identified subgroups based on the five psychoneurological symptoms. Mann-Whitney U tests and multivariable logistic regression compared targeted metabolites between subgroups.We identified two distinct symptom subgroups (low, 81%; high, 19%). Compared with participants in the low symptom subgroup, patients in the high symptom subgroup had higher BMI (p = .024) and were currently using antidepressants (p = .008). Using multivariable analysis, lower tryptophan levels (p = .019) and higher kynurenine/tryptophan ratio (p = .028) were associated with increased risk of being in the high symptom subgroup after adjusting for BMI and antidepressant status.The tryptophan-kynurenine pathway and impaired tryptophan availability may contribute to the development of psychoneurological symptoms.

Background: A CDK4/6 inhibitor (CDK4/6i) in combination with endocrine therapy (ET) is standard first-line therapy for advanced, hormone receptor (HR)-positive, HER2-negative breast cancer (BC). However, not all patients respond and responders eventually develop drug resistance and disease progression. Exosomes are small extracellular vesicles that are secreted by both normal and tumor cells as a mechanism for intercellular communication. The protein cargo of exosomes reflects biological processes activated in cancer cells and may serve as predictive biomarkers to select patients most likely to benefit from treatment and to identify mechanisms of resistance. Methods: Whole blood was collected in Streck tubes at baseline and at time points during treatment from patients with advanced, HR+/HER2- BC enrolled in a single arm, phase 2 trial of first line therapy with palbociclib plus tamoxifen that was conducted by The Big Ten Cancer Research Consortium (NCT02668666). Plasma was separated and stored at -80C within 48 hours of collection. Different exosome protein isolation methods were evaluated and optimized to maximize protein recovery. Exosome and plasma proteins were extracted, purified, and digested with trypsin. Tryptic peptides were isotopically labeled with Tandem Mass Tag (TMT) 10plex for protein expression level quantitation. Triplicate samples from each patient were analyzed by LC-MS/MS with QExactive HF Orbitrap mass spectrometer. An unsupervised clustering method was used to classify patients based on exosomal proteomic profiles. Results: We developed a sensitive and efficient exosome extraction method to obtain exosome protein from minimal volumes of patient plasma. The optimized exosome isolation method quantitatively identified 800 proteins from a 100 µl plasma sample. Significant enrichment of exosome-specific markers was observed when comparing patient samples with healthy donor samples. A network model was developed to differentiate responders/stable disease patients from non-responders using exosome proteomics data generated from pretreatment plasma samples. Preliminary data from the first 22 patients analyzed (responders, n= 6; stable disease, n=12, and non-responder, n=4) identified a network of 45 proteins that predicted response/stable disease vs progressive disease with high specificity (95%) and sensitivity (89%). We also noted significant differences in the exosome proteomic profiles of patients with de novo vs. recurrent metastatic disease. A network of 22 proteins differentiated de novo vs recurrent metastatic disease with > 85% sensitivity and 78% specificity, providing molecular evidence differentiating the two disease states. This finding is relevant in light of the higher response rate and improved PFS in patients with de novo metastatic disease in this trial, and confirms that this approach may provide molecular insight into mechanisms of primary resistance to CDK4/6i. Results for the entire trial cohort of 46 patients will be presented, along with analysis of serial samples collected at various time points during treatment. Conclusion: This proof-of-concept study demonstrates that an ultrasensitive exosome proteomics platform combined with deep learning methods is ideally suited for developing predictive protein biomarkers and for exploring molecular mechanisms of drug resistance. If results are confirmed, this novel approach holds great promise for identifying protein biomarkers that could be used to select patients unlikely to respond to ET and CDK4/6i in order to spare them ineffective treatment and for selecting participants for clinical trials of novel agents. Additionally, exosome proteomics data generated from serially collected specimens can be used to identify mechanisms of resistance that emerge during therapy. This approach can be widely applied to other treatment regimens and disease sites. This study was funded by Pfizer. Citation Format: Ziwei Zhang, Xiuyuan Ma, Julia Ekiert, Gayatry Mohapatra, Louis Coleman, Cristina I. Truica, Anne Blaes, Jatin Rana, Tandra Pavankumar, Lauren Green, Menggang Yu, Deborah Toppmeyer, Ruth O’Regan, Kari B. Wisinski, Oana C. Danciu, Kent Hoskins, Yu Gao. Quantitative proteomic analysis of plasma exosomes from patients with advanced hormone receptor-positive/HER2-negative breast cancer receiving palbociclib and tamoxifen [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 P5-02-47.

Background: Palbociclib is a CDK4/6 inhibitor used to treat metastatic hormone receptor-positive (HR+) breast cancer (MBC) in combination with endocrine therapy. Tamoxifen is an effective treatment for HR+ MBC, with different toxicity profile compared with aromatase inhibitors (AI) and fulvestrant. Preclinical data demonstrated synergy for the combination of tamoxifen and palbociclib, being effective in a model of acquired tamoxifen resistance. Methods: We conducted a non-randomized, open-label, single-arm, multicenter, phase II trial of palbociclib in combination with tamoxifen in patients with HR+/HER2 - advanced BC, with no prior therapy for MBC. Ovarian suppression was recommended for pre-menopausal women. Primary objective was progression free survival, PFS. Secondary objectives: objective response rate, ORR (CR or PR) based on RECIST 1.1 or MDA Criteria (for patients with bone only disease); safety and tolerability (using CTCAE v4); clinical benefit rate, CBR (CR, PR or SD lasting min 24 weeks); 2-year overall survival. Correlative objectives: proteomic analysis of plasma exosomes to identify mechanisms of primary and secondary resistance to tamoxifen/palbociclib. Results: Between 6/30/2016 and 7/02/2019, we enrolled 49 patients (47 evaluable): 23 pts with de-novo metastatic disease and 24 pts with recurrent BC (12 pts were on adjuvant treatment with AI at time of recurrence and 12 pts on surveillance). As of 6/30/2022 data cut-off, 2 pts were still on treatment. This is an updated analysis with median follow-up time of 24 months (range 8-51). Median age was 60 (range 39-82). The median PFS was 19.8 months with 95% CI (8-41) for pts with de-novo MBC and 7 months (2-12) for pts with recurrent BC. The ORR was 30% overall, 39% for pts with de novo MBC, 21% for pts with recurrent BC. CBR was 64% overall, 77% for pts with de novo MBC and 50% for pts with recurrent BC. CBR was 65% for white pts and 55% for AA pts. Best response per RECIST1.1: 14 pts (34%) had PR, 18 pts (44%) had SD, 9 pts (22%) had PD. All 6 pts with bone only disease had SD. The most common drug related grade ≥ 3 AE was neutropenia (51%), transient and manageable by dose modifications, no cases of febrile neutropenia. Four patients (8%) developed thromboembolic events (grades 2, 3, 4) and discontinued treatment. One patient died while on treatment from PD. More than 800 exosome proteins were detected in the samples analyzed so far. Exosomal protein networks in pretreatment samples predicted treatment response with 89% sensitivity and 95% specificity in unsupervised clustering. Data on correlative objectives will be presented in a separate abstract. Conclusions: The combination of palbociclib and tamoxifen showed tolerable, expected safety profile. This may be an alternative approach for selected patients in first line treatment of HR+ MBC, especially those who present with de-novo metastatic disease and are intolerant to AI; although this small study indicates a lower PFS. Table 1: Baseline Demographics Citation Format: Oana C. Danciu, Kent Hoskins, Jennifer Weiss, Cristina I. Truica, Anne Blaes, Deimante Tamkus, Jatin Rana, Tandra Pavankumar, Lauren Green, Yu Gao, Menggang Yu, Qianqian Zhao, Deborah Toppmeyer, Ruth O’Regan, Kari B. Wisinski. A single arm phase II trial of Palbociclib in combination with Tamoxifen as first line therapy for metastatic hormone receptor positive breast cancer [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 P4-01-38.

Importance Given the widespread use of the 21-gene recurrence score for identifying candidates for adjuvant chemotherapy, it is important to examine the performance of the Oncotype DX Breast Recurrence Score test in diverse patient populations to validate this approach for tailoring treatment in women in racial/ethnic minority groups. Objective To examine whether breast cancer–specific mortality for women with hormone-dependent breast cancer differs by race/ethnicity across risk categories defined by the Oncotype DX Breast Recurrence Score test and whether the prognostic accuracy of the 21-gene recurrence score differs by race/ethnicity. Design, Setting, and Participants This retrospective, population-based cohort study used the Surveillance, Epidemiology, and End Results Oncotype DX 2004-2015 database to obtain breast cancer–specific survival data on US women 18 years and older who were diagnosed with first primary stage I to III, estrogen receptor–positive breast cancer between January 1, 2004, and December 31, 2015, and had tumor testing through the Genomic Health Clinical Laboratory. Data were analyzed from April 20 to September 27, 2020. Main Outcomes and Measures The primary outcome was breast cancer–specific mortality among women from different racial/ethnic groups stratified by the 21-gene recurrence score risk categories. Secondary analyses compared the prognostic accuracy of the recurrence score among the different racial/ethnic groups. Results A total of 86 033 patients with breast cancer (mean [SD] age, 57.6 [10.6] years) with Oncotype DX Breast Recurrence Score test information were available for the analysis, including 64 069 non-Hispanic White women (74.4%), 6719 non-Hispanic Black women (7.8%), 7944 Hispanic women (9.2%), 6950 Asian/Pacific Islander women (8.0%), and 351 American Indian/Alaska Native women (0.4%). Black women were significantly more likely than non-Hispanic White women to have a recurrence score greater than 25 (17.7% vs 13.7%;P Conclusions and Relevance In this cohort study, Black women in the US were more likely to have a high-risk recurrence score and to die of axillary node–negative breast cancer compared with non-Hispanic White women with comparable recurrence scores. The Oncotype DX Breast Recurrence Score test has lower prognostic accuracy in Black women, suggesting that genomic assays used to identify candidates for adjuvant chemotherapy may require model calibration in populations with greater racial/ethnic diversity.

African American (AA) women have a 4- to 5-fold greater risk of death from hormone receptor-positive (HR +) breast cancer (BC) compared to white women, even after controlling for stage at diagnosis, treatment, and other prognostic factors. Biologic mechanisms are activated in HR + BC arising in AA women that result in a higher rate of distant metastases and/or resistance to endocrine therapies. We are performing a metabolomic analysis of serum from AA and white women with newly diagnosed BC, as well as a racially diverse, healthy control population, to identify potential oncometabolites that promote aggressive phenotypes in HR+ BC cells. The association between candidate oncometabolites and established demographic variables related to poor outcomes in AA women with BC, including neighborhood socioeconomic deprivation and individual patient and tumor characteristics, will also be explored. AA and white women, age 20-79, with a new diagnosis of stage I-III ER+ BC who have not yet initiated treatment have been recruited from 3 cancer institutions in Chicago. Control subjects (women presenting for a screening mammogram without breast symptoms and no history of cancer) have been recruited in mammography centers. Serum for metabolite profiling and demographic data were collected. By collecting serum samples prior to initiation of any treatment, the profiles generated will also reflect the metabolome of the tumor itself. Analyses will be adjusted for tumor intrinsic subtype (Luminal A, Luminal B, HER-2 enriched and basal-like) since different molecular pathways predominate in the different subtypes and metabolite profiles are expected to vary. Target enrollment is 300 subjects; to date we have enrolled 21 AA women with HR + BC and 73 AA controls, 15 white women with HR +BC and 11 white women controls. Metabolomic analysis and demographic data and neighborhood/geo-spatial analysis will be presented with the poster. We expect to identify biochemical differences in serum that are related to race and cancer status. Associations between candidate oncometabolites and key neighborhood-level and individual-level variables that are associated with BC disparities will also be generated. Citation Format: Oana C. Danciu, Zeynep Madak-Erdogan, Hariyali Patel, Landan Banks, Jermya Buckley, Garth Rauscher, Anita Fareeduddin, Elonia Martin, Carlos Garcia, Lauren Schulte, Deanna Taiym, Julie Kim, William Gradishar, Scott Hegerty, Archana Bargaje, Joanna Frasor, Kent Hoskins. Integrated molecular approach to identify biologic factors contributing to breast cancer disparities in Chicago [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr C022.