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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.

PurposeProvide real-world data regarding the risk for SARS-CoV-2 infection and mortality in breast cancer (BC) patients on active cancer treatment.MethodsClinical data were abstracted from the 3778 BC patients seen at a multisite cancer center in New York between February 1, 2020 and May 1, 2020, including patient demographics, tumor histology, cancer treatment, and SARS-CoV-2 testing results. Incidence of SARS-CoV-2 infection by treatment type (chemotherapy [CT] vs endocrine and/or HER2 directed therapy [E/H]) was compared by Inverse Probability of Treatment Weighting. In those diagnosed with SARS-CoV-2 infection, Mann–Whitney test was used to a assess risk factors for severe disease and mortality.ResultsThree thousand sixty-two patients met study inclusion criteria with 641 patients tested for SARS-COV-2 by RT-PCR or serology. Overall, 64 patients (2.1%) were diagnosed with SARS-CoV-2 infection by either serology, RT-PCR, or documented clinical diagnosis. Comparing matched patients who received chemotherapy (n = 379) with those who received non-cytotoxic therapies (n = 2343) the incidence of SARS-CoV-2 did not differ between treatment groups (weighted risk; 3.5% CT vs 2.7% E/H, P = .523). Twenty-seven patients (0.9%) expired over follow-up, with 10 deaths attributed to SARS-CoV-2 infection. Chemotherapy was not associated with increased risk for death following SARS-CoV-2 infection (weighted risk; 0.7% CT vs 0.1% E/H, P = .246). Advanced disease (stage IV), age, BMI, and Charlson’s Comorbidity Index score were associated with increased mortality following SARS-CoV-2 infection (P ≤ .05).ConclusionBC treatment, including chemotherapy, can be safely administered in the context of enhanced infectious precautions, and should not be withheld particularly when given for curative intent.

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.

Purpose The functional composition and diversity of the gut microbiome (estrobolome) may affect breast cancer risk by modulation of systemic sex hormones. Gut bacteria with β-glucuronidase enzymatic activity may deconjugate estrogens, leading to increased estrogen reabsorption into the circulation thereby increasing breast cancer risk. We investigated the relationship between the gut bacterial microbiome and endogenous estrogens and related sex hormones in women with hormone receptor-positive breast cancer compared to healthy control women. Methods In this prospective case-control study, postmenopausal women (n = 46) with newly diagnosed stage I-III estrogen and/or progesterone receptor-positive breast cancer were compared with healthy postmenopausal female controls (n = 22). Bacterial composition of the gut microbiome was analyzed by 16S rRNA gene sequencing from fecal specimens. Plasma and urine sex hormones were quantified using high-performance liquid chromatography/mass spectrometry. Results We found evidence that some β-glucuronidase positive bacteria were enriched in the breast cancer patients compared to healthy controls, whereas abundances of some β-glucuronidase negative bacteria were reduced. There was also a wide distribution of prevalence of β-glucuronidase positive taxa in both the breast cancer subjects and healthy controls, as well as higher probability of breast cancer subjects having higher average β-glucuronidase levels. Significant differences were found in endogenous progesterone levels between the breast cancer patients and healthy controls. Conclusion This pilot study showed differences in the gut microbiome and endogenous progesterone levels among postmenopausal women with hormone receptor-positive breast cancer compared with healthy controls. These interesting findings may have implications for breast cancer risk and prevention and warrant further exploration.

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.

Metaplastic breast cancer (MPBC) is a rare subtype that accounts for

Background: The COVID-19 pandemic presented a unique challenge to our healthcare system and rapidly changed the delivery of cancer care. During the height of the pandemic in New York State, non-emergent surgery, including cancer surgery, was postponed. For patients with hormone receptor positive breast cancer, “bridge” neoadjuvant hormonal therapy was initiated until surgery could be safely performed. Objective: We present our institutional experience with this approach and lessons learned, including oncologic outcomes and factors which may lead to increased medication compliance. Method: This is a single institution, retrospective, observational chart review. Using data from the NYU Perlmutter Cancer Center, we created a database of patients who were diagnosed with ER+ stage 0, I, or II breast cancer and were offered preoperative endocrine therapy (tamoxifen or aromatase inhibitors) between March 12, 2020 and June 1, 2020. Variables collected included demographics, tumor characteristics, as well as the rates of medication uptake and compliance. Patients eligible for review were adult (age>18) males and females who had initial visits at our two cancer centers between March 12, 2020 and June 1, 2020, during the height of the COVID-19 pandemic in New York. Results: Of 192 newly diagnosed breast cancer patients seen at the NYU Perlmutter Cancer Center during the study time period, 136 (71%) patients had early stage ER positive breast cancer. Forty-five patients (23%) had not yet undergone surgery, and were recommended to receive presurgical hormonal therapy as a bridge. Average age: 60.5 +/- 13.8 years old (range 31-89). Thirty-four patients (75.6%) had invasive cancer, 8 had DCIS (17.8%), 3 had DCIS with microinvasion (6.7%). There were 9 patients (20%) who did not take the medication. Thirty-six patients (80%) took medication for an average of 43.6 +/- 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 remaining patients include one who is refusing all treatment, one patient who relocated out of state, and another patient who has not yet scheduled surgery, but is still taking an aromatase inhibitor. Conclusion: Despite traditionally low uptake and adherence to endocrine therapy, acceptance of neo-adjuvant bridge therapy during the COVID-19 pandemic was high (80%). We plan to investigate our patient population further, especially psychosocial and behavioral factors that influence willingness to take endocrine therapy – and apply these lessons to management of early-stage ER positive breast cancer.

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.

Recent attention has focused on the antitumor immune response in breast cancer, in particular, the role of tumor-infiltrating lymphocytes (TILs). In certain breast cancer subtypes, the presence of TILs has prognostic value and is associated with clinical outcome and improved survival. The potential predictive value of TILs has also been investigated in regard to cytotoxic and antihuman epidermal growth factor receptor 2 (HER-2) therapies, but could also serve as a selection marker for novel immunotherapies. In this article, we review the current literature on TILs in breast cancer and discuss how TILs are emerging as a promising biomarker in mediating antitumor immunity.

Distant metastasis is the leading cause of tumor-related death from breast cancer. Hematogenous dissemination of tumor cells from the primary tumor to distant sites cannot be detected by standard imaging methods. There has been growing interest in the role of circulating tumor cells (CTCs) in the peripheral blood, which may serve as a marker of occult systemic micrometastatic disease. The detection and characterization of CTCs has provided important insight into early development of metastasis, as well as prognostic and predictive information in metastatic and early breast cancer. In this review, we describe the biology, detection strategies, and clinical application of CTCs. The genetic and molecular characterization of CTCs has great potential to improve the understanding of tumor biology and to optimize personalized cancer treatment.

Resistance to endocrine therapies in hormone receptor (HR)-positive breast cancer is a significant challenge. Prior studies have shown that low-dose oral cyclophosphamide can transiently deplete regulatory T cells (Tregs) and improve anti-tumor immunity. We investigated the combination of exemestane with cyclophosphamide in patients with advanced HR-positive breast cancer and assessed changes in circulating immune cell subsets. This was a single-arm phase II trial of exemestane with cyclophosphamide in patients with metastatic HR-positive/HER2-negative breast cancer who had progressed on prior endocrine therapy (ClinicalTrials.gov: NCT01963481). Primary endpoint was progression-free survival (PFS) at 3 months (RECIST 1.1). Secondary objectives included median PFS, objective response rate, duration of response, and safety. Circulating Tregs (FOXP3+Helios+) and other immune cell subsets were monitored during treatment and compared with healthy controls. Twenty-three patients were enrolled. Treatment was well tolerated, without grade 4/5 toxicities. Objective responses were seen in 6/23 patients (26.1%; 95% CI 10.2–48.4%) and were durable (median 11.6 months). Three-month PFS rate was 50.1% (95% CI 33.0–76.0%); median PFS was 4.23 months (95% CI 2.8–11.7). No treatment-related decrease in Tregs was observed. However, elevated baseline levels of Naive Tregs [greater than 2.5 (the median of the naive Tregs)] were associated with relative risk of disease progression or death [hazard ratio 11.46 (95% CI 2.32–56.5)]. In addition, the baseline levels of Naive Tregs (adj-p = 0.04), Memory Tregs (adj-p = 0.003), CD4 + Central Memory T cells (adj-p = 0.0004), PD-1 + CD4 + Central Memory T cells (adj-p = 0.008), and PD-1 + CD4 + Effector Memory T cells (adj-p = 0.009) were significantly greater in the patients than in the healthy controls; the baseline levels of %CD4 + Naive T cells (adj-p = 0.0004) were significantly lower in patients compared with healthy controls (n = 40). Treg depletion was not observed with low-dose cyclophosphamide when assessed by the specific marker FOXP3 + Helios +; however, baseline naive Tregs were associated with 3-month PFS. Exemestane/cyclophosphamide combination had favorable safety profile with evidence of clinical activity in heavily pretreated patients.

Breast cancer is a heterogeneous disease, with different subtypes having a distinct biological, molecular, and clinical course. Assessments of standard clinical and pathological features have traditionally been used to determine the use of adjuvant systemic therapy in patients with early stage breast cancer; however, the ability to identify those who will benefit from adjuvant chemotherapy remains a challenge, leading to the overtreatment of some patients. Advances in molecular medicine have substantially improved the accuracy of gene-expression profiling of breast tumours, resulting in improvements in the ability to predict a patient's risk of breast cancer recurrence and likely response to endocrine therapy and/or chemotherapy. These genomic assays, several of which are commercially available, have aided physicians in tailoring treatment decisions for patients at the individual level. Herein, we describe the available data on the clinical validity of the most widely available assays in patients with early stage breast cancer, with a focus on the development, validation, and clinical application of these assays, in addition to the anticipated outcomes of ongoing prospective trials. We also review data from comparative studies of these assays and from cost-effectiveness analyses relating to their clinical use.

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.

The standard platinum-based treatment of previously untreated advanced ovarian cancer continues to evolve because despite high response rates to such first-line treatment, a majority of patients will experience relapse. For many years, the optimal treatment for women with advanced ovarian cancer has been maximum cytoreductive surgery followed by intravenous (IV) platinum and taxane chemotherapy. Later, several randomized multicenter phase III clinical trials demonstrated that intraperitoneal (IP) chemotherapy was superior to standard IV chemotherapy when there was minimal residual disease after primary debulking surgery. The underlying rationale for use of IP therapy is based on the dose-effect relationship for platinum drugs in ovarian cancer. However, barriers to implementation of IP therapy in the routine clinical setting include concern for toxicity, tolerability of planned treatment, and catheter-related complications. In this article, we highlight the key trials and recent directions in IP therapy of ovarian cancer and briefly discuss another approach to the delivery of IP chemotherapy, known as hyperthermic intraperitoneal chemotherapy.

The huge communities of residential microbes, including bacteria, viruses, Archaea, and Eukaryotes, that colonize humans are increasingly recognized as playing important roles in health and disease. A complex populous ecosystem, the human gastrointestinal (GI) tract harbors up to 10(11) bacterial cells per gram of luminal content, whose collective genome, the gut metagenome, contains a vastly greater number of individual genes than the human genome. In health, the function of the microbiome might be considered to be in dynamic equilibrium with the host, exerting both local and distant effects. However, 'disequilibrium' may contribute to the emergence of disease, including malignancy. In this review, we discuss how the intestinal bacterial microbiome and in particular how an 'estrobolome,' the aggregate of enteric bacterial genes capable of metabolizing estrogens, might affect women's risk of developing postmenopausal estrogen receptor-positive breast cancer. Estrobolome composition is impacted by factors that modulate its functional activity. Exploring variations in the composition and activities of the estrobolome in healthy individuals and in women with estrogen-driven breast cancer may lead to development of microbiome-based biomarkers and future targeted interventions to attenuate cancer risk.

Learning Objectives After completing this course, the reader will be able to: Describe the need for additional vigilance regarding renal dysfunction when platinums, pegylated liposomal doxorubicin, bevacizumab, and gemcitabine are used for prolonged treatment of recurrent ovarian cancer in combination or sequentially following pre-existing renal damage.Describe and quantify the risk of chronic kidney disease in patients treated for ovarian cancer. CME This article is available for continuing medical education credit at CME.TheOncologist.com Background and Objective. Ovarian cancer is usually diagnosed at an advanced stage, with most patients undergoing surgery followed by platinum- and taxane-based chemotherapy. After initial clinical remission, the majority recur, leading to additional treatments, including not only platinums and taxanes but also pegylated liposomal doxorubicin (PLD), gemcitabine, topotecan, and, more recently, bevacizumab, which may extend survival times. PLD, in particular, has been extensively studied by our group, with encouraging therapeutic results. We, however, observed instances of chronic kidney disease (CKD) developing among patients who received long-term treatment for recurrent ovarian cancer. To document the frequency and contributing factors to the emergence of CKD, we initiated a retrospective review at two institutions. Patients and Methods. Fifty-six consecutive patients with recurrent ovarian cancer receiving treatment at New York University Cancer Institute were reviewed for the presence of renal disease in 1997–2010. At Shaare Zedek Medical Center, 73 consecutive patients with ovarian cancer were reviewed in 2002–2010. Patients were diagnosed with CKD if they had an estimated GFR 3 months and were staged according to the National Kidney Foundation guidelines. Results. Thirteen patients (23%) developed stage ≥3 CKD. Three patients had renal biopsies performed that showed thrombotic microangiopathy. Conclusions. CKD is emerging as a potential long-term consequence of current chemotherapy for recurrent ovarian cancer.

Ovarian cancer arising in women with BRCA mutations is known to have a more favorable outcome and to be more responsive to platinum-based regimens than in those without a hereditary background. We analyze our previously published intraperitoneal (IP) studies in relation to BRCA mutation status and update their outcomes. Among 62 patients with ovarian cancer enrolled in IP platinum doublet studies in clinical trials (with etoposide (n = 18), with floxuridine (n = 30), and with topotecan (n = 14)), a deleterious BRCA mutation was eventually identified in 10 patients. The outcomes in these BRCA mutation carriers are described and compared with survival of others in respective trials. Ten patients that were confirmed to have BRCA mutations—all with high-grade and stages IIC to IV disease—survived a median of 10 years (range: 4–18+) after receiving IP cisplatin-based regimens. Two continue with no evidence of disease since their IP treatment, while four others remain alive with recurrences after 8, 9, 10, and 11 years, respectively. This experience suggests that IP cisplatin leads to favorable long term outcomes in advanced ovarian cancer in women with defective homologous recombination (i.e., with deleterious BRCA mutations). Whether such cisplatin dose-intensification from IP relative to (intravenous) IV drug administration leads to superior results in these mutation carriers requires further study.

To the Editor: Jhaveri et al.1 provide a comprehensive review of glomerular diseases seen with malignancy and its treatments, including chemotherapy-induced thrombotic microangiopathy (TMA). However, they have overlooked evidence for renal TMA after pegylated liposomal doxorubicin (PLD) for ovarian cancer.

e11010 Background: We originally reported that p27 loss in T1a/b breast carcinomas was associated with lack of estrogen and progesterone (ER/PR) hormone receptors, but not in T1c node negative tumors (Mirchandani et al, Anticancer Research 2011). The current study explored the association of p27 expression with lymph node (N) status. Methods: 217 consecutive patients with T1 tumors were identified from 2001-2003. All patients underwent sentinel node biopsy (and complete lymphadenectomy when positive on frozen section): 111 were N0 and 106 were N+. Immunohistochemistry was performed for ER/PR, Her2, and nuclear p27 (low vs normal) and tumors were graded (well, moderate, and poorly differentiated). Analysis was conducted to define associations between standard variables and p27 expression among node positive and node negative tumor carriers (Table). Results: Low p27 expression was found in 21% of N0 and 36% of N+ T1 breast cancer patients (Chi-square=6.14, p-value=0.01). However from a series of multivariable analyses, only tumor size was significantly associated with node positivity. Conclusions: Poorly differentiated tumors, T1c tumors, and low p27 expression were associated with lymph node positivity, but only tumor size was significant in multivariable analysis. Contrary to our prior report, the relationship between low p27 and ER/PR- is strongest in the T1c subset (data not shown). Future studies will expand study cohorts to explore whether low p27 expression is a biomarker of poor outcome at 10 years in patients with T1 tumors treated with antiestrogens. [Table: see text]

e15551 Background: Treatment-related CKD and hypertension (HTN) are emerging as problems in patients receiving multiple treatments for recurrent epithelial ovarian cancer (rEOC). Methods: 8 patient...