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Background: Identifying when to start CDK4/6 inhibitors or use chemotherapy in hormone receptor positive (HR+) metastatic breast cancer (MBC) remains challenging. The 21-gene Oncotype DX Breast Recurrence Score® test is validated to predict chemotherapy benefit in early stage HR+ breast cancer but has not been studied for use in the MBC setting.Objective: To assess the feasibility of obtaining Recurrence Scores from metastatic sites after standard of care biopsy in HR+, HER2 negative patients and correlate Recurrence Score results from matched primary breast cancer when available. Methods: A total of 48 metastatic biopsies were retrieved retrospectively from the residual tissue of patients with primary HR+, HER2 negative breast cancer. This included 36 from bone and 12 from other sites [liver (7), lung (1), rectum (1), brain (1), skin (2)]. Slides were sent to Genomic Health Inc. for RNA isolation and Recurrence Score result determination using standardized protocols. Recurrence Score results were available for 18 matched primary and metastatic biopsy samples. The percent success rate for Recurrence Score result was determined for the various metastatic sites and results compared between matched primary and metastatic site. Results: Recurrence Score results were obtained in 48% of metastatic biopsies (23 of 48 samples) including bone (17), liver (4), lung (1), and skin (1). Reasons for Recurrence Score failure included insufficient RNA (17), poor quality RNA (1), failed QC (4), and other (3). The mean Recurrence Score from the 23 metastatic sites was 35 (range: 1–66). Notably, 70% (16/23) of successful metastatic biopsies yielded Recurrence Scores in the high-risk range (>25). None of the 23 metastatic biopsies gained HER2 by RT-PCR. Among the 18 paired samples, higher recurrence score results were observed in all but three of the metastatic biopsy samples with mean Recurrence Score results of 20 (range 7 to 41) for the primary and 35 (range 1-66) for the metastatic site. For paired samples, 72% of metastatic biopsies yielded Recurrence Scores >25 compared to 17% of primary sample. Primary Recurrence Scores were not predictive of metastatic scores (r2=0.052). Estrogen receptor (ER) expression status was conserved in 87% whereas progesterone receptor (PR) was lost in 69% of the metastatic lesion. Among the pairs, 5 had de novo metastatic disease. In these, the Recurrence Score was higher in the metastatic biopsy in each case compared to the matched primary (mean 36 versus 23, respectively). Among de novo cases, there was 100% concordance in ER positive and HER2 negative expression and only 60% concordance in PR expression between primary and metastatic sites. Conclusion: Using standard of care metastatic biopsy samples, a Recurrence Score result was successfully generated in 48% of samples including bone. This small series demonstrates wide variability in Recurrence Score results in metastatic disease with overall higher scores, common loss of PR, and minimal correlation to matched primary disease. Further examination of the potential significance of the Recurrence Score for treatment decisions in the metastatic setting requires additional tissue sampling during biopsy as insufficient RNA was the primary reason for failure. Citation Format: Julie Anne L Gemmill, Patricia Thompson, Rebecca Batiste, Caterina Vacchi-Suzzi, Christina Preece, Jules Cohen, Lea Baer, Carolyn Mies, Michelle Turner, Christy A Russell, Alison Stopeck. The feasibility of obtaining oncotype DX breast recurrence score® results from metastatic sites of patients with hormone receptor positive metastatic breast cancer [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 PS5-37.

Background: In hormone receptor-positive / HER2-positive (HR+/HER2+) breast cancer, the HER2 and estrogen receptor (ER) signals merge on the cyclin D1-CDK4/6-RB1 pathway. Thus, a combined pharmacological intervention with individual drugs targeting HER2, ER and CDK4/6 is warranted. Here, we present the safety and efficacy results of the combination of tucatinib with letrozole and palbociclib in patients (pts) with HR+/HER2+ metastatic breast cancer (MBC) (NCT03054363). Methods: Pts with HR+/HER2+ MBC previously treated with at least 2 HER2-targeted agents were enrolled in this phase IB/II clinical trial. Pts with untreated asymptomatic or stable treated brain metastasis (BM) were included. Pts with treated progressing BM were enrolled after local treatment and classified as treated stable. Treatment consisted of tucatinib 300mg PO BID and letrozole 2.5mg PO daily continuously, and palbociclib 125mg PO daily 21 days on, 7 days off. Due to drug-drug interaction issues found in the middle of the trial and not related to this study, the dose of sensitive CYP3A4 substrate palbociclib was reduced to 75mg for all study participants, as it became evident that tucatinib is a strong CYP3A4 inhibitor. The primary end-points were assessment of safety using CTCAE v.4.03 criteria, and progression free survival (PFS). Secondary end-points included pharmacokinetic evaluation (PKs) and objective response rate by RECIST 1.1. BM response was evaluated using RANO-BM criteria. All pts who received at least one cycle of therapy were assessed for safety. Results: Between 11.21.2017 and 04.20.2020, we enrolled 42 pts of whom 40 were evaluable. Median age was 52.5 years (range, 22 to 82) and the median number of prior lines of therapy for MBC was 2 (range, 0 to 7); 23 pts (58%) had visceral disease and 15 (38%) had BM. All pts had prior therapy with trastuzumab and pertuzumab and 18 pt (45%) had prior T-DM1. As of 06.15.2020 data cut off, 14 patients were on active therapy while 26 were off study (22 due to progressive disease [PD], 1 due to toxicity and 3 for other reasons). Median follow up time was 6 months. The combination was well tolerated with manageable and expected adverse events (AEs). The most common grade ≥3 AEs were neutropenia (25 pts, 60%), leukopenia (10 pts, 24%), diarrhea (8 pts, 19%), fatigue (6 pts, 14%), and infections (6 pts, 14%). One pt came off study due to asymptomatic grade 4 elevated LFTs that resolved without sequelae. There were no deaths due to AEs. Among 26 pts with measurable disease at the time of data cut-off, 8 pts (31%) had partial response, 16 pts (62%) had stable disease (SD) (7 pts [27%] had SD for ≥ 6 months and 6 pts [23%] have not yet reached 6 months of follow up) and 2 pts (8%) had PD. Among 14 patients with BM and evaluable disease by RANO-BM, 1 pt had complete response in the brain, 6 pts had SD in the brain for ≥6 months, and 7 pts had SD for 2-6 months (4 pts on active therapy have not yet reached 6 months of follow up). Median PFS is 8.7 months (10.1 months for pts without BM and 6.0 months for those with BM). Updated analysis including PKs, tumor response, and PFS will be presented. Conclusion: The combination of tucatinib with letrozole and palbociclib showed a tolerable and manageable safety profile and evidence of considerable anti-tumor activity that warrant further clinical investigation in pts with HR+/HER2+ MBC. Citation Format: Elena Shagisultanova, William Gradishar, Ursa Brown-Glaberman, Pavani Chalasani, Andrew J. Brenner, Alison Stopeck, Jose Mayordomo, Jennifer R. Diamond, Peter Kabos, Virginia F. Borges. Interim safety and efficacy analysis of phase IB / II clinical trial of tucatinib, palbociclib and letrozole in patients with hormone receptor and HER2-positive metastatic breast cancer [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 PS10-03.

Human epidermal growth factor receptor 2 (HER2) positive (+) breast cancer is a disease with distinct clinicopathological features. Survival for women with HER2+ disease has increased with the development of novel systemic therapeutic agents, however the brain is increasingly reported as the first site of relapse. As patients with HER2-positive breast cancer live longer, CNS progression after radiation therapy and / or surgery is an emerging clinical challenge. The average progression free interval intracranially is unknown for women who receive radiation for brain metastases while on modern HER2 targeted therapy. Multiple novel systemic agents are under investigation for the treatment of HER2 positive breast cancer metastatic to the brain. In order to establish a historical control for early phase clinical trials, understanding this time to progression is critical. In our retrospective chart review, we sought to determine the time to progression intracranially for women with HER2+ breast cancer who receive CNS radiation and/or surgery while on modern HER2 targeted systemic therapy. We present preliminary results from our review of 48 patients with HER2+ breast cancer with brain metastases treated at two academic referral centers between 2010-2017. 36 of these patients received some form of local therapy for brain metastases. Mean age at the time of diagnosis with primary breast cancer was 52, with a mean age of 55 at the time of diagnosis of brain metastases. The minority of patients (n=16) were stage IV at the time of their initial diagnosis. Standard of care systemic treatment was given in 43/48 cases. Mean length of time from the diagnosis of the primary breast cancer to the diagnosis of brain metastases was 34.6 months, including 3 patients diagnosed at initial presentation and at the other extreme, 2 patients diagnosed 9 years after their primary diagnosis of cancer. Of the patients who received treatment for brain metastases and for whom data was available (n=33), mean time from first treatment for brain metastases to first brain recurrence was 8.24 months (range: 1 to 24 months). 7 patients (21%) recurred within 3 months. In 9 patients mortality data was available. Mean time from treatment to death was 20 months (range 1 - 58 months). For patients who underwent surgery alone as primary treatment, mean time until first recurrence was 7.1 months (n=14), compared with a mean of 7.8 months for patients who received WBRT (n=26). Patients who received both surgery and radiation as a primary treatment had a mean time from first treatment to recurrence of 11.5 months (n=4). Only 34% of patients changed systemic treatment after the diagnosis of brain metastases. 5 patients had brain metastases as their only site of measurable disease. Only 1 of these patients had a change in systemic treatment after the diagnosis of brain metastases. These results suggest that the time from initial local treatment for brain metastases to recurrence is devastatingly short. Future clinical trials in metastatic HER2+ breast cancer should consider the impact novel therapeutics have on brain metastases in addition to overall and progression free survival. These data provide a historical reference for evaluating the impact of novel therapies on HER2-postive brain metastases. Citation Format: Jacklyn Marie Nemunaitis, Krisha Mehta, Selina Liu, Ursa Brown-Glaberman, Alison Stopeck. Retrospective analysis of time to progression intracranially in HER2+ breast cancerpatients with brain metastases who receive treatment with radiation [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 PS14-20.

Skeletal-related events (SREs) are complications of bone metastases and carry a significant patient and economic burden. Denosumab is a receptor activator of nuclear factor-κB ligand (RANKL) inhibitor approved for SRE prevention in patients with multiple myeloma and patients with bone metastases from solid tumors. In phase 3 trials, denosumab showed superiority to the bisphosphonate zoledronate in reducing the risk of first on-study SRE by 17% (median time to first on-study SRE delayed by 8.2 months) and the risk of first and subsequent on-study SREs by 18% across multiple solid tumor types, including some patients with multiple myeloma. Denosumab also improved pain outcomes and reduced the need for strong opioids. Additionally, a phase 3 trial showed denosumab was noninferior to zoledronate in delaying time to first SRE in patients with newly diagnosed multiple myeloma. Denosumab has a convenient 120 mg every 4 weeks recommended dosing schedule with subcutaneous administration. Rare but serious toxicities associated with denosumab include osteonecrosis of the jaw, hypocalcemia, and atypical femoral fracture events, with multiple vertebral fractures reported following treatment discontinuation. After a decade of real-world clinical experience with denosumab, we are still learning about the optimal use and dosing for denosumab. Despite the emergence of novel and effective antitumor therapies, there remains a strong rationale for the clinical utility of antiresorptive therapy for SRE prevention. Ongoing studies aim to optimize clinical management of patients using denosumab for SRE prevention while maintaining safety and efficacy.

Introduction: Breast cancer is the most common cancer in women. In 2013, 5% of US women presenting with de novo Stage IV breast cancer cases were under age 40, and 16% under age 50. The purpose of our study was to analyze changes in demographics and clinical characteristics of patients with de novo Stage IV breast cancer at our tertiary care institution with a focus on younger women. Methods: Our study is a retrospective chart review of 159 female patients who presented with de novo Stage IV breast cancer to our institution during years 2007-2019. Patients with recurrent Stage IV breast cancer were excluded. Charts of patients were reviewed and the following data was recorded: age at diagnosis, race, insurance, menopausal status, symptoms, family history, how cancer was diagnosed, prior breast imaging, genetics testing, tumor histology, and sites of metastasis. Data was further subdivided into younger (under age 50) and older (over age 69) groups. Results: Data analysis revealed median age of 61 and range of 26-92. 14/159 women (9%) diagnosed with de novo stage IV breast cancer were younger than 40. 40/159 (25%) were younger than 50, and 119/159 (75%) were age 50 or older. Over the last decade, proportion of younger women presenting with de novo Stage IV breast cancer did not change, while 86% increase was seen in older age group. Among younger women, 72% were Non-Hispanic Whites, 10% Hispanic and 12% Black. Over the last decade, proportion of non-Hispanic whites younger than 50 with de novo Stage IV disease decreased by 38%, 50% increase was seen in Blacks and four-fold increase in Hispanics. Majority of women noted a breast mass prior to diagnosis, 72% of younger group and 75% older group. 35% of younger group presented with additional symptoms such as bone pain compared to 52% older women. 27% of younger group initially presented with an ulcerated breast lesion compared to 47% older group. Proportion with family history of breast cancer was similar, 57% in younger group and 52% older group. 90% of younger women had invasive ductal cancer. Tumors were hormone receptor positive in 65% of younger women compared to 82% older group. 90% of younger women were insured, compared to 100% older group. 60% of younger group were diagnosed by their primary care physician compared to 42% older group. 17% younger women had prior breast imaging. All women younger than 50 were offered genetics testing, 10% elected to undergo testing. Of those women, 18% under age 40 and 31% under age 50 were found to have deleterious mutations. Conclusion: Our study analyzed the demographics and clinical characteristics of younger patients presenting with de novo metastatic breast cancer over the last 10 years. In our tertiary center serving a suburban area, the proportion of women younger than 40 with de novo Stage IV breast cancer was 9% compared to 5% nationwide. Similarly, the proportion younger than 50 was 25% compared to 16% nationwide. Overall, the proportion of younger women presenting with de novo Stage IV breast cancer has not significantly changed over the past decade. This stability is particularly interesting in view of recent changes in area demographics in which the Hispanic population has increased by 2% over the past 4 years. In our study, the racial breakdown did significantly change with 38% decrease in non-Hispanic whites while 50% increase was seen in Blacks and four-fold increase in Hispanics. Finally, 90% of younger women were insured suggestive of sufficient access to care. In fact, a majority of the younger were initially diagnosed by their primary care physician. However, only a minority had prior breast imaging highlighting the need for increased awareness and education of both community and primary providers in areas of high incidence of premenopausal Stage IV breast cancer. Citation Format: Lea Baer, Adam Khorasanchi, Alison Stopeck, Andrzej Kudelka, Jules Cohen. Need for increased awareness in high incidence areas of premenopausal de novo stage IV breast cancer [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 P6-11-09.

Introduction: Breast cancer is the most common cancer in women. In 2013, 16% of US women presenting with de novo Stage IV breast cancer cases were under age 50. The purpose of our study was to analyze the demographics and clinical characteristics of patients with de novo Stage IV breast cancer at our large tertiary care institution in the view of dramatic changes in the racial and ethnic makeup of Suffolk County, Long Island over the last 10 years. Methods: Our study is a retrospective chart review of 159 female patients who presented with de novo Stage IV breast cancer to our institution during the years 2007-2019. Patients with recurrent Stage IV breast cancer were excluded. Charts of patients were reviewed and the following data was recorded: age at diagnosis, race, insurance status, menopausal status, presenting symptoms, family history, setting in which breast cancer was diagnosed, tumor histology, and sites of metastasis. Data was further subdivided into younger (under age 50) and older age groups (over age 69). Characteristics were compared using these groups. Results: Data analysis revealed median age at diagnosis of 61, with a range between 26 and 92. 25% percent of women were under age 50, 50% ages 50-69 and 25% percent were 70 years of age or older. Over the last decade, proportion of younger women with de novo Stage IV breast cancer did not change significantly while there was a 14% increase in women presenting between ages 50 to 69, and 86% in the older subgroup. 80% were Non-Hispanic White, 9% Hispanic, 7% African-American. Over this past decade, non-Hispanic whites increased by 27%, 175% increase in Hispanics, and 20% increase in African-Americans. Overall, women were well-insured with 90% in younger group and 100% in older group having coverage at time of presentation. 60% of younger group were first diagnosed by their primary care physician compared to 42% of older group. Only 17% of younger group were diagnosed incidentally compared to 40% of older group. A majority of women had a known mass prior to diagnosis, 72% in younger group and 75% older group. 35% of younger group presented with other symptoms such as bone pain, weight loss compared to 52% of older group. 27% of younger women initially presented with an unrelated condition compared to 47% of older group. Proportion of patients with family history of breast cancer were similar, 57% in younger group and 52% in older group. Overall, 26% were premenopausal. 73% had invasive ductal cancer. Majority had hormone receptor positive tumors, 65% in younger group compared to 82% older group. Finally, 54% of patients presented with multiple metastatic sites, 30% in both younger and older groups. Conclusion: Our study analyzed the demographics and clinical characteristics of patients with de novo Stage IV breast cancer at our large tertiary care institution over the last 10 years. The proportion of women 50 or younger diagnosed with de novo Stage IV breast cancer was 25% percent compared to 16% nationwide. The proportion of women presenting at age 70 or older has significantly increased over the past decade. This may be due to improving women’s life expectancy in the US but changes in patterns of screening of older women needs to be evaluated as well. Over this past decade there was a 175% increase in Hispanic women presenting with de novo Stage IV breast cancer. This is in the setting of changing demographics of Suffolk County, Long Island which has increased its Hispanic population by 2% over the past 4 years according to census data. This dramatic change in mostly insured patients highlights the need for improved awareness and community outreach in this population. Citation Format: Adam Khorasanchi, Lea Baer, Alison Stopeck, Andrzej Kudelka, Jules Cohen. Recent demographic changes show significant impact on age distribution and clinical characteristics of women presenting with de novo stage IV breast cancer [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 P2-08-29.

Background. Preclinical and observational evidence supports cancer prevention activity of non-steroidal anti-inflammatory drugs (NSAIDs) in the breast via suppression of prostaglandin E2 (PGE2) synthesis by cyclooxygenase-2 (COX2). Evidence includes linking of PGE2 to aromatase activity and estrogen synthesis in breast adipose tissue, as well as effects on collagen and breast density (BD). Methods. In an open-label trial, we evaluated the effect of the non-selective NSAID sulindac at 150 mg bid for 12 months on BD in 52 postmenopausal women taking adjuvant aromatase inhibitors (AIs) for breast cancer. BD was measured using a fat-water decomposition MRI based BD measure (MRD) previously shown to be more quantitative than mammographic density. A non-randomized observation cohort of 46 postmenopausal women on AI without NSAID use was conducted in parallel to assess the effect of AI on MRD over 12 months. Eligible participants were recruited at two study sites and included women with an intact, unaffected contralateral breast and BI-RADS ≥ 2. Each subject’s MRI_BD measures at baseline and at 6 and 12 months were included in linear mixed models for longitudinal data. Log-transformation was applied to the outcome of BD. Covariates included log-transformed baseline BD, time on AI, and baseline body mass index (BMI) and change in BMI. Breast tissue collagen fiber alignment for 30 women with paired breast biopsies, before and after 6 months on sulindac, was examined using Second-Harmonic Generation (SHG) microscopy and analysis of the distribution (histogram) of ‘straight’ fibers in three randomly selected areas of breast tissue. Straightness of individual fibers was calculated as the linear length of a fiber divided by the distance along the fiber. Results. Participants on sulindac intervention had a significant change in BD relative to baseline BD at 6 (p=0.05) and 12 months (p Citation Format: Patricia Thompson, Chuan Huang, Betsy Wertheim, Christina Preece, Jie Yang, Jessica Martinez, Denise Roe, Pavani Chalasani, Alison Stopeck. Sulindac reduces breast density and alters collagen alignment in patients on aromatase inhibitors [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 PD3-09.

PURPOSE: To examine benefit of sulindac for relief of musculoskeletal symptoms (MSS) in patients stable on aromatase inhibitors (AIs). METHODS: Sulindac was evaluated at 150 mg twice daily for effects on MSS at 3, 6, 9, and 12 months in 50 postmenopausal women stable on AI therapy for a median of 12.5 months for hormone receptor positive breast cancer. A separate, non-randomized group of 50 similar patients was observed for change in MSS over 12 months. MSS severity was assessed using the Western Ontario and McMaster Universities Osteoarthritis (WOMAC) Index and Brief Pain Inventory Short Form (BPI-SF). The Functional Assessment of Cancer Therapy – General form (FACT-G) measured quality of life (QOL). Change in MSS and QOL across time was assessed in each group using linear mixed effects models. RESULTS: Stiffness, not pain, was the main complaint at baseline. At 12 months, sulindac patients reported decreases (improvements) in mean [95% CI] Total WOMAC score (−5.85 [−9.73, −1.96]) and WOMAC pain (−5.40 [−10.64, −0.18]), Stiffness (−9.53 [−14.98, −4.08]) and Physical Function (−5.61 [−9.62, −1.60]) subscales, but not BPI-SF worst pain. Among sulindac patients with higher baseline MSS severity, 35% experienced ≥50% improvement in Total WOMAC, and Total FACT-G scores (6.18 [2.08, 10.27]; p = 0.003). For the observation group, MSS and QOL did not improve over 12 months, even among those with higher baseline MSS severity. CONCLUSIONS: Sulindac may relieve MSS in AI patients, especially physical function, and stiffness. Randomized controlled trials should further evaluate NSAIDs on AI-MSS and AI adherence.

Circulating blood plasma derived extracellular vesicles (BEVs) containing proteins hold promise for their use as minimally invasive biomarkers for predicting response to cancer therapy. The main goal of this study was to establish the efficiency and utility of the particle purification liquid chromatography (PPLC) BEV isolation method and evaluate the role of BEVs in predicting breast cancer (BC) patient response to neoadjuvant chemotherapy (NAC).PPLC isolation was used to separate BEVs from non-EV contaminants and characterize BEVs from 17 BC patients scheduled to receive NAC. Using LC-MS/MS, we compared the proteome of PPLC-isolated BEVs from patients (n = 7) that achieved a pathological complete response (pCR) after NAC (responders [R]) to patients (n = 10) who did not achieve pCR (non-responders [NR]). Luminal MCF7 and basaloid MDA-MB-231 BC cells were treated with isolated BEVs and evaluated for metabolic activity by MTT assay.NR had elevated BEV concentrations and negative zeta potential (ζ-potential) prior to receipt of NAC. Eight proteins were enriched in BEVs of NR. GP1BA (CD42b), PECAM-1 (CD31), CAPN1, HSPB1 (HSP27), and ANXA5 were validated using western blot. MTT assay revealed BEVs from R and NR patients increased metabolic activity of MCF7 and MDA-MB-231 BC cells and the magnitude was highest in MCF7s treated with NR BEVs.PPLC-based EV isolation provides a preanalytical separation process for BEVs devoid of most contaminants. Our findings suggest that PPLC-isolated BEVs and the five associated proteins may be established as predictors of chemoresistance, and thus serve to identify NR to spare them the toxic effects of NAC.

Clinical practice guidelines recommend the use of bone-targeting agents for preventing skeletal-related events (SREs) among patients with bone metastases from solid tumors. The anti-RANKL monoclonal antibody denosumab is approved for the prevention of SREs in patients with bone metastases from solid tumors. However, real-world data are lacking on the impact of individual risk factors for SREs, specifically in the context of denosumab discontinuation.We aim to identify risk factors associated with SRE incidence following denosumab discontinuation using a machine learning approach to help profile patients at a higher risk of developing SREs following discontinuation of denosumab treatment.Using the Optum PanTher Electronic Health Record repository, patients diagnosed with incident bone metastases from primary solid tumors between January 1, 2007, and September 1, 2019, were evaluated for inclusion in the study. Eligible patients received ≥ 2 consecutive 120 mg denosumab doses on a 4-week (± 14 days) schedule with a minimum follow-up of ≥ 1 year after the last denosumab dose, or an SRE occurring between days 84 and 365 after denosumab discontinuation. Extreme gradient boosting was used to develop an SRE risk prediction model evaluated on a test dataset. Multiple variables associated with patient demographics, comorbidities, laboratory values, treatments, and denosumab exposures were examined as potential factors for SRE risk using Shapley Additive Explanations (SHAP). Univariate analyses on risk factors with the highest importance from pooled and tumor-specific models were also conducted.A total of 1,414 adult cancer patients (breast: 40%, prostate: 30%, lung: 13%, other: 17%) were eligible, of whom 1,133 (80%) were assigned to model training and 281 (20%) to model evaluation. The median age at inclusion was 67 (range, 19-89) years with a median duration of denosumab treatment of 253 (range, 88-2,726) days; 490 (35%) patients experienced ≥ 1 SRE 83 days after denosumab discontinuation. Meaningful model performance was evaluated by an area under the receiver operating curve score of 77% and an F1 score of 62%; model precision was 60%, with 63% sensitivity and 78% specificity. SHAP identified several significant factors for the tumor-agnostic and tumor-specific models that predicted an increased SRE risk following denosumab discontinuation, including prior SREs, shorter denosumab treatment duration, ≥ 4 clinic visits per month with at least one hospitalization (all-cause) event from the baseline period up to discontinuation of denosumab, younger age at bone metastasis, shorter time to denosumab initiation from bone metastasis, and prostate cancer.This analysis showed a higher cumulative number of SREs, prior SREs relative to denosumab initiation, a higher number of hospital visits, and a shorter denosumab treatment duration as significant factors that are associated with an increased SRE risk after discontinuation of denosumab, in both the tumor-agnostic and tumor-specific models. Our machine learning approach to SRE risk factor identification reinforces treatment guidance on the persistent use of denosumab and has the potential to help clinicians better assess a patient's need to continue denosumab treatment and improve patient outcomes.

Background Adjuvant bisphosphonates, when given in a low-estrogen environment, can decrease breast cancer recurrence and death. Treatment guidelines include recommendations for adjuvant bisphosphonates in postmenopausal patients. SWOG/Alliance/Canadian Cancer Trials Group/ECOG-ACRIN/NRG Oncology study S0307 compared the efficacy of three bisphosphonates in early-stage breast cancer. Methods Patients with stage I–III breast cancer were randomly assigned to 3 years of intravenous zoledronic acid, oral clodronate, or oral ibandronate. The primary endpoint was disease-free survival (DFS) with overall survival as a secondary outcome. All statistical tests were two-sided. Results A total of 6097 patients enrolled. Median age was 52.7 years. Prior to being randomly assigned, 73.2% patients indicated preference for oral vs intravenous formulation. DFS did not differ across arms in a log-rank test (P = .49); 5-year DFS was 88.3% (zoledronic acid: 95% confidence interval [CI] = 86.9% to 89.6%), 87.6% (clodronate: 95% CI = 86.1% to 88.9%), and 87.4% (ibandronate: 95% CI = 85.6% to 88.9%). Additionally, 5-year overall survival did not differ between arms (log rank P = .50) and was 92.6% (zoledronic acid: 95% CI = 91.4% to 93.6%), 92.4% (clodronate: 95% CI = 91.2% to 93.5%), and 92.9% (ibandronate: 95% CI = 91.5% to 94.1%). Bone as first site of recurrence did not differ between arms (P = .93). Analyses based on age and tumor subtypes showed no treatment differences. Grade 3/4 toxicity was 8.8% (zoledronic acid), 8.3% (clodronate), and 10.5% (ibandronate). Osteonecrosis of the jaw was highest for zoledronic acid (1.26%) compared with clodronate (0.36%) and ibandronate (0.77%). Conclusions We found no evidence of differences in efficacy by type of bisphosphonate, either in overall analysis or subgroups. Despite an increased rate of osteonecrosis of the jaw with zoledronic acid, overall toxicity grade differed little across arms. Given that patients expressed preference for oral formulation, efforts to make oral agents available in the United States should be considered.

Purpose: Recent observations suggest a positive association between the presence of tumor-associated myeloid and lymphoid immune cells and clinical responses to HER2 therapies. The specific immune cell composition of HER2+ tumors and the effects of therapy on the tumor immune microenvironment remains poorly understood; limiting efforts to effectively direct immunomodulatory agents in HER2+ breast cancer. We sought to assess the feasibility of a multiplex immunofluorescence strategy to characterize the immune milieu of HER2+ tumors, pre and post treatment. Methods: We conducted a feasibility study using the Perkin Elmer OPAL multiplex dye chemistry for immunofluorescence of tumor, myeloid, and lymphoid cells in pretreatment biopsy and surgical resection tissues of 11 patients who received neoadjuvant HER2 antibody with chemotherapy. Two panels of up to 6 antibodies were studied including a predominantly myeloid panel targeting CD80, CD68, CD163, CD206, PD-L1, and cytokeratin; and a 'lymphoid/proliferation' panel targeting FoxP3, cytokeratin, Granzyme B, CD4, CD8, and Ki67. For paired samples, analysis of pre/post differences were analyzed using two tailed, t-test. Results: 100% of the pre-treatment biopsy samples yielded high quality immune and tumor cell immunofluorescence profiles for both panels. In contrast, post treatment specimens were more challenging. For the post treatment tissues, ˜25% of specimens failed to yield results in at least one panel. As shown in Table 1, the %CD206+ M2 type macrophage population increased between pre and post treatment (p=0.012). This was reflected in a decrease in the M1:M2 ratio and variability in the ratio in favor of M2 (median 0.34 [IQR = 1.01] to 0.11 [IQR=0.10], p=0.0003). In the lymphoid panel, we observed a non-significant reduction in % FoxP3+CD4 T cells with less variability between patients post treatment and a significant decrease in total CD8+ T cells. Further, there was a significant reduction in %Granzyme B positive T cells (median 6.63 to MarkerSampleMinMedianMaxIQR%CD206+ Mono/MacPre1.358.7135.8911.05%CD206+ Mono/MacPost25.438.9777.621.54M1/M2 RatioPre0.110.342.141.01M1/M2 RatioPost0.030.110.210.1%Ki67+ T cellsPre0.137.9220.0411.06%Ki67+ T cellsPost04.5621.836.31%PD-L1+ MyeloidPre01.0512.060.95%PD-L1+ MyeloidPost00.554.261.47%Granzyme B T cellsPre2.926.6333.727.2%Granzyme B T cellsPost00.892.481.73%FoxP3+ CD4 +Pre01.6456.0416.44%FoxP3+ CD4 +Post01.166.824.14#Total CD8+ T cellsPre5788,36635,42615,744#Total CD8+ T cellsPost121,3717,9043,658 Conclusions: Multiplex immune profiling is a practical approach to characterize the tumor immune microenvironment in biopsy and post treatment specimens. Neoadjuvant HER2 targeted chemotherapy significantly shifts the myeloid population to an M2 (immunosuppressive) phenotype with evidence for a reduction in the number of Ki67 and Granzyme B+ T cells. These preliminary results suggest immunomodulatory agents that are able to induce or maintain an M1 polarized tumor microenvironment may have utility to enhance long term anti-tumor immunity in HER2 disease. Citation Format: Thompson PA, Uhlik M, Preece C, Gorden K, Harrison B, Graff J, Stopeck A. M2 macrophages increase after neoadjuvant HER2 targeted chemotherapy [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-12-11.

Introduction: Breast cancer is the most common cancer in women. In postmenopausal women with early stage estrogen receptor positive breast cancer, aromatase inhibitors (AI) are a common treatment option. AI's are reported to lead to a high early discontinuation rate in younger post-menopausal women due to poor tolerance. The most common side effects reported to lead to early discontinuation are arthralgia, hot flashes, fatigue, and night sweats. The reported tolerance to AI therapy in women age 75 or older is not well documented. Our study looks at women, ages 75 and older, diagnosed with early stage breast cancer who were placed on adjuvant AI therapy and focuses on tolerability, incidence of common side effects, rate of treatment changes, and on discontinuation rates. Objective: This study evaluates the tolerability, treatment side effects and the discontinuation rate of AI in women over the age of 75 with early stage breast cancer. Methods: Our study is a retrospective chart review of 58 patients' ages 75 to 95 with early stage breast cancer treated with adjuvant AI. Charts of patients were reviewed and duration of treatment, patient reported side effects, treatment changes, and discontinuation rate were recorded. Results: Data analysis showed that 36/55 (65.5%) of patients did not report significant side effects to AI. 6/55 (10.9%) patients required therapy changes due to side effects. 5/6 required one treatment change and 1/6 required multiple treatment changes. In 5/6 therapy was changed to another AI. Only 2/55 (3.6%) of patients discontinued therapy. In both patients who discontinued AI, therapy was discontinued due to medical complications unrelated to AI therapy. Average time to discontinuation was 11 months. The most common reported side effects were arthralgia 9/55 (16.4%), fatigue 3/55 (5.5%), hot flashes 4/55 (7.3%), rash 3/55 (5.5%) and hair thinning 3/55 (5.5%). The most common reported side effect which led to treatment change was arthralgia 4/6 (66.7%). With a median follow up time of 24 months, breast cancer specific mortality was 1/55 (1.8%). Reported Side Effects on AIn=55 patientsPatients who noted symptomsPatients who changed therapy due to symptomsFatigue30Arthralgia94Hot flashes40Rash31Vaginal dryness10Hair thinning31 Conclusion: Our study evaluated the tolerance of AI in older women diagnosed with early stage breast cancer. 36/55 (65.5%) of elderly patients reported no significant side effects suggesting that AI's are well tolerated in this population and the known side effects are significantly less common than previously reported in a younger cohort in whom arthralgia as well as vasomotor symptoms affect as many as 30% of women. This improved tolerance led to a significantly lower early discontinuation rate than previously reported in the younger cohort: discontinuation rate of 3.6% by 24 months in the 75 or older population versus 20% by 24 months in the younger cohort of post-menopausal women treated with AI. Reference: 1 Wagner, L.I., Zhao, F., Goss, P.E. et al. Breast Cancer Res Treat (2018) 169: 537. https://doi-org.proxy.library.stonybrook.edu/10.1007/s10549-018-4713-2 Citation Format: Chaudhry B, Baer L, Kudelka A, Cohen J, Stopeck AT. Aromatase inhibitors are significantly better tolerated by early stage breast cancer patients 75 or older and with significantly lower early discontinuation rate [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-11-22.

Background: CPI monotherapy provides substantial clinical benefit to patients (pts) in multiple cancers, yet response rates are limited (˜15-30%) and fails to benefit the majority. In these pts there is limited or no ongoing T cell-based immune response. Imprime PGG (Imprime), a novel beta glucan derived from Saccharomyces, may expand the clinical benefit of CPI therapy by stimulating an anti-cancer immune response. Acting as a pathogen-associated molecularpattern (PAMP), Imprime enlists innate immune functions including cytotoxic effector mechanisms, reversal of immunosuppression and cross-talk with the adaptive immune system.Imprime-mediated innate immune activation requires formation of an immune complex with naturally-occurring anti-beta glucan antibodies (ABA); sufficient ABA levels is required for complex formation. Imprime is now being studied in combination with pembrolizumab (KEYTRUDA®,Pembro), a humanized mAb against PD-1 which has been previously studied in TNBC pts. Methods: In this study of patients who previously failed chemotherapy for metastatic TNBC, Imprime is being used in combination with Pembro in a Simon 2 stage design. Asample size of 12 evaluable pts in Stage 1 was planned.Evaluable pts received at least one dose of study treatment (tx), had measurable disease at baseline per RECIST v1.1, had at least one post-baseline scan or discontinued tx as a result of progressive disease, death, or a tx-related adverse event before the first post-baseline scan.Pts received Imprime (4 mg/kg IV days 1, 8, 15 of each 3-week cycle) + Pembro 200 mg on D1 of each cycle. Criteria to advance to Stage 2 were ≤4 grade 3/4 AEs during the first tx cycle (other than infusion reactions) and ≥1 objective response. Study primary endpoints are ORR and safety; secondary endpoints are TTR, CRR, DoR, PFS, and OS. Exploratory endpoints include ORR and PFS per irRECIST. Biopsies and blood samples are being collected to assess tx impact on immune activating events at the tumor site and in the periphery. Results: A review of efficacy and safety data was conducted at the end of Stage 1. Thirteen pts (12 evaluable) were enrolled into Stage 1. Safety review noted 2 grade 3 adverse events that met protocol definition of Stage 1 events (1 pt: cellulitis and 1 pt: pleural infusion; both unrelated to treatment). Two events lead to 2 pts discontinuing treatment (infusion reaction and pancreatitis) and only 1 autoimmune event was observed (pancreatitis). Observed efficacy responses in the evaluable pts included 1 complete response (CR; ongoing) and 2 partial responses (PR; ongoing). Secondary efficacy endpoints have not been assessed. Early translational results support proposed MOA and analysis of Stage 1 translational data is ongoing. Conclusion: The use of Imprime with Pembro was well tolerated and met both safety and efficacy requirements to move forward with Stage 2 of the study. No significant safety concerns were identified in Stage 1. Further investigation is thus warranted and enrollment into Stage 2 is ongoing. Updated data will be presented. Citation Format: O'Day S, Borges V, Chmielowski B, Rao R, Abu-Khalaf M, Stopeck A, Lowe J, Mattson P, Breuer K, Gargano M, Bose N, Uhlik M, Graff J, Chisamore M, Cox J, Osterwalder B. Imprime PGG, a novel innate immune modulator, combined with pembrolizumab in a phase 2 multicenter, open label study in chemotherapy-resistant metastatic triple negative breast cancer (TNBC) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-09-08.

Purpose: Statins may mediate suppression of molecular pathways conferring benefit in cancer. Statins have shown anti-tumor effects in preclinical studies and have been associated with decreased recurrence and improved disease-specific survival. While designed to target cholesterol biosynthesis, statins can also have liver, bone and brain effects. We collected data on statin use in the S0307 adjuvant bisphosphonate trial to test the hypothesis that statin use may decrease risk of recurrence to liver, bone and brain as well as second primary (contralateral) breast cancers, and may act synergistically with bisphosphonates to decrease the risk of recurrence to bone. Patients and Methods: In S0307, 6097 patients diagnosed with Stage I-III breast cancer who had undergone surgery and were receiving adjuvant systemic therapy were randomized to receive zoledronic acid, clodronate, or ibandronate for 3 years. No significant difference was found in disease-free survival (DFS) among the 3 groups, including a sub-analysis of patients > age 55. Statin use was infrequent in younger women in S0307, consequently we analyzed statin use in those > age 55. Cox proportional hazard models were used to determine which variables were independently associated with DFS and to estimate hazard ratios (HR) and 95% confidence intervals (CI). Results: Among women aged ≥ 55 years, 684 (27%) reported taking a statin at baseline and 1,848 did not. Both groups were similar in terms of hormone receptor and HER2 status (p = 0.82). Median age in the statin group was 64.3 versus 61.0 years in the no statin group, mean BMI 31.2 v. 29.5, mean tumor size 2.1cm v. 2.3cm, negative lymph nodes 60% v. 54%, Stage I disease 47% v. 36%, and receipt of chemotherapy 62% v. 71% (all p < 0.01). In the statin group, 122 (17.8%) experienced a DFS event compared to 313 (16.9%) in the no statin group (HR 1.18, CI 0.95-1.46). No difference was observed by statin use in overall recurrence (p=0.28), distant recurrence (p=0.64), or recurrences to the bone (p=0.64), liver (p=0.38) or brain (p=0.65) at initial recurrence. There was no synergy between statin use and specific bisphosphonates. Recurrence and statin useOutcomeGroup 1: On stan at baseline n=684Group 2: No statin at baseline n=1848DFS events122 (17.8%)313 (16.9%)Died without recurrence51 7.5%)97 (5.2%)Recurrence71 (10.4%)216 (11.7%)Contralateral breast cancer9 (1.3%)17 (0.9%)Distant recurrence48 (7%)157 (8.5%)Bone as 1st site of distant recurrence (% distant recurrence)31 (65%)76 (48%)Liver as 1st site of distant recurrence (% distant recurrence)6 (13%)24 (16%)Brain/CNS as 1st site of distant recurrence (% distant recurrence)5 (10%)17 (11%) Conclusions: We found no evidence that statins reduce risk of second primary breast cancers or distant metastases among post-menopausal women with early-stage breast cancer. Despite promising preclinical data, they did not appear to act in synergy with a specific bisphosphonate. Though women in the statin group had less advanced disease at study entry, statin use was not associated with improved DFS. Results are limited by lack of information about type of statin used, adherence, or initiation of statin in control group. Citation Format: Kizub D, Miao J, Stopeck A, Thompson P, Paterson AH, Clemons M, Dees EC, Ingle JN, Falkson CI, Barlow W, Hortobagyi GN, Gralow JR. Statin use, site of recurrence, and survival among post-menopausal women taking bisphosphonates as adjuvant therapy for breast cancer (SWOG S0307) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-17-03.

Introduction: Breast cancer is the most common cancer in women. In estrogen receptor positive breast cancers aromatase inhibitors (AI) are a common treatment option. AIs are associated with a reduction in bone mineral density, and patients with osteopenia at baseline have a higher risk of developing subsequent osteoporosis while on AI therapy. Women age 75 and older are a fast growing subset of breast cancer patients and commonly have osteopenia or osteoporosis at time of breast cancer diagnosis. Studies of long-term effects of AI on bone density in these older women who are at higher risk of osteoporosis and musculoskeletal events are lacking at this time. Objective: To evaluate the objective change in bone density in women over the age of 75 diagnosed with early stage breast cancer and treated with AI. Methods: A retrospective chart review of 49 patients ages 75 to 95 diagnosed with early stage breast cancer and treated with AI. Pretreatment DEXA scan results were recorded as well as prevalence of bone targeted therapy at the time of breast cancer diagnosis. Incidence of bone targeted therapy initiated subsequent to cancer diagnosis and changes in T score on follow up DEXA scans were collected as well. Incidence of musculoskeletal events and osteonecrosis of the jaw were recorded. Results: 40/49 (81.6%) of study women were found to have osteopenia (23/49 [46.9%]) or osteoporosis (17/49 [34.7%]) on pre-treatment DEXA scans. Only 16/49 (32.7%) of patients were on bone-targeted treatment prior to breast cancer diagnosis. Of the patient with baseline osteoporosis, only 4/17 (23.5%) were on bone targeted treatment prior to breast cancer diagnosis. 25/49 (51%) of women were initiated on bone targeted therapy subsequent to breast cancer diagnosis and following review of pretreatment DEXA scan results. 5/49 (10.2%) of women were started on bisphosphonates and 7/49 (14.3%) were started on Denosumab. On the first subsequent DEXA scan at a median follow up of 2 years, 14/21(66.7%) of women were noted to have stable DEXA findings (defined as change in T score less than 0.5). 7/21 (33.3%) had a worsening T score on repeat DEXA. Of those patients with worsening T score, 3/7 (42.9%) changed categories (either from normal density to osteopenia or from osteopenia to osteoporosis. 3/49 (6%) of patients sustained a fracture while on AI therapy. There were no reported events of osteonecrosis of the jaw. Subsequent DEXA showing stabilitySubsequent DEXA showing worsening T scoreFractureBaseline Normal bone density1 (n=3)2 (n=3)1 (n=9)Baseline Osteopenia9 (n=12)3 (n=12)0 (n=12)Baseline Osteoporosis4 (n=6)2 (n=6)2 (n=17) Conclusion: Many elderly women are found to have osteopenia or osteoporosis at the time of breast cancer diagnosis and AI initiation. Most elderly patients had stable findings on subsequent bone density testing. Women with known osteoporosis initiated on bone-targeted therapy and AI did not have significant worsening in bone health. With appropriate treatment and monitoring elderly women with baseline decreased bone density can be treated safely with aromatase inhibitors. Citation Format: Baer L, Chaudhry B, Kudelka A, Cohen J, Stopeck AT. Aromatase inhibitors and bone health in women 75 and older treated for early stage breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-11-24.

TPS1115 Background: Hormone receptor (HR) positive/ human epidermal growth factor receptor 2-negative (Her2-) breast cancer is generally considered ‘immunologically cold’ in comparison to TNBC or Her2+ breast cancer. Keynote-028 results showed a modest ORR of 12% to anti-PD1 antibody, pembrolizumab (PEM) in previously treated HR+/ HER2-/programmed death ligand 1-positive (PD-L1-positive) advanced breast cancer patients (pts). With limited options available, there is significant unmet need to expand clinical benefit from ICI. Odetiglucan, a novel beta glucan, acts as a pathogen-associated molecular pattern (PAMP) that drives a cascade of immune activating events. It repolarizes the immunosuppressive microenvironment, activates the maturation of antigen presenting cells and significantly enhances efficacy of ICI therapy in preclinical tumor models. In a Ph2 trial (IMPRIME 1) of odetiglucan + PEM in 44 pts with heavily pretreated metastatic TNBC, an ORR=15.9%, DCR=54.5%, mDOR=12.7mo, mPFS=2.86 mo, 12 mo OS rate=57.6%, and mOS=16.4 mo were observed. Clinical benefit was particularly evident in a subset of pts, mTNBC “converters” (12/44 pts) who were originally diagnosed with ER/PR+ disease and progressed through endocrine therapies +/- CDK4/6 inhibitors. In these 12 pts, an ORR=50%, DCR=83%, mDOR=11.2, mPFS=5.6 mo, 12-mo OS rate=64.8%, and mOS=17.4 mo were observed. Methods: Odetiglucan + PEM is now being explored in pts with hormone-resistant metastatic breast cancer (MBC). This is a phase 2, Simon’s 2-Stage study of MBC pts who have progressed through prior hormonal therapy with >1 CDK4/6 inhibitor. Pts will receive odetiglucan 4 mg/kg/wk + PEM 200 mg Q3wk. Stage 1 will enroll 23 pts. If >4 pts have an objective response after 12 wks of treatment, the study will proceed to Stage 2 enrolling an additional 24 pts (N=47). Rejection of the null hypothesis requires >10 objective responses. Main eligibility criteria include: MBC having failed prior hormonal therapy with >1 CDK4/6 inhibitor

Purpose: To evaluate the effect of sulindac, a nonselective anti-inflammatory drug (NSAID), for activity to reduce breast density (BD), a risk factor for breast cancer. Experimental Design: An open-label phase II study was conducted to test the effect of 12 months' daily sulindac at 150 mg twice daily on change in percent BD in postmenopausal hormone receptor–positive breast cancer patients on aromatase inhibitor (AI) therapy. Change in percent BD in the contralateral, unaffected breast was measured by noncontrast magnetic resonance imaging (MRI) and reported as change in MRI percent BD (MRPD). A nonrandomized patient population on AI therapy (observation group) with comparable baseline BD was also followed for 12 months. Changes in tissue collagen after 6 months of sulindac treatment were explored using second-harmonic generated microscopy in a subset of women in the sulindac group who agreed to repeat breast biopsy. Results: In 43 women who completed 1 year of sulindac (86% of those accrued), relative MRPD significantly decreased by 9.8% [95% confidence interval (CI), −14.6 to −4.7] at 12 months, an absolute decrease of −1.4% (95% CI, −2.5 to −0.3). A significant decrease in mean breast tissue collagen fiber straightness (P = 0.032), an investigational biomarker of tissue inflammation, was also observed. MRPD (relative or absolute) did not change in the AI-only observation group (N = 40). Conclusions: This is the first study to indicate that the NSAID sulindac may reduce BD. Additional studies are needed to verify these findings and determine if prostaglandin E2 inhibition by NSAIDs is important for BD or collagen modulation.

High-resolution PET imaging has considerable potential to improve management of breast cancer, especially if it could be acquired simultaneously with the clinical standard of breast MRI. In this multimodal approach, PET contributes critical information on specific molecular subtypes and heterogeneity, while avoiding the challenge of reproducibly positioning the breast which confronts technologists when PET and MRI images are acquired separately. Using a compact, high-resolution and MR-compatible PET system (VersaPET) mounted into a breast MRI table, we have begun to assess the feasibility of this approach by collecting preliminary FDG data on primary tumors in breast cancer patients. In order to augment this approach to examine nodal involvement, we also performed a simulation study that incorporates novel detector geometries to expand the FOV to include axillary lymph nodes which are critical for diagnosing metastasis. We evaluated scanner geometries with limited angle sampling and features including time of flight (TOF) and depth of interaction (DOI) readouts, using GATE simulation and detection-based tasks using channelized Hotelling observer (CHO). Our simulation result indicates superior performance for detection of low-grade (3:1 lesion to tissue contrast), small (3 mm diameter) lesions using the proposed scanners compared to whole-body PET. We show that the incorporation of a DOI resolution of 2 mm substantially improves the detection tasks for the proposed scanner designs, while TOF capability is less impactful.

BackgroundThe global coronavirus disease 2019 (COVID-19) pandemic offers the opportunity to assess how hospitals manage the care of hospitalized patients with varying demographics and clinical presentations. The goal of this study was to demonstrate the impact of densely populated residential areas on hospitalization and to identify predictors of length of stay and mortality in hospitalized patients with COVID-19 in one of the hardest hit counties internationally.MethodsThis was a single-center cohort study of 1325 sequentially hospitalized patients with COVID-19 in New York between March 2, 2020, to May 11, 2020. Geospatial distribution of study patients’ residences relative to population density in the region were mapped, and data analysis included hospital length of stay, need and duration of invasive mechanical ventilation (IMV), and mortality. Logistic regression models were constructed to predict discharge dispositions in the remaining active study patients.ResultsThe median age of the study cohort (interquartile range [IQR]) was 62 (49–75) years, and more than half were male (57%) with history of hypertension (60%), obesity (41%), and diabetes (42%). Geographic residence of the study patients was disproportionately associated with areas of higher population density (rs = 0.235; P = .004), with noted “hot spots” in the region. Study patients were predominantly hypertensive (MAP > 90 mmHg; 670, 51%) on presentation with lymphopenia (590, 55%), hyponatremia (411, 31%), and kidney dysfunction (estimated glomerular filtration rate < 60 mL/min/1.73 m2; 381, 29%). Of the patients with a disposition (1188/1325), 15% (182/1188) required IMV and 21% (250/1188) developed acute kidney injury. In patients on IMV, the median (IQR) hospital length of stay in survivors (22 [16.5–29.5] days) was significantly longer than that of nonsurvivors (15 [10–23.75] days), but this was not due to prolonged time on the ventilator. The overall mortality in all hospitalized patients was 15%, and in patients receiving IMV it was 48%, which is predicted to minimally rise from 48% to 49% based on logistic regression models constructed to project disposition in the remaining patients on ventilators. Acute kidney injury during hospitalization (odds ratioE, 3.23) was the strongest predictor of mortality in patients requiring IMV.ConclusionsThis is the first study to collectively utilize the demographics, clinical characteristics, and hospital course of COVID-19 patients to identify predictors of poor outcomes that can be used for resource allocation in future waves of the pandemic.

BACKGROUND Increased breast density is a significant independent risk factor for breast cancer, and recent studies show that this risk is modifiable. Hence, breast density measures sensitive to small changes are desired. PURPOSE Utilizing fat-water decomposition MRI, we propose an automated, reproducible breast density measurement, which is nonionizing and directly comparable to mammographic density (MD). STUDY TYPE Retrospective study. POPULATION The study included two sample sets of breast cancer patients enrolled in a clinical trial, for concordance analysis with MD (40 patients) and reproducibility analysis (10 patients). FIELD STRENGTH/SEQUENCE The majority of MRI scans (59 scans) were performed with a 1.5T GE Signa scanner using radial IDEAL-GRASE sequence, while the remaining (seven scans) were performed with a 3T Siemens Skyra using 3D Cartesian 6-echo GRE sequence with a similar fat-water separation technique. ASSESSMENT After automated breast segmentation, breast density was calculated using FraGW, a new measure developed to reliably reflect the amount of fibroglandular tissue and total water content in the entire breast. Based on its concordance with MD, FraGW was calibrated to MR-based breast density (MRD) to be comparable to MD. A previous breast density measurement, Fra80-the ratio of breast voxels with