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Background: Socioeconomically disadvantaged and immigrant cancer survivors account for a significant and growing proportion of the breast cancer population in the US. Research on symptom burden and control among Chinese American (CA) breast cancer survivors (BCS) is scarce. Among all BCS, over 55% report treatment-related symptoms (e.g., fatigue and pain) and psychological stress (e.g., fear of recurrence). In our preliminary cross-sectional study, we found similar rates (~58%) but showed that CA (especially low-acculturated) BCS were particularly likely to report fatigue, pain, and poorer physical functioning relative to non-Hispanic White (NHW) BCS. We understand very little about whether CA and NHW BCS have different ways of managing symptoms, improving quality of life and decreasing risk for functional decline. We therefore propose a study to examine how CA and NHW BCS, two culturally distinct groups with divergent social resources, adapt to breast cancer. Study design: This longitudinal, prospective study will investigate sociocultural influences on individual coping behaviors and how they in turn affect racial differences in inflammation markers, symptom severity, and functional outcomes in breast cancer. This study will enroll 260 CA and 260 NHW female BCS to examine multifactorial pathways to breast cancer survivorship outcomes. The CA cases will be age- and stage-matched to the NHW cases. Utilizing a multilevel biobehavioral framework, we will investigate the dynamics of biological, sociocultural, and behavioral (diet and exercise) influences on symptom severity, physiologic status, and functional outcomes. Participants will complete telephone survey interviews and provide blood samples at baseline and 6- and 12-month follow-up. Pro-inflammatory cytokines (e.g., IL-1β, IL-1a, IL-6, IL8, IL10, TNFα, TNFꞵ, and CRP) and cortisol will be analyzed. In-depth individual interviews with a subset of participants will be conducted to investigate causal factors in order to develop individually and culturally appropriate interventions to improve future clinical care for targeted breast cancer survivor populations. This study is supported by NIH R01CA248413. Eligibility criteria: Eligible participants are CA and NWH women (age >= 18) who are diagnosed with invasive breast cancer (stage I, II, or III), are 1-5 years post diagnosis, and have completed primary treatment (e.g., surgery, radiation, chemotherapy, and/or targeted therapy). Patients currently on adjuvant endocrine therapy are allowed. Specific aims: Aim 1: Examine whether CA BCS’ symptom, functional, and physiologic outcomes (e.g., cytokines and cortisol), and trajectory of these outcomes differ from NHW BCS at baseline, 6- and 12-month follow-up, controlling for covariates. Aim 2: Examine to what extent social resources mediate BCS’ individual behavior (e.g., medical communication, diet, and physical activity) and to what extent such pathways explain outcome differences (Aim1) among BCS. Aim 3: Examine whether race and acculturation moderate the mediational pathways. Statistical methods: Multiple general linear mixed models will be performed to examine racial differences in the trajectory of symptom and biobehavioral outcomes across time, controlling for covariates (Aim 1). To examine mediation and moderation effects (Aims 2 and 3), we will use a cross-lagged path analysis model to simultaneously describe reciprocal relationships, or directional influences, between variables over time. Present accrual and target accrual: A total of 520 participants (260 CA and 260 NHW) will be enrolled at NYU Perlmutter Cancer Center, Columbia University Irving Medical Center, Georgetown University Medical Center, and Texas A&M University community networks. Contact information: Judy Huei-yu Wang, PhD: jw235@gunet.georgetown.edu or 202-687-6306 Maryann Kwa, MD: maryann.kwa@nyulangone.org or 212-731-6364 Citation Format: Maryann Kwa, Marc Schwartz, Katherine D. Crew, Jeanine M. Genkinger, Roger L. Brown, Leena Hilakivi-Clarke, Joanna Kitlinska, Douglas W. Roblin, Michael Antoni, Sylvia Adams, Kathie-Ann Joseph, Lei-Shih Chen, Judy Huei-yu Wang. A longitudinal investigation of sociocultural and behavioral influences on symptom management, biological response, and functioning among Chinese American and White female breast cancer survivors [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 OT3-14-01.

Background: Neoadjuvant endocrine therapy has traditionally been considered a treatment option for locally advanced and/or surgically high-risk women with hormone positive disease. Early stage hormone-positive breast cancer, on the other hand, is usually managed with upfront surgery, with post-operative hormone therapy as a risk-reducing adjunct. During the COVID-19 pandemic, however, widespread closures of operating rooms throughout the country resulted in many breast cancer patients being offered presurgical endocrine therapy as a bridge to surgery. We explored the demographic and clinicopathologic characteristics of these patients and quantified their rate of uptake. Methods: The Institutional Breast Cancer Database was queried for all patients who were diagnosed with ER+ stage 0, I, or II breast cancer and were offered presurgical endocrine therapy (tamoxifen or aromatase inhibitor) by a medical oncologist from 3/12/2020 to 4/30/2020. Variables of interest included demographics, tumor characteristics, and rate of medication uptake and compliance. Results: Of 192 newly diagnosed breast cancer patients seen at NYU Perlmutter Cancer Center during this time period, 136 patients had early stage ER+ breast cancer. Forty-five patients had not yet undergone surgery, and were recommended to receive presurgical hormonal therapy as a bridge given the COVID-19 pandemic (Table 1). The average age was 60.5 years old (SD=13.8 years, range 31-89), and all were female. Thirty-four of 44 patients were post-menopausal (75.6%), while 10 were premenopausal (22.2%), and one was perimenopausal (2.2%). Twenty-six patients were white (57.8%), 12 were black (26.7%) 3 were Asian (6.7%), and 4 were other (8.9%). Thirty-four patients (75.6%) had invasive disease, while 8 had ductal carcinoma in situ (DCIS, 17.8%), and 3 had DCIS with microinvasion (6.7%). Nine patients (20%) did not take the medication for various reasons: 1 contracted COVID-19, 1 refused any treatment, 1 decided to transfer care out of state, 1 preferred to take a homeopathic remedy instead of endocrine therapy, 1 preferred to wait for surgery without medication, and 4 were scheduled for surgery sooner than anticipated and did not start the medication. The remaining 36 patients (80%) took medication for an average of 43.6 days (SD=27.3 days, range 9-101 days) prior to surgery. Twenty-eight patients (77.8%) took an aromatase inhibitor, and 8 (22.2%) took tamoxifen. Forty-two patients have now undergone surgery (93.3%); the remainder include the patient who is refusing all treatment, the patient who transferred out of state, and one patient who has not yet scheduled surgery, but is reportedly still taking an aromatase inhibitor. Conclusion: Improving adherence to long-term adjuvant endocrine therapy is an urgent need as patient acceptance is low. Reported completion rates range around 50%, and have not been improved by educational or technology-based interventions. The unique situation posed by the current COVID-19 pandemic has temporarily changed the management of early-stage breast cancer, and resulted in a high initial acceptance of endocrine therapy (80%), although duration is shorter in this presurgical setting. Further investigations will evaluate length of use, the psychosocial and behavioral factors that influence willingness to take endocrine therapy, and apply these lessons to management of early-stage hormone-positive breast cancer. Patient Demographics and Tumor CharacteristicsVariablesTotal (N=45)%Median Age (years)60.5 (31-89)RaceWhite2657.8Black1226.7Asian36.7Other48.9Menopause StatusPre-menopausal1022.2Peri-menopausal12.2Post-menopausal3475.6Mean BMI (kg/m2)28.3 (17.8-46.5)PalpabilityNon-palpable3066.7Palpable1533.3Mammographic Breast DensityEntirely Fatty24.4Scattered Fibroglandular1737.8Heterogeneously Dense2453.3Extremely Dense24.4HistologyDCIS817.8DCIS with microinvasion36.7Invasive carcinoma3475.6Clinical Stage0817.8I2760II1022.2Endocrine Therapy(N=36)Tamoxifen822.2Aromatase Inhibitor2877.8Mean Duration of Endocrine Therapy (days)43.6 (9-101) Citation Format: Cindy Cen, Freya Schnabel, Sylvia Adams, Magdalena Plasilova, Janet Yeh, Marleen Meyers, James Speyer, Elliot Belenkov, Maryann Kwa, Yelena Novik, Elena Katz, Amber Guth. “Bridge” neoadjuvant endocrine therapy for early stage breast cancer patients during COVID-19 at an academic hospital in NYC: Lessons learned [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS12-26.

Introduction: Breast carcinomas can be classified by hormone receptors and human epidermal growth factor receptor-2 (HER-2) status. HER-2 status is assessed using immunohistochemistry (IHC) and/or fluorescent in situ hybridization (FISH). Immunophenotypic triple negative breast cancers (iTNBC) may harbor an amplification of HER-2 detected by FISH (iTNBC-FISHAmp) or may be negative by FISH (iTNBC-FISHNeg). The discrepancy between protein expression and gene amplification in these tumors poses relevant questions on tumor biology and for treatment implications. Here we investigate iTNBC-FISHAmp and iTNBC-FISHNeg by gene expression profile. Methods: A total of 40 iTNBC were selected. HER-2 IHC scores (0 or 1+) were annotated. All the tumors were tested by FISH showing 20 iTNBC-FISHAmp and 20 iTNBC-FISHNeg. The tumor morphology was reviewed by 2 pathologists, and stromal tumor infiltrating lymphocytes (sTILs) were estimated as high (H-sTILs) or low (L-sTILs). The areas of tumor with best cellularity were selected for RNA extraction. Gene expression profiling using a panel of 776 genes across 33 biological signatures was performed using Nanostring technology. Results: ERBB2 gene expression was significantly higher in iTNBC-FISHAmp when compared to iTNBC-FISHNeg tumors (p Citation Format: Paolo Cotzia, Theodore Vougiouklakis, Ursula Andreo, George Jour, Christopher Schwartz, Maryann Kwa, Sylvia Adams, Francisco Esteva, Deborah Axelrod, Freya Schnabel, Matija Snuderl, Farbod Darvishian. Gene expression profiling in immunophenotypic triple negative breast carcinomas harboring HER-2 amplification identifies tumors with distinct molecular signatures and increased ERBB2 gene expression [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 P4-07-10.

Background: Resistance to endocrine therapies in HR-positive breast cancer is a significant challenge. The steroidal aromatase inhibitor (AI) exemestane (EXE) has demonstrated short-term efficacy in metastatic HR-positive HER2-negative breast cancer (mHR+BC) that has progressed during treatment with a non-steroidal AI. Combination strategies have not shown a survival benefit. Immunotherapy represents a promising approach as it may increase durability of responses. Low dose cyclophosphamide (CTX) has demonstrated efficacy in combination with neoadjuvant letrozole in HR+BC, conceivably by enhancing anti-tumor immune responses. Here we investigated whether EXE combined with immunomodulatory CTX could provide durable responses in heavily pretreated patients and assessed immunological profiles (NCT01963481). Methods: Phase II trial of EXE (25mg PO daily) with CTX (50 mg PO daily) enrolled postmenopausal women (n=23) with mHR+BC who had progressed on prior endocrine therapy (including nonsteroidal AI, tamoxifen, and/or fulvestrant); prior chemotherapy was allowed. The primary endpoint was PFS (per RECIST 1.1) at 3 months; secondary endpoints were response rate, tolerability, and immune correlates. Detailed functional immune profiling of peripheral T cell subsets were performed by flow cytometry at baseline, 1, 3, 6, 9 & 12 months, with healthy donors available as controls. Results: All 23 patients have been enrolled, and 21 are evaluable for response. Median age was 54 (range 31-77), median prior lines of endocrine therapy was 2 (1-3) and chemotherapy was 1 (0-5). The majority (15/23) had visceral organ involvement. Combination treatment was well tolerated with one grade 3 urinary tract infection but no grade 4 or 5 toxicity. An objective response was observed in 19% of patients (4/21, 1 CR and 3 PR) and an additional 33% (7/21) had SD, resulting in a 3-month-PFS of 48.5% (95% CI, 30.5-77.1). Responses were durable in all patients, lasting =/> 9 months and included patients with liver metastases. Comparison of peripheral immune cell subsets of patients (n=16) at baseline to age/sex-matched healthy controls demonstrated an increased proportion of CD4+ memory T cells with central memory phenotype (CD45RO+CD27+, p Conclusion: EXE and CTX had a favorable safety profile with evidence of clinical activity in patients with heavily pretreated mHR+BC, including durable responses in liver and bone. Correlative studies are ongoing to identify potential biomarkers of response or resistance to therapy. Citation Format: Kwa M, Novik Y, Oratz R, Jhaveri K, Wu J, Gu P, Meyers M, Muggia F, Bonakdar M, Abidoglu C, Kozhaya L, Li X, Joseph B, Iwano A, Friedman K, Goldberg JD, Unutmaz D, Adams S. Phase II trial of exemestane with immunomodulatory oral cyclophosphamide in metastatic hormone receptor (HR)-positive breast cancer: Prolonged progression-free survival (PFS) in patients with distinct T regulatory cell (Treg) profile. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-11-11.

BACKGROUND: Receptor activator of NF-kB (RANK) and its ligand (RANKL) have a well-established role in osteoclast-driven bone remodeling, however RANK/RANKL expression can also be seen on mammary epithelial cells and immune cells (IC). In breast cancer (BC) mouse models, RANKL is a paracrine effector of the mitogenic activity of progesterone and inhibition of RANKL can attenuate development of BC as well as the incidence of metastases. Pre-clinical evidence demonstrates that RANKL exerts effects on IC such as regulatory T cells (Tregs) and tumor associated macrophages (TAMs) within the tumor microenvironment (TME), thereby promoting tumor progression and metastases. Clinical studies also support a deleterious role for these IC subsets specifically in breast cancer, with high density of either Tregs or TAMs associated with increased risk for distant recurrence. Despite this preclinical support for targeting the RANK/RANKL pathway, clinical trials in early stage BC have had discordant results regarding the clinical benefit of denosumab (RANKL antagonist). As such, it is of significant clinical relevance to identify a drug response signature following treatment as this may suggest biomarkers predictive of benefit from adjuvant denosumab. This window-of-opportunity study was designed to evaluate the pharmacodynamic biomarkers of RANKL inhibition, as well as denosumab’s impact on the TME in paired tumor specimens from patients with BC following treatment with denosumab. Defining the immunomodulatory effects of denosumab may additionally provide biologic rationale for synergistic combination with specific immunotherapy agents. TRIAL DESIGN: This study is a single-arm open label Phase 0 (pre-surgical/window of opportunity) trial. Following diagnostic core needle biopsy, patients receive one dose of denosumab 120 mg given subcutaneously prior to surgical resection. ELIGIBILITY CRITERIA: ≥18 years of age with histologically-confirmed invasive BC >1 cm by radiographic or clinical criteria with available tissue from the core biopsy and planned surgery. Patients are ineligible for this study if neoadjuvant therapy is being considered. STUDY OBJECTIVES: The primary objective is to identify pharmacodynamics markers of RANKL inhibition in early BC. Planned analyses include protein and transcriptomic analyses of known targets of RANKL and compare treatment effect in both RANK/RANKL+ and RANK/RANKL- BC. As a secondary objective, the effect of RANKL inhibition on host immune response will be assessed by comparing pre-treatment biopsy specimens and surgical excision specimens from patients treated with denosumab and untreated controls matched for BC subtype and menopausal status. Planned analyses include RANK/RANKL expression on IC subsets, enumeration of tumor infiltrating lymphocytes by H&E, immunophenotype by immunohistochemistry (e.g. cytotoxic T lymphocytes, Tregs, TAMs) and expression of immune related genes (nanoString Pancancer Immune Panel). STATISTICAL METHODS: As RANK/RANKL protein expression is expected in 25-30% of BC, we plan to enroll 35 subjects to ensure at least 10 subjects with RANK/RANKL+ tumors will be included in our study cohort. With 10 subjects with tumors with high RANK/RANKL expression at baseline, a change from baseline of a single gene of >|1.7| standard deviations between subjects with and without RANK/RANKL expression is detectable based on a 2-sided two sample t-test with power of 80% and false discovery rate of 10%. Differential gene expression analysis will be performed comparing denosumab treated patients with RANK/RANKL+ vs. RANK/RANKL- BC, and between treated patients and untreated controls. PRESENT ACCRUAL: 29 of the planned 35 patients have been enrolled to date. Citation Format: Douglas Kanter Marks, Deborah Axelrod, Maryann Kwa, Nancy Tray, Karen Hiotis, Amber Guth, Yelena Novik, James Speyer, Victor Ty, Adriana Heguy, Judith Goldberg, Farbod Darvishian, Sylvia Adams. Impact of RANKL inhibition on tumor microenvironment of early-stage breast cancer, a pre-surgical trial [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 OT1-01-03.