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PURPOSE: Seviteronel (INO-464) is an oral, selective cytochrome P450c17a (CYP17) 17,20-lyase (lyase) and androgen receptor (AR) inhibitor with in vitro and in vivo anti-tumor activity. This open-label phase 1 clinical study evaluated safety, tolerability, pharmacokinetics (PK) and activity of once-daily (QD) seviteronel in women with locally advanced or metastatic TNBC or ER+ breast cancer. METHODS: Seviteronel was administered in de-escalating 750 mg, 600 mg and 450 mg QD 6-subject cohorts. The 750 mg QD start dose was a phase 2 dose determined for men with castration-resistant prostate cancer [1]. Enrollment at lower doses was initiated in the presence of dose-limiting toxicities (DLTs). The primary objective of this study was to determine seviteronel safety, tolerability and MTD. The secondary objectives included description of its PK in women and its initial activity, including clinical benefit rate at 4 (CBR16) and 6 months (CBR24). RESULTS: Nineteen women were enrolled. A majority of adverse events (AEs) were Grade (Gr) 1/2, independent of relationship; the most common were tremor (42%), nausea (42%), vomiting (37%) and fatigue (37%). Four Gr 3/4 AEs (anemia, delirium, mental status change and confusional state) deemed possibly related to seviteronel occurred in four subjects. DLTs were observed at 750 mg (Gr 3 confusional state with paranoia) and 600 mg (Gr 3 mental status change and Gr 3 delirium) QD, with none at 450 mg QD. The recommended phase 2 dose (RP2D) was 450 mg QD, and at the RP2D, 4 of 7 subjects reached at least CBR16 (2 TNBC subjects and 2 ER+ subjects achieved CBR16 and CBR24, respectively); no objective tumor responses were reported. CONCLUSIONS: Once-daily seviteronel was generally well tolerated in women with and 450 mg QD was chosen as the RP2D.

Obesity, a cause of subclinical inflammation, is a risk factor for the development of postmenopausal breast cancer and is associated with poorer cancer outcomes. Docosahexaenoic acid (DHA), an omega-3 fatty acid, possesses anti-inflammatory properties. We hypothesized that treatment with DHA would reduce the expression of proinflammatory genes and aromatase, the rate-limiting enzyme for estrogen biosynthesis, in benign breast tissue of overweight/obese women. A randomized, placebo-controlled, double-blind phase II study of DHA given for 12 weeks to overweight/obese women with a history of stage I–III breast cancer, DCIS/LCIS, Paget's disease, or proliferative benign breast disease was carried out. In this placebo controlled trial, the primary objective was to determine whether DHA (1,000 mg by mouth twice daily) reduced breast tissue levels of TNFα. Secondary objectives included evaluation of the effect of DHA on breast tissue levels of COX-2, IL1β, aromatase, white adipose tissue inflammation, and gene expression by RNA-seq. Red blood cell fatty acid levels were measured to assess compliance. From July 2013 to November 2015, 64 participants were randomized and treated on trial (32 women per arm). Increased levels of omega-3 fatty acids in red blood cells were detected following treatment with DHA (P < 0.001) but not placebo. Treatment with DHA did not alter levels of TNFα (P = 0.71), or other biomarkers including the transcriptome in breast samples. Treatment with DHA was overall well-tolerated. Although compliance was confirmed, we did not observe changes in the levels of prespecified biomarkers in the breast after treatment with DHA when compared with placebo. Cancer Prev Res; 11(4); 203–14. ©2018 AACR. See related editorial by Fabian and Kimler, p. 187

A growing body of literature supports the conclusion that the androgen receptor (AR) plays an important role in breast cancer pathogenesis and may prove to be a relevant therapeutic target for patients with AR-driven breast cancer. This has been most apparent in the subset of patients with triple-negative breast cancer (TNBC), in whom approximately 50% of tumors may have androgen dependence. Recent phase 2 clinical trials of agents that antagonize AR or reduce androgen production have shown clinical benefit and efficacy to varying degrees. This review highlights three of these recent trials of AR+ TNBC and acknowledge ongoing research in this exciting area.

Context Most estrogen-dependent breast cancers occur after menopause, despite low levels of circulating estrogens. Breast expression of the estrogen-biosynthetic enzyme, aromatase, is proposed to drive breast cancer development after menopause. However, the effects of menopause on breast aromatase expression are unknown. Objective To determine the effect of menopause on breast aromatase expression in relation to body mass index (BMI), white adipose tissue inflammation (WATi), and systemic markers of metabolic dysfunction. Design, setting, and participants Cross-sectional study of 102 premenopausal (age 27 to 56) and 59 postmenopausal (age 45 to 74) women who underwent mastectomy for breast cancer treatment/prevention. Outcome Breast tissue was assessed for the presence of crown-like structures and the expression and activity of aromatase. Systemic markers examined include interleukin (IL)-6, insulin, glucose, leptin, adiponectin, high-sensitivity C-reactive protein (hsCRP), cholesterol, and triglycerides. Multivariable analysis was performed for aromatase messenger RNA (mRNA) in relation to BMI, WATi, and blood markers. Results Postmenopausal women had higher BMI and more breast WATi than premenopausal women. Fasting levels of IL-6, glucose, leptin, hsCRP, and homeostatic model assessment 2 insulin resistance score were higher in the postmenopausal group. BMI was positively correlated with aromatase mRNA in both pre- and postmenopausal women. Aromatase levels were higher in breast tissue of postmenopausal women, with levels being higher in inflamed vs noninflamed, independent of BMI. Adipocyte diameter and levels of leptin, hsCRP, adiponectin, and high-density lipoprotein cholesterol were more strongly correlated with aromatase in postmenopausal than premenopausal women. Conclusions Elevated aromatase in the setting of adipose dysfunction provides a possible mechanism for the higher incidence of hormone-dependent breast cancer in obese women after menopause.

Rates of obesity have increased significantly over the last three decades in the United States and globally. In addition to contributing to heart disease and diabetes, obesity is a major unrecognized risk factor for cancer. Obesity is associated with worsened prognosis after cancer diagnosis and also negatively affects the delivery of systemic therapy, contributes to morbidity of cancer treatment, and may raise the risk of second malignancies and comorbidities. Research shows that the time after a cancer diagnosis can serve as a teachable moment to motivate individuals to adopt risk-reducing behaviors. For this reason, the oncology care team—the providers with whom a patient has the closest relationships in the critical period after a cancer diagnosis—is in a unique position to help patients lose weight and make other healthy lifestyle changes. The American Society of Clinical Oncology is committed to reducing the impact of obesity on cancer and has established a multipronged initiative to accomplish this goal by 1) increasing education and awareness of the evidence linking obesity and cancer; 2) providing tools and resources to help oncology providers address obesity with their patients; 3) building and fostering a robust research agenda to better understand the pathophysiology of energy balance alterations, evaluate the impact of behavior change on cancer outcomes, and determine the best methods to help cancer survivors make effective and useful changes in lifestyle behaviors; and 4) advocating for policy and systems change to address societal factors contributing to obesity and improve access to weight management services for patients with cancer.

Cellular proliferation, growth, and division following DNA (deoxyribonucleic acid) damage are tightly controlled by the cell-cycle regulatory machinery. This machinery includes cyclin-dependent kinases (CDKs) which complex with their cyclin partners, allowing the cell cycle to progress. The cell-cycle regulatory process plays a critical role in oncogenesis and in the development of therapeutic resistance; it is frequently disrupted in breast cancer, providing a rational target for therapeutic development. Palbociclib is a potent and selective inhibitor of CDK4 and -6 with significant activity in breast cancer models. Furthermore, it has been shown to significantly prolong progression-free survival when combined with letrozole in the management of estrogen receptor-positive metastatic breast cancer. In this article we review the cell cycle and its regulatory processes, their role in breast cancer, and the rationale for CDK inhibition in this disease. We describe the preclinical and clinical data relating to the activity of palbociclib in breast cancer and the plans for the future development of this agent., Video abstract

1544 Background: Elevated body mass index (BMI) is associated with increased risk of estrogen receptor (ER)-positive postmenopausal breast cancer. The risk is also elevated in women with a normal BMI but excess body fat. These risks may be driven by breast white adipose tissue inflammation (WATi), which is associated with elevated aromatase levels and systemic metabolic dysfunction (e.g. hyperinsulinemia). We hypothesized that body fat assessment is superior to BMI for detecting the pathophysiology that promotes obesity-related breast cancer, particularly among normal BMI women. Methods: Non-tumorous breast tissue was collected from women undergoing mastectomy for breast cancer treatment or prevention. Breast WATi was detected by the presence of crown-like structures in the breast, which are composed of a dead/dying adipocyte surrounded by CD68+ macrophages. Body composition was measured prior to mastectomy via dual energy X-ray absorptiometry. Exercise behavior was also assessed prior to surgery using the Godin Leisure Time Exercise Questionnaire. Associations among categorical variables were examined using Χ2 or Fisher’s exact test. Relationships between continuous variables were examined using the Spearman correlation. Results: From April 5, 2016 to August 31, 2018, 100 patients were enrolled; median age 49 (range 29 to 82) years. Breast WATi was present in 56/100 (56%) women and was associated with elevated BMI and body fat levels, breast adipocyte hypertrophy, postmenopausal status, metabolic syndrome and decreased physical activity (P < 0.05). Among 39 women with normal BMI, breast WATi was present in 14 (36%) and was associated with elevated body fat levels, breast adipocyte hypertrophy, dyslipidemia, and decreased physical activity (P < 0.05). There was no statistically significant association between BMI and breast WATi in the normal BMI group. Menopausal status and total fat mass had greater sensitivity and specificity for the detection of breast WATi compared to a BMI-based model (AUC 0.843 vs. 0.779, respectively). Conclusions: Measurement of body fat is superior to BMI for predicting breast inflammation, which has been shown to promote obesity-related breast cancer.

TPS1106 Background: ICB (atezolizumab, anti-PD-L1) is known to improve survival when added to chemo, however only in PD-L1-positive, triple-negative MBC. ICB is less effective in hormone receptor positive (HR+) MBC, or when administered following palliative chemo. Novel approaches are required to broaden clinical benefit of ICB, particularly in PD-L1-negative, HR+, or chemo-experienced MBC. Dual ICB with anti-PD-1 (nivolumab) and anti-CTLA-4 (ipilimumab) is associated with enhanced activity in melanoma other malignancies, but has not been explored extensively in MBC. Androgen receptor (AR) blockade, in addition to known direct cytostatic effects in AR-expressing MBCs (50% of TNBC, > 75% of HR+ MBC), may also modulate immune response. AR blockade has been shown experimentally to stimulate thymic production of naïve T-cell clones, which in turn can facilitate de novo anti-tumor immune responses. Concurrent ICB can enhance the activity of these T-cell clones by interfering with PD-1-mediated peripheral tolerance. This combination approach is promising in MBC in light of known AR positivity, and the routine use of lymphodepleting chemo regimens in the curative-intent setting. Methods: This is a phase II trial of dual immune checkpoint blockade (nivolumab 240mg IV q2w; ipilimumab 1mg/kg IV q6w) plus AR blockade (bicalutamide, 150mg PO daily, dose reduction allowed) in triple-negative MBC (cohort A: AR-positive [ > 1% by IHC]; cohort B: AR-negative) or HR+ MBC (cohort C) in subjects who received 0/1 prior chemotherapies in the non-curative setting. Objectives include 24-week clinical benefit rate by iRECIST (primary), safety (CTCAE v4.0), and other response measures (RECIST1.1, PFS, OS). Efficacy for each cohort is defined as > 20% improvement in response over historical control (30% per EMBRACE clinical trial) employing a Simon 2-stage design to minimize futility (n = 46/cohort, stage I n = 15). Thymic generation of T-cells will be measured via quantitative deep sequencing of T-cell receptors (TcR, ImmunoSEQ assay) and TcR excision circles (TRECs), as well as real-time flow cytometry using surrogate cell surface markers of recent thymic emigration. Enrollment has commenced, sites: Earle A. Chiles Research Institute (Portland, OR), Memorial Sloan Kettering Cancer Center (New York, NY). Clinical trial information: NCT03650894.

546 Background: A subset of TNBC is dependent on AR signaling. Enzalutamide (ENZA), an AR-antagonist, has activity in patients (pts) with metastatic AR+ TNBC, with a clinical benefit rate of 33%. This study tests the feasibility of adjuvant ENZA for the treatment (tx) of early stage, AR+ TNBC. We now report the primary endpoint (endpt) and safety. Methods: Eligible pts have centrally confirmed, Stage I-III, ER/PR < 1%, HER2(-), AR ≥1% BC and completed all planned surgery, chemotx and radiation (RT) < 6 months of tx start. AR testing by IHC per MSK methods. Tx consists of ENZA 160mg daily for 1 year (y) with the option to extend tx to 2y. Toxicity per NCI CTCAEv4 every (q) 4 weeks (wk) for 12 wk, then q3 months. Primary endpt: feasibility of 1y ENZA defined as the discontinuation rate due to toxicity, consent withdrawal or tolerability. 50 pts are enrolled to have 46 evaluable pts required to discriminate between feasibility of 50% and 70%, with type I error 5% and 88% power. Pts who have disease progression (PD) or die during 1st y of ENZA and do not have tx discontinuation due to the above will not be included in the primary analysis. If 29 pts complete 1y, adjuvant ENZA will be deemed feasible. Secondary endpts: safety and 3y DFS and OS. Exploratory endpts: PROs and biomarker development. Results: Between 5/2016-6/2018, 50 pts were enrolled. Pt and tumor characteristics (N = 50): Median age 55y (33-81); Stage: I 20 (40%), II 23 (46%), III 7 (14%); Grade (gr): 2 = 26%, 3 = 74%. AR > 10% = 35 (70%), AR ≤10% = 15 (30%). Chemotx 47/50 (94%): Neoadjuvant (neo) 40%, Adjuvant (adj) 60%; Anthracycline/Taxane-based 38/47 (81%), Platinum 1/47 (2%), Docetaxel/Cyclophosphamide 3/47 (6%), other 5/47 (11%). 13/19 who received neo tx failed pCR; 9/13 (69.2%) received adj capecitabine. RT: 38/50 (76%). 27 pts completed 1y of tx. 7 pts will be evaluable by 6/1/19. 1 pt to complete 1y 6/21/19. 15 pts are off tx: PD (3), toxicity (5), noncompliance (4), withdrawal of consent (3). Tx-related AEs, any gr, > 10% (N = 50): fatigue (48%), hot flashes (22%), headache (18%), hyperglycemia (18%), nausea (18%), WBC decreased (16%), dizziness (14%), arthralgia (12%), dyspnea (12%). Tx-related, gr 3 AEs: fatigue (6%), hyperglycemia (2%), hypertension (2%). No gr 4/5 AEs or seizures. 11 pts had dose reduction. Conclusions: Feasibility of adjuvant ENZA will be fully evaluable in 4/2019 and is anticipated to meet the prespecified statistical expectations for primary endpt. ENZA is well tolerated following locoregional tx and standard of care systemic tx. Secondary analyses and correlatives are ongoing to define the role of AR in TNBC. Clinical trial information: NCT02750358.

Background: Enzalutamide (ENZA) is a potent novel oral inhibitor of androgen receptor (AR) signaling. AR expression is observed in ∼70% of breast cancers (BC) and across the 3 major histologic subtypes (ER+, HER2+ and triple negative) [Collins LC et al. Mod Pathol 2011; 24:924-31]. Based on findings in preclinical models of AR+ BC, the potential therapeutic effect of ENZA in AR+ BC is being evaluated. This is the first trial of ENZA in women with advanced BC (aBC). Methods: This Phase 1 study in patients (pts) with aBC comprised a dose-escalation stage evaluating ENZA 80 mg/d or 160 mg/d (3+3 design) to determine the Phase 2 dose, and a dose-expansion stage evaluating the Phase 2 dose alone (C1) or in combination with the aromatase inhibitors (AI), anastrozole (C2) or exemestane (EXE; C3). Pts on single-agent ENZA must have received ≥2 treatment regimens for aBC. Tumor tissue was collected at screening for central analysis of AR expression. In the dose-escalation stage, single-dose ENZA was given on Day 1 with pharmacokinetic (PK) sampling through Day 8, followed by ENZA daily until discontinuation criteria were met, dose-limiting toxicities (DLTs) were recorded through Day 35. In C2 and C3, pts received ≥14 days of AI before starting ENZA, and AI PK sampling occurred on Days -1 and 29 of ENZA dosing to assess PK interactions. Blood for central assessment of estrogens was collected at Days 1, 29 and with tumor assessments performed at 2 months then ∼every 3 months thereafter. Results: The dose-escalation stage (n = 15) defined the Phase 2 dose as 160 mg/d. A single DLT (adrenal insufficiency) occurred in a pt at the 80 mg/d dose. This pt had pre-existing history of adrenal insufficiency and a PK interaction with her daily steroids could not be excluded. As of 1 May 2013, the dose-expansion stage has enrolled 3 pts in C1, 10 in C2, and 16 in C3. For pts receiving single-agent ENZA (n = 18) median age/ECOG was 58/1 and median prior therapies for aBC was 5; these values were 55/0 and 3 for combination cohorts (n = 26). Common (>15%) treatment-related adverse events (AEs) in the single-agent ENZA cohorts included nausea and nasal congestion and in C2 and C3 included nausea, fatigue, back pain, decreased appetite, and hot flush. To date, no serious treatment-related AEs have been reported for single-agent ENZA (other than the DLT) or in C2; in C3 back pain, hypercalcemia and nausea were observed. For single-agent ENZA, a preliminary PK analysis indicates that the apparent clearance and volume of distribution are approximately 0.4 L/h and 120 L, respectively, and steady-state trough concentration is approximately 13 μg/mL. ENZA + EXE resulted in ∼50% reduction in exposure to EXE (AUC pre vs post ENZA: 134±65 vs 70±39 ng.h/mL). PK, tolerability, estrogen levels and anti tumor activity in all cohorts will be presented. Conclusions: The PK and tolerability of single-agent ENZA appear similar in women with aBC vs. data reported in men. As ENZA reduced exposure to EXE, effects on estrogens (i.e., EXE pharmacodynamics) are being assessed and will be reported. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr PD3-6.

Background: In post-menopausal women, obesity is a risk factor for the development of BC that expresses the estrogen and progesterone receptors (ER/PR). In mouse models of obesity, we previously described crown-like structures (CLS), consisting of macrophages surrounding dead adipocytes in white adipose tissue (WAT) of the mammary gland, which were associated with increased levels of proinflammatory mediators known to be involved in carcinogenesis. We translated these findings to women (n = 30), and provided the first evidence of CLS in the human breast (CLS-B). The presence and severity of CLS-B (CLS-B index) correlated with elevated body mass index (BMI), increased adipocyte size, activation of NF-κB, and increased levels of proinflammatory mediators (TNF-α, IL-1β, COX-2 and PGE2) and aromatase. We expanded our population to prospectively validate these preliminary findings. Methods: We prospectively collected WAT from women undergoing breast and reconstructive surgery. WAT was subjected to immunohistochemistry for CD68, a macrophage marker, to detect CLS-B by light microscopy. Adipocyte diameter was measured on photomicrographs using the Canvas 11 Software. Endpoints were 1) CLS-B presence/absence and 2) CLS-B index (proportion of slides with CLS-B). Associations between CLS-B and clinicopathologic features were analyzed using logistic regression and Fisher's exact test. Results: From 04/2010-02/2012, WAT (100 mastectomy and 5 abdominal reconstructions) was obtained from 101 women; median age 49 (range 26-80). CLS-B were found in 54 (53%) patients (pts). CLS-B were seen in 9/37 (24%) normal weight pts (BMI Conclusions: Findings from this prospective study, the largest reported to date, extend our previous observation that CLS-B are associated with BMI and adipocyte size. These results provide a plausible pathophysiological link between obesity and BC. Breast inflammation occurs in association with all BC phenotypes. Preliminary data suggest concordance between breasts and between abdominal and breast WAT. Hence, abdominal WAT may prove useful as a surrogate for breast WAT; biopsies of abdominal subcutaneous WAT are more easily done, which could prove useful in developing interventions to attenuate WAT inflammation. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-06-03.

Greater than 70% of human breast cancers express the androgen receptor (AR). Emerging preclinical and clinical data suggest that AR may play a role in breast cancer pathogenesis and may serve as a therapeutic target in certain more difficult-to-treat breast cancer subtypes, such as triple-negative breast cancer. Although this is an area of active investigation, the clinical significance of this hormone receptor as a prognostic/predictive marker and its functional role in tumorigenesis is unclear. This review provides an update on the advances made in the last several years regarding the role of AR as a prognostic/predictive biomarker in breast cancer, the underlying biology of AR signaling in breast cancer development and the available clinical data for the use of androgen inhibition in the treatment of AR+ triple-negative breast cancer.

The quantity and makeup of dietary fat intake are known to impact human health. Use of Omega-3 (ω-3) polyunsaturated fatty acid (PUFA) supplements has gained increasing attention for a variety of purported health benefits, including cancer prevention. Preclinical evidence has been encouraging and recent studies have expanded our understanding of the mechanisms by which ω-3 PUFAs may protect against breast cancer. However, epidemiologic studies have yielded mixed results. Recent population studies have attempted to delineate factors that may influence the effects of ω-3 PUFAs such as total fat intake and the ratio of ω-3 to ω-6 PUFA intake. Several clinical trials, including some currently ongoing, are investigating novel strategies that favorably alter endogenous fatty acid profiles in an effort to develop clinically feasible prevention methods. Identification of well-defined subpopulations that are most likely to benefit from a targeted prevention approach will likely be crucial in this effort.

Purpose There is growing evidence that inflammation is a central and reversible mechanism through which obesity promotes cancer risk and progression. Methods We review recent findings regarding obesity-associated alterations in the microenvironment and the local and systemic mechanisms through which these changes support tumor growth. Results Locally, hyperadiposity is associated with altered adipose tissue function, adipocyte death, and chronic low-grade inflammation. Most individuals who are obese harbor inflamed adipose tissue, which resembles chronically injured tissue, with immune cell infiltration and remodeling. Within this distinctly altered local environment, several pathophysiologic changes are found that may promote breast and other cancers. Consistently, adipose tissue inflammation is associated with a worse prognosis in patients with breast and tongue cancers. Systemically, the metabolic syndrome, including dyslipidemia and insulin resistance, occurs in the setting of adipose inflammation and operates in concert with local mechanisms to sustain the inflamed microenvironment and promote tumor growth. Importantly, adipose inflammation and its protumor consequences can be found in some individuals who are not considered to be obese or overweight by body mass index. Conclusion The tumor-promoting effects of obesity occur at the local level via adipose inflammation and associated alterations in the microenvironment, as well as systemically via circulating metabolic and inflammatory mediators associated with adipose inflammation. Accurately characterizing the obese state and identifying patients at increased risk for cancer development and progression will likely require more precise assessments than body mass index alone. Biomarkers of adipose tissue inflammation would help to identify high-risk populations. Moreover, adipose inflammation is a reversible process and represents a novel therapeutic target that warrants further study to break the obesity-cancer link.

Purpose: Several lines of evidence support targeting the androgen signaling pathway in breast cancer. Enzalutamide is a potent inhibitor of androgen receptor signaling. Preclinical data in estrogen-expressing breast cancer models demonstrated activity of enzalutamide monotherapy and enhanced activity when combined with various endocrine therapies (ET). Enzalutamide is a strong cytochrome P450 3A4 (CYP3A4) inducer, and ETs are commonly metabolized by CYP3A4. The pharmacokinetic (PK) interactions, safety, and tolerability of enzalutamide monotherapy and in combination with ETs were assessed in this phase I/Ib study.Experimental Design: Enzalutamide monotherapy was assessed in dose-escalation and dose-expansion cohorts of patients with advanced breast cancer. Additional cohorts examined effects of enzalutamide on anastrozole, exemestane, and fulvestrant PK in patients with estrogen receptor–positive/progesterone receptor–positive (ER+/PgR+) breast cancer.Results: Enzalutamide monotherapy (n = 29) or in combination with ETs (n = 70) was generally well tolerated. Enzalutamide PK in women was similar to prior data on PK in men with prostate cancer. Enzalutamide decreased plasma exposure to anastrozole by approximately 90% and exemestane by approximately 50%. Enzalutamide did not significantly affect fulvestrant PK. Exposure of exemestane 50 mg/day given with enzalutamide was similar to exemestane 25 mg/day alone.Conclusions: These results support a 160 mg/day enzalutamide dose in women with breast cancer. Enzalutamide can be given in combination with fulvestrant without dose modifications. Exemestane should be doubled from 25 mg/day to 50 mg/day when given in combination with enzalutamide; this combination is being investigated in a randomized phase II study in patients with ER+/PgR+ breast cancer. Clin Cancer Res; 23(15); 4046–54. ©2017 AACR.

The androgen receptor (AR) is expressed in 70–90% of invasive breast cancers. Despite the ubiquitous expression of AR in both primary and metastatic breast cancers, the clinical significance of this hormone receptor as a prognostic/predictive marker and its functional role in tumorigenesis remains poorly understood. This review summarizes the recent progress made in understanding the role of the AR as a prognostic/predictive marker in breast cancer and the underlying mechanisms by which the androgen-signaling pathway may be involved in breast cancer pathogenesis. In addition, this review examines the available clinical data for the use of androgen-blocking agents in the treatment of breast cancer and explores the ongoing development of newer AR-targeted agents in this setting.

Background BM develops in 65–70% of pts with MBC. RANK and its ligand (RANK-L) can be critical in the development and progression of BM. Src overexpression and deregulation occurs in many solid tumors but it has not been fully characterized although an association between Src activity defined by a gene expression signature and BM particularly in ER+ pts has been described. (Zhang XH et al. Cancer Cell. 2009) Our goal was to elucidate the relationship between Src and RANK expression in BT and BM in relation to estrogen-/progesterone-receptor (ER/PR)/HER2 expression and tumor histology (invasive ductal carcinoma (IDC) vs invasive lobular carcinoma (ILC)). Methods: Immunohistochemistry (IHC) for RANK (R&D Systems clone 80707) and Src (Cell Applications Inc. Phospho Tyr-416) protein expression was performed on archived paraffin embedded BT and BM. Scoring: 0=negative, 1+=weak, 2+=intermediate, 3+=strong and the percent of positive tumor cells; RANK+ = 2–3+, > 1% of cells; Src+ = 1–3+; > 1% of cells. Associations between RANK/Src expression and tumor characteristics were assessed using the chi-square test or McNemar's test for pairs, as appropriate. Results: From the MSKCC database, using an IRB-approved waiver of consent, we identified 54 pts with MBC who underwent surgical biopsy of a metastatic bone lesion at our center between 2005–2010, and had tissue available for further testing. 17 corresponding BT samples were identified. At the time of diagnosis, 43 (79.5%) primary tumors were ER or PR (+); 6 (11%) were HER2+; 41 (76%) were invasive ductal carcinoma. 87% of BM expressed RANK and 44% expressed Src. (Table 1) No significant correlation between RANK or Src expression in BM and ER/PR/HER2 status of BT was observed. A significant correlation between RANK expression and BT histology was observed, (p=0.0016): 93% of IDC were RANK (+), in comparison to 50% of invasive lobular carcinomas. RANK expression was not significantly different between primary tumor and metastatic bone samples (p=0.99). There was a borderline significant difference in Src expression between primary and metastatic site (p=.06). Conclusions: In our cohort, no correlation between RANK or Src by IHC and ER/PR/HER2 was identified but RANK expression was more common in IDC than ILC. Fidelity was high for RANK between primary and metastatic lesions while Src expression may possibly vary. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-16-06.

1017Background: Overall response rates of 5-7% have been reported with checkpoint inhibitor monotherapy in PD-L1-unselected mTNBC as second line or subsequent therapy. RT is frequently used to enha...

14 Background: Overall response rates of 13-19% have been reported with checkpoint inhibitor monotherapy in chemotherapy-resistant, PD-L1-positive mTNBC. RT is frequently used to enhance local control in mTNBC and has been reported to induce distant (abscopal) tumor responses when combined with immunotherapy. In this study, we evaluate the safety and efficacy of RT combined with a programmed cell death protein 1 (PD-1) inhibitor, pembro, in a single-arm, two-stage, phase II study in mTNBC. Methods: Eligible women had biopsy-proven mTNBC, ECOG performance status 0-2, and ≥2 measurable sites of metastatic disease with at least one site requiring RT. A total RT dose of 3000 cGy was delivered in 5 daily fractions. Pembro 200 mg was given intravenously within 3 days of first RT fraction, then every 3 weeks +/-3 days until disease progression. The primary endpoint was overall response rate at week 13 in the non-irradiated lesions by RECIST v1.1. Secondary endpoints included safety and overall survival. Tumor biopsies were obtained at baseline and at week 7. PD-L1 expression was not required for study entry. Results: Of the 17 women enrolled, the median age was 52 y (range 37-73y). and the median number of prior chemotherapies received for metastatic disease was 3 (range 0 to 8). Of the 8 women not evaluable at 13 weeks: 5 died secondary to disease-related complications (at weeks 2, 6, 7, 8, and 9) and 3 came off study due to disease progression prior to week 13. Of the 9 women evaluable at week 13, 3 (33%) had a partial response, 1 (11%) had stable disease and 5 (56%) had disease progression. The 3 partial responses represented 60%, 54%, and 34% decreases in tumor burden by RECIST v1.1 and were durable for 31, 21, and ongoing at 22 weeks, respectively. The stable disease response was durable for 22 weeks. Common toxicities were mild and included fatigue, myalgia and nausea. Conclusions: The combination of pembro and RT is well-tolerated. This is a poor prognosis population with 5/17 (29%) of patients dying within 12 weeks of study entry. However, durable responses were observed outside of the RT field in 3/9 (33%) patients who were unselected for PD-L1 expression and evaluable at 13 weeks. Clinical trial information: NCT02730130.

Purpose: Obesity, insulin resistance, and elevated levels of circulating proinflammatory mediators are associated with poorer prognosis in early-stage breast cancer. To investigate whether white adipose tissue (WAT) inflammation represents a potential unifying mechanism, we examined the relationship between breast WAT inflammation and the metabolic syndrome and its prognostic importance. Experimental Design: WAT inflammation was defined by the presence of dead/dying adipocytes surrounded by macrophages forming crown-like structures (CLS) of the breast. Two independent groups were examined in cross-sectional (cohort 1) and retrospective (cohort 2) studies. Cohort 1 included 100 women undergoing mastectomy for breast cancer risk reduction (n = 10) or treatment (n = 90). Metabolic syndrome–associated circulating factors were compared by CLS-B status. The association between CLS of the breast and the metabolic syndrome was validated in cohort 2, which included 127 women who developed metastatic breast cancer. Distant recurrence-free survival (dRFS) was compared by CLS-B status. Results: In cohorts 1 and 2, breast WAT inflammation was detected in 52 of 100 (52%) and 52 of 127 (41%) patients, respectively. Patients with breast WAT inflammation had elevated insulin, glucose, leptin, triglycerides, C-reactive protein, and IL6 and lower high-density lipoprotein cholesterol and adiponectin (P < 0.05) in cohort 1. In cohort 2, breast WAT inflammation was associated with hyperlipidemia, hypertension, and diabetes (P < 0.05). Compared with patients without breast WAT inflammation, the adjusted HR for dRFS was 1.83 (95% CI, 1.07–3.13) for patients with inflammation. Conclusions: WAT inflammation, a clinically occult process, helps to explain the relationship between metabolic syndrome and worse breast cancer prognosis. Clin Cancer Res; 22(9); 2283–9. ©2015 AACR.

Background: AR mutations have been described as a mechanism of resistance to AR antagonists in prostate cancer. There are limited data regarding the presence of AR mutations in breast cancer. We aim to describe the presence of tumor AR mutations in a cohort of patients (pts) with breast cancer who are candidates for targeted cancer therapy, who underwent tumor genomic profiling as part of a clinical trial at MSK (NCT01775072). Methods: MSK-IMPACT is a targeted tumor sequencing assay capable of detecting mutations and other critical genetic aberrations in 410 cancer genes; these data are available through an institutional database. Following IRB approval and using an electronic medical record, we examined the subset of pts in this database with breast cancer for the presence of AR mutations and performed a chart review for clinicopathologic features and outcomes. Statistics are descriptive. Results: As of 03JUN2015, 628 of 4,379 samples that underwent MSK-IMPACT testing since 2012 were from invasive breast cancers. 6 of 628 (1%) harbored AR mutations (Table 1), none of which contribute to a reported or predicted functional alteration. Table 1MutationTypeAllele FrequencyFunctional Impact According to MutationAssessorR31HMissense0.21LowR856CMissense0.31MediumA430TMissense0.12NeutralG409RMissense0.18MediumQ445PMissense0.47MediumQ73LMissense0.25Neutral Patient/tumor characteristics are shown in Table 2. Five out of 6 patients recurred between 7.4 and 117.4 months (mo) from the date of initial diagnosis. One patient is without disease recurrence at 3.9mo from diagnosis at date of last contact, 7.9mo ago. Table 2MutationStage at DiagnosisHIstologyER%/PR%/HER2AR%Sites of MBCSite of IMPACTR31HT1N0Lobular90/20/1+-SkinSkinR856CT3N3Ductal20/0/1+0Chest wall, LNLNA430TT2N1Ductal95/0/--Bone, liverBreastG409RT2N0Ductal90/80/FISH 1.3-Bone, liverLiverQ445PT3N3Ductal99/50/1+-LNBreast/LNQ73LT3N0Malignant Phyllodes--N/ABreastMBC metastatic breast cancer; LN lymph node; N/A not applicable Conclusions: AR mutations were uncommon in this dataset of 628 breast cancers. Similarly, TCGA sequencing data has revealed only 12 invasive breast cancers with AR mutations (2.2% of 973 samples). The functional significance of these mutations has not been demonstrated. As tissue from therapeutic studies using AR antagonists for the treatment of breast cancer become available, mutations or amplification in AR may be more readily identified as a potential mechanism of resistance to AR-targeted therapy. Acknowledgments: We gratefully acknowledge the members of the Molecular Diagnostics Service in the Department of Pathology and the Marie-Josée and Henry R. Kravis Center for Molecular Oncology. Citation Format: Gucalp A, Proverbs-Singh TA, Razavi P, Chandarlapaty S, Patil S, Ross DS, Zehir A, Baselga J, Hudis CA, Traina TA. Androgen receptor (AR) mutations in a cohort of patients with breast cancer (BC) who have undergone tumor genomic profiling. [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 P6-07-08.

1102 Background: Seviteronel (Sevi), an oral selective CYP17-lyase and AR inhibitor that blocks testosterone and estradiol production and competitively antagonizes the AR, is in Ph 2 clinical development for BC and prostate cancer. The primary objective of this ongoing Ph 2 study (NCT02580448) is to estimate the activity of once daily Sevi in women with AR+ TNBC and ER+ BC as measured by clinical benefit rate (CBR) at 16 and 24 weeks (wk), respectively. Methods: Patients (pts) with ER+/HER2-normal metastatic BC following progression of ≥1 prior line of endocrine therapy or TNBC were enrolled with no limit of prior therapies in either cohort. Evaluable pts had AR ≥10% via central IHC staining (TNBC only) and 1 post-baseline scan. Sevi was administered at 450 mg oral daily. Scans were performed every 8 wk. Circulating tumor cell (CTC) enumeration was performed by EPIC CTC analysis. A Simon’s 2-stage design was employed to determine activity (≥2 of 13 CBR16 in TNBC and ≥2 of 12 CBR24 in ER+ BC allow for accrual to Stage 2). Results: As of 4 Oct, 2016, 16 pts with AR+ TNBC (6 evaluable) and 14 pts with ER+ BC (11 evaluable) were enrolled. 67% had visceral metastases; 10% had stable brain metastases. 60% had ≥2 lines of prior therapy for advanced disease. 13 of 14 (93%) TNBC pts who underwent central AR testing had AR ≥10%. Four pts in the TNBC cohort and 8 pts in the ER+ cohort remain on therapy. CBR16 (TNBC) and CBR24 (ER+) was 2 of 6 (33%) and 2 of 11 (18%) allowing Stage 2 accrual in both cohorts. 7 of 10 evaluable pts with CTCs present at baseline had a CTC decline at C2D1, including all that met CBR (-94.3% [-27.5, -100] median [range]). The most common adverse events (≥ 25%) were fatigue (50%), nausea (43%) and decreased appetite (33%); all Grade 1/2. Updated CBR data will be presented at the time of presentation. Conclusions: Sevi Stage 1 activity is suggested by CBRs, along with associated CTC declines in heavily pre-treated pts with high disease burden. The observed safety profile is consistent with on-target pharmacology. Stage 2 enrollment is ongoing. Sevi may provide a novel treatment option for women with AR+ TNBC or ER+ BC. Clinical trial information: NCT02580448.

1089 Background: The AR may be a novel therapeutic target for pts with AR-driven TNBC. ENZA, a potent AR inhibitor approved in men with metastatic prostate cancer, was evaluated in this phase 2 study of pts with AR+ TNBC. A genomic signature associated with AR-driven biology was identified; updated OS results in pts treated with 0-1 prior lines of therapy are presented. Methods: This is an open-label, Simon two-stage study (NCT01889238) of ENZA monotherapy in advanced AR+ TNBC (AR > 0% by IHC). Bone-only disease and unlimited prior regimens were allowed; CNS metastases or seizure history were exclusionary. The primary endpoint was clinical benefit rate at 16 weeks (CBR16) in evaluable pts (AR > 10% and ≥1 postbaseline assessment). OS was an exploratory endpoint. Results in intent-to-treat (ITT) and evaluable pts were presented previously (Traina TA et al. J Clin Oncol. 2015;33:1003). Results: 118 pts were enrolled (ITT). CBR16 in 78 evaluable pts was 33.3%. Of the 118 ITT pts, 56 were Dx+ and 62 were Dx–; ≥50% received 0-1 prior lines of therapy (28 Dx+, 37 Dx–). As of 26 Nov 2016 there were 83 deaths (median follow-up 28 mo); median OS (mOS) was 13 mo (95% CI; 8-18). In the Dx+ subgroup there were 32 deaths (mOS 20 mo [95% CI; 13-29]) vs 51 deaths in the Dx– subgroup (mOS 8 mo [95% CI; 5-11]). In pts with 0-1 prior lines of therapy, there were 13 deaths in the Dx+ subgroup (mOS 29 mo [95% CI; 19-not reached] vs 28 in the Dx– subgroup (mOS 10 mo [95% CI; 7-15]). The most common adverse events (AEs) were fatigue and nausea; fatigue was the only grade 3 related AE in > 5% of pts. A multi-covariate Cox analysis identified Dx status (+ vs –) and line of therapy (0-1 vs ≥2) as the only variables significantly associated with OS. Conclusions: In this study, the mOS of pts with Dx+ TNBC who received 0-1 prior lines of therapy appears longer than that of unselected historic controls. ENZA may represent a therapeutic option in pts with AR+ TNBC who would otherwise receive cytotoxic chemotherapy and is currently being evaluated in ENDEAR, a phase 3 study in pts with Dx+ advanced TNBC and 0-1 prior lines of therapy. Clinical trial information: NCT01889238.

1037 Background: The combination of taxanes with HP for first line treatment of HER2-positive MBC is associated with improved progression-free (PFS) and overall survival (OS). Treatment per physician’s choice with anti-HER2 therapy after second line therapy is associated with a median PFS of 3 months. While continued use of H in therapeutic combinations after progression on H-based therapy is standard, the efficacy of continuing HP-based treatment after progression on P-based therapy is unknown. Methods: This is a single arm phase II trial of G with HP. Eligible patients (pts) had HER2-positive (IHC 3+ or FISH > 2.0) MBC with prior HP-based treatment and ≤ 3 prior chemotherapies. Pts received G (1200 mg/m2) on days 1 and 8 of a q 3 week (w) cycle, and H (8 mg/kg load → 6 mg/kg) and P (840 mg load → 420 mg) q3w. The primary endpoint is PFS at 3 months. Secondary endpoints include OS, safety and tolerability. An exploratory endpoint is to compare PFS by RECIST criteria versus 18-F FDG-PET response criteria. The study therapy will be considered successful if at least 27/45 (60%) patients are progression free at 3 months. Results: As of 1-27-17, 41 of 45 pts are enrolled; 34 are evaluable at 3 months and 7 have not had 3-month evaluation. At 3 months, 26/34 (76%) are progression free (1 CR, 8 PR, 17 SD); 8 pts progressed. There are no cardiac or febrile neutropenic events to date. 4 pts required G dose reduction (3 grade 3 neutropenia and 1 grade 3 vomiting) and the study was amended to lower initial G dose to 1000 mg/m2. Conclusions: The preliminary 3 month-PFS is 76% in evaluable pts (95% CI 60% to 88%). The updated 3 month-PFS results will be presented. Continuation of P beyond progression is associated with apparent clinical benefit. A randomized trial is justified to confirm this clinically important observation. Clinical trial information: NCT02252887.

95 Background: Two trials have demonstrated overall response rates of 19% with immune checkpoint inhibitors alone in chemotherapy-resistant triple negative breast cancer (TNBC). Radiation therapy (RT) is frequently used to enhance local control in TNBC and has been reported to induce distant (abscopal) tumor responses when combined with immunotherapy. We evaluate the safety and efficacy of the combination of RT and pembrolizumab, a programmed cell death protein 1 (PD-1) inhibitor, in a single-arm, two-stage, phase II study in metastatic TNBC. Results from the first stage are reported. Methods: Eligibility criteria includes women with biopsy-proven TNBC, ECOG performance status 0-2, ≥ 2 measurable sites of metastatic disease with at least one site requiring RT. A total RT dose of 3000 cGy is delivered in one week in 5 fractions. Pembrolizumab is given intravenously at 200 mg/kg D1+/- 3 days and then every 3 weeks until disease progression as defined by RECIST v 1.1. The primary endpoint is overall response rate at week 13 in the non-targeted, non-irradiated lesions. Secondary endpoints include safety and overall survival. Tumor biopsies are obtained at baseline and at week 7. PD-L1 expression was not required for study entry. Results: Nine patients were enrolled in the first phase and assessed for antitumor activity and safety. Median age was 52 years (range 37-73). Three patients died secondary to disease-related complications (at weeks 2, 6 and 8) and 1 came off study due to disease progression prior to week 13. Of the 5 patients evaluable at week 13, 2 had a partial response, 1 had stable disease and 2 had disease progression. Common toxicities were mild and included fatigue, myalgia and nausea. One grade 3 event was reported - hyperbilirubinemia not attributable to study therapy after one dose of pembrolizumab. Conclusions: The combination of pembrolizumab and RT was well-tolerated in the first stage of a phase II study. Responses were observed outside of the RT fields in 2 of 5 patients who were evaluable at 13 weeks. The contribution of RT to pembrolizumab is unknown and will be investigated in the second stage of the study, which is ongoing. Correlative studies are planned. Clinical trial information: NCT02730130.

507 Background: High body mass index (BMI) is an established risk factor for developing ccRCC but is associated with better survival in clinical studies. The obesity paradox may be influenced by metabolically healthy patients classified as obese, and metabolically unhealthy patients classified as normal weight. We evaluated white adipose tissue inflammation (WATi) in perinephric fat as a new marker of metabolic dysregulation and examined its association with clinicopathological characteristics. Methods: In July 2015, we established a prospective cohort study at Memorial Sloan Kettering Cancer Center to investigate the prognostic significance of perinephric WATi among patients undergoing nephrectomy. Perinephric WAT is collected during surgery and patients are followed for clinical outcomes. WATi is defined by the presence of dead/dying adipocytes surrounded by macrophages forming crown-like structures (CLS) and detected through immunohistochemistry. Clinicopathological data are abstracted from the electronic medical record. Wilcoxon rank-sum, Chi-square, or Fisher’s exact tests describe the relationship between CLS status and clinicopathological characteristics on the first 38 ccRCC patients. Results: The study cohort had a median age of 56 years (range 47-64 years) and was predominantly male (71%). CLS were detected in 50% of patients, did not differ by age or sex, and were present in all BMI levels; 59% of obese, 38.5% of overweight, and 33% of normal weight patients (p = 0.47). CLS was significantly associated with advanced disease characteristics including higher stage (p = 0.03) and local invasion (p = 0.02). Median tumor size was larger in patients who were CLS+ (3.5 cm, range 2.65-5.75) than CLS- (2.2 cm, range 1.55-3.00; p = 0.02). Conclusions: Perinephric WATi was found in ccRCC patients of all BMI levels and associated with factors related to poor prognosis. Patients with occult inflammation may be at higher mortality risk, regardless of their BMI. Recruitment of additional cases and analyses to examine how CLS influences ccRCC survival are on-going.

63 Background: Obesity, a common cause of chronic inflammation, is associated with an increased risk of high grade, lethal prostate cancer (PC) and poor outcomes. The existence or clinical importance of periprostatic white adipose tissue inflammation (WATi) in patients (pts) with PC has not been previously described. We examined the relationships among periprostatic WATi and 1) tumor clinicopathologic features, and 2) host factors including age, body mass index (BMI), and circulating metabolic factors. Methods: Periprostatic WAT was collected prospectively from men with PC undergoing radical prostatectomy. WATi was defined by the presence of dead/dying adipocytes surrounded by macrophages forming crown-like structures (CLS). Tumor characteristics and host factors were measured. Wilcoxon rank-sum, Chi-square, or Fisher’s exact tests were used to examine the relationship between WATi and tumor and host characteristics. Results: From 11/2011-8/2015, periprostatic WAT was obtained from 169 pts (median age 62 years, range: 39 -77). Fasting blood samples were collected from 154 pts. CLS were present in 84 (49.7%) of pts. Presence of CLS was associated with higher median BMI (P = 0.02); 40/65 (61.5%) obese pts, 36/83 (43.4 %) overweight pts, and 8/21 (38.1 %) normal weight pts had CLS. Pts with CLS were more likely to have high grade prostate cancer (Gleason grade group IV/V, P = 0.02), larger adipocytes (P = 0.004), and positive surgical margins at the time of surgery (P = 0.04). WATi correlated with higher circulating levels of insulin, triglycerides, and leptin/adiponectin ratio, and lower high density lipoprotein cholesterol, compared to pts without WATi (P’s < 0.05). Conclusions: Periprostatic WATi is common in men with PC. It is associated with high grade PC and alterations in systemic factors that contribute to PC development and progression. Periprostatic WATi may represent a therapeutic target for improving PC risk and outcomes.

Background: Elevated body mass index (BMI) is associated with increased risk of postmenopausal breast cancer, which may be partly attributable to an inflammation-aromatase axis. Most individuals with elevated BMI harbor white adipose tissue inflammation (WATi), defined by the presence of crown-like structures in the breast (CLS-B). CLS-B are composed of a dead/dying adipocyte surrounded by CD68+ macrophages. This inflammation is associated with activation of NF-κB and elevated expression of aromatase, which could contribute to tumor development. Additionally, WATi correlates with several circulating changes, including hyperinsulinemia, which increase breast cancer risk. Although breast WATi correlates with rising BMI, it is also present in some normal BMI individuals. Beyond inherited germline syndromes, the etiology of breast cancer in individuals with normal BMI is not well understood. Here we examined the impact of breast WATi on breast aromatase expression and circulating factors in women with normal BMI. Methods: Non-tumorous breast tissue and fasting blood were collected from 72 women with BMI < 25 kg/m2 undergoing mastectomy at MSKCC. Breast inflammation was detected by the presence of CLS-B using CD68 immunohistochemistry. The primary objective was to determine if breast WATi in normal BMI individuals correlates with elevated aromatase levels in the breast, measured by qPCR, western blotting, immunofluorescence and enzyme activity. Secondary objectives included assessment of breast adipocyte size and circulating metabolic and inflammatory factors. Results: Breast inflammation was present in 39% of women. Median BMI was 23.0 (range 18.4 to 24.9) in women with breast WATi versus 21.8 (range 17.3 to 24.6) in those without inflammation (P=0.04). Aromatase mRNA expression was positively correlated with WATi (CLS-B/cm2; P=0.002). Those with severe WATi had highest aromatase mRNA levels, compared to those with no or mild WATi (P=0.005). Aromatase protein, assessed by measuring adipose stromal cell-specific immunofluorescence or western blotting, and activity were also higher in CLS-B+ cases compared to CLS-B- (P Conclusions: A metabolically unhealthy state occurs in women with inflamed breast adipose despite having a normal BMI. This subclinical inflammatory state is characterized by elevated aromatase in the breast, insulin resistance, and dysplipidemia. The presence of enlarged adipocytes in the breasts of normal BMI women with inflammation suggests a state of hyperadiposity which could not be predicted based on BMI alone. These findings indicate that normal BMI metabolic obesity may be associated with increased cancer risk. Our results suggest that objective measurements of adiposity rather than BMI may help to identify individuals at increased risk for disease. Citation Format: Iyengar NM, Brown KA, Zhou XK, Subbaramaiah K, Giri DD, Gucalp A, Howe LR, Zahid H, Bhardwaj P, Wendel NK, Falcone DJ, Morrow M, Wang H, Williams S, Pollak M, Hudis CA, Dannenberg AJ. Metabolic obesity, adipose inflammation and aromatase: Potential drivers of breast cancer risk in women with normal body mass index [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr PD5-05.

Although substantial progress has been made in the screening and management of breast cancer, globally it remains the most common cause of cancer and cancer death in women. While breast cancer is potentially curable when detected at an early stage, it remains incurable in the metastatic setting. Thus, given its high prevalence, improved prevention and treatment of metastases remains a clinically meaningful unmet need. We review here the advances made in the last several years in the screening and treatment of breast cancer and explore how our increased insight into the underlying biology of breast cancer has influenced our efforts to individualize patient care.

Background: The heterogeneity of TNBC includes a subtype that is androgen dependent and whose growth is inhibited by antiandrogen therapy. We conducted a multicenter phase II trial which established the activity of bicalutamide for the treatment of patients (pts) with metastatic ER/PR-negative breast cancer TBCRC011 (Gucalp CCR 2013). We now report results of whole genome, next generation sequencing of the 26 evaluable pts to molecularly classify the study population and to identify potential biomarkers of response to bicalutamide. We hypothesized that those pts whose tumors express increased AR output are most likely to benefit from anti-androgen therapy. Methods: Archival formalin-fixed, paraffin-embedded (FFPE) samples were collected from either primary or metastatic site and RNA was isolated using standard techniques. Whole transcriptome sequencing was performed using the Illumina HiSeq 2000 platform. This data set was compared to that of TCGA, the PAM50 and the Lehmann TN subtypes for molecular classification. Bioinformatic analysis defined a model of AR transcriptional output based on androgen stimulated AR+ ER/PR- breast cancer cell lines (HCC202, SUM185, MDA453) that was applied to the TBCRC011 data set as a predictor of response. Gene set analysis was performed to test secondary hypotheses. Results: 21/26 pts provided adequate gene expression estimates for further analysis. Principal component analysis in comparison to whole transcriptomes from breast cancers in the TCGA show that TBCRC011 tumors associate with the basal like (BL) intrinsic subtype, and this was confirmed by PAM50 classification. Relative AR expression of TBCRC011 cases was similar to that of BLBC in the TCGA. There is a weak but statistically significant positive correlation between AR expression by IHC and transcriptome (r=0.395, p=0.034). An expression-based model of AR activity was derived from AR+ ER/PR- cell lines exposed to androgen. TBCRC011 samples segregate with the TCGA samples predicted to be AR responsive by this model. However, the AR output signature did not predict clinical benefit (CR+PR+SD>24 weeks) as defined in TBCRC011. Unexpectedly, by the Lehmann TNBC subtype criteria TBCRC011 tumors were not consistently molecularly classified as luminal AR (BL1-1, BL2-1, Immunomodulatory-5, Luminal AR-4, Mesenchymal-2, Mesenchymal Stem Like-2, Unclassified-6). None of the 4 pts with clinical benefit were classified as BL by the Lehmann model. Gene set analysis revealed that estrogen signal pathways were associated with the number weeks on therapy, and that samples with high scoring AR by IHC exhibited expression patterns of medullary breast cancer. Conclusions: The majority of samples demonstrated expression variation consistent with TCGA basal like breast cancer. Although cell line models predict enrichment of AR activity in both the TCGA basal like and TBCRC011 cohorts, this AR output signature did not predict clinical benefit of bicalutamide. Molecular classification found clinical benefit beyond the luminal AR subtype but exclusive of basal like 1 and 2. Whether IHC or molecular subtype is the optimal biomarker for pt selection for antiandrogen therapy remains uncertain. Citation Format: Tiffany A Traina, Ayca Gucalp, William Polkinghorn, Steven Isakoff, Sara Tolaney, Lisa Carey, James Ingle, Lisle Nabell, Andres Forero, Hope Rugo, Kimberly Blackwell, Minetta Liu, Matthew Soloway, Lisle Mose, Dilip Giri, Agnes Viale, Clifford Hudis, Charles Sawyers, Joel Parker. Whole transcriptome analysis of AR+ ER/PR- metastatic breast cancers treated with bicalutamide on TBCRC011 [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-04-01.

1088Background: Seviteronel (Sevi), a CYP17-L inhibitor (reduces androgen and estrogen biosynthesis) and AR antagonist, has activity in castration resistant prostate cancer (CRPC) at a dose of 750 mg nightly. Sevi potently and dose-dependently inhibits the growth of ER(+)/AR(+) tamoxifen-resistant (TAMR) MCF7 and ER(-)/AR(+) MDA-MB-453 cells. In a TAMR xenograft BC model, Sevi decreases tumor growth > enzalutamide, an AR antagonist (Ellison et al. SABCS 2015). Approximately 80% of BCs, including a subset of TNBC that expresses AR, are potential targets for Sevi based on its mechanism of action (MOA). The primary objective of this Ph 1 study is to establish the recommended Ph 2 dose (RP2D) in women with BC (NCT02580448). Methods: Eligible pts have AR(+) TNBC or ER(+)/HER2-normal metastatic BC. ER(+) pts must have had ≥ 1 prior line of endocrine therapy; no limit to prior treatment for TNBC. Sevi start dose was 750 mg, administered nightly with dinner (28 d cycle) (n = 6/cohort). AR(+) status was confirmed ...

TPS1103Background: Patients (pts) with triple negative breast cancer (TNBC) have limited effective therapeutic options and generally experience a more aggressive clinical course. Emerging evidence demonstrates that the androgen-signaling pathway plays a role in BC pathogenesis and may be a valuable therapeutic target. In TBCRC011, we tested the efficacy of the AR antagonist, bicalutamide (B) in pts with AR+/ER/PgR- MBC. B was well-tolerated and demonstrated a clinical benefit rate (CBR) of 19% in this population (Gucalp et al. CCR 2013). Palbociclib (P) is a competitive inhibitor of CDK4/6 and has been shown to reduce growth of AR+/ER/PgR- MDA-MB-453 BC cells via reduced Rb phosphorylation. In postmenopausal pts with luminal ER+ MBC the addition of P to letrozole significantly improved median progression-free survival (PFS) in comparison to letrozole monotherapy. Given the luminal signature of AR+ TNBC and the presence of intact Rb in this ER(-) subtype, we are testing the efficacy of B+P in pts with meta...

VT-464, an oral dual lyase-selective CYP17 inhibitor and AR antagonist (wild-type and mutated forms [e.g., F876L and T877A]), is in multiple Phase (Ph) 2 studies as treatment for men with castration-resistant prostate cancer (CRPC). VT-464 inhibits the growth of multiple BC cell lines in vitro including MCF7 (ER(+)/AR low), tamoxifen-resistant MCF7, and MDA-MB-453 (ER(-)/AR(+)) in a dose-dependent manner and with greater potency/efficacy than enzalutamide (submitted, Ellison et al., 2015). A subset of TNBC and most ER(+) BC express AR, making them potential targets for VT-464 since it directly inhibits both androgen/estrogen synthesis and AR transcriptional activity. Objectives: The primary objective of Ph 1, now enrolling, is to establish the once-daily dose of VT-464 in women. Secondary objectives include safety, PK and efficacy endpoints, including determination of clinical benefit rate (CBR) which is the primary objective of Ph 2. Exploratory objectives include the determination of the extent of AR expression and signaling in breast tissue and to evaluate the relationship of expression with VT-464 effects on circulating tumor biomarkers, circulating hormones and clinical outcomes. Study Design: This study is an open-label, single arm, Ph 1/2 study of VT-464 in women with AR(+) TNBC or ER(+)/HER2 normal unresectable locally advanced or metastatic BC. Ph 1 will follow a modified 3+3 Fibonacci design with cohort expansion to 6 patients following a single DLT in the first 28-days of treatment. Approximately 2-3 dose-levels will be explored in Ph 1. Ph 1 start dose will be the MTD for men with CRPC. AR(+) TNBC and ER(+)/HER2 BC cohorts will be expanded in Ph 2 using the MTD from Ph 1. Ph 2 will follow a Simon's two-stage design with pre-determined futility parameters. Eligible patients will have ER≥1% BC or AR≥1% (as determined by central IHC testing using the Dako antibody) TNBC. ER(+) patients must be postmenopausal and must have received at least 1 prior line of endocrine therapy. Additional eligibility criteria include: ≥ 18 years of age, ECOG PS ≤ 1, unresectable locally advanced or metastatic BC, available representative tumor specimen to enable correlative science. Treatment Plan: Eligible patients will receive VT-464 once-nightly with dinner in a continuous dosing schedule. Adverse events and concomitant medications will be collected from the time of signing of informed consent until 30 days after end of study visit (EOS). Safety labs will be monitored monthly through EOS. Dense PK will be collected after the first dose of study drug in Ph 1 and single morning samples collected approximately every two cycles thereafter in Ph 1 and Ph 2 until EOS. Blood samples for steroids, circulating tumor DNA and circulating tumor cells will be collected through Cycle 2 and then at EOS. Tumor biopsy will be collected at baseline and at disease progression. Radiographic response will be assessed every 8 weeks and EOS. Patient Accrual: Accrual is ongoing with 12-18 patients expected to be enrolled in Ph 1. Citation Format: Gucalp A, Hudis C, Norton L, Patil S, Kurman MR, Eisner JR, Moore WR, Traina TA. A phase 1/2 study of once-daily oral VT-464 in patients with advanced androgen receptor (AR) positive triple negative (TNBC) or estrogen receptor (ER) positive breast cancer (BC). [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 OT2-01-03.

It is estimated that over 200,000 new cases of invasive breast cancer will be diagnosed in the United States in 2012 and approximately 40,000 women will die from their disease. Triple-negative breast cancer (TNBC), which lacks expression of the estrogen receptor (ER) and progesterone receptor (PR), and does not overexpress the human epidermal growth factor receptor-2 (HER-2) represents approximately 15 % of all breast cancers and is often associated with a more aggressive underlying biology. Patients with TNBC more often experience rapid disease progression with poorer disease-related and overall survival in the first few years after diagnosis in comparison to their hormone-receptor positive counterparts. Furthermore, this subset of breast cancers has limited therapeutic options aside from traditional cytotoxic chemotherapy agents as they do not benefit from generally well-tolerated endocrine-targeted therapies and anti-HER2 drugs. In this chapter we will review the epidemiology, risk factors, prognosis and the varied molecular and clinicopathologic features that characterize TNBC. In addition this review summarizes the available data for the use of cytotoxic chemotherapy in the treatment of TNBC and explores the ongoing development of targeted therapeutic agents for the treatment of this subgroup of breast cancers.

Triple-negative breast cancer (TNBC), a subtype distinguished by negative immunohistochemical assays for expression of the estrogen and progesterone receptors (ER/PR) and human epidermal growth factor receptor-2(HER2) represents 15% of all breast cancers. Patients with TNBC generally experience a more aggressive clinical course with increased risk of disease progression and poorer overall survival. Furthermore, this subtype accounts for a disproportionate number of disease-related mortality in part due to its aggressive natural history and our lack of effective targeted agents beyond conventional cytotoxic chemotherapy. In this paper, we will review the epidemiology, risk factors, prognosis, and the molecular and clinicopathologic features that distinguish TNBC from other subtypes of breast cancer. In addition, we will examine the available data for the use of cytotoxic chemotherapy in the treatment of TNBC in both the neoadjuvant and adjuvant setting and explore the ongoing development of newer targeted agents.

Background SRC activation is associated with cell migration, proliferation, and metastasis. Saracatinib is an oral tyrosine kinase inhibitor (TKI) selective for SRC. We performed this trial to evaluate the efficacy and safety of saracatinib monotherapy in patients with estrogen receptor (ER) – and progesterone receptor (PR) – metastatic breast cancer (MBC). Patients and Methods Patients who had undergone ≤ 1 previous chemotherapy regimen for measurable ER – and PR – MBC received saracatinib 175 mg orally daily. The primary endpoint was disease control defined as complete response (CR) + partial response (PR) + stable disease (SD) > 6 months. Secondary endpoints included toxicity and progression-free survival (PFS). Levels of circulating tumor cells (CTCs) in response to therapy were measured over time. Results Nine patients were treated on study. After a median of 2 cycles (range 1-3), no patient had achieved CR, PR, or SD >6 months. The median time to treatment failure was 82 days (12-109 days).The majority (89%) of patients discontinued saracatinib because of disease progression. One patient acquired potentially treatment-related grade 4 hypoxia with interstitial infiltrates and was removed from the study. Common adverse events included fatigue, elevated liver enzymes, nausea, hyponatremia, dyspnea, cough, and adrenal insufficiency. Conclusions These efficacy results were not sufficiently promising to justify continued accrual to this study. Based on this series, saracatinib does not appear to have significant single-agent activity for the treatment of patients with ER − /PR − MBC.

Purpose of review HIV-infected individuals remain at an increased risk for developing malignancies despite the use of combined antiretroviral therapy. Lymphomas comprise a large proportion of the malignancies that affect the HIV-infected population in developed countries. This review summarizes the recent progress made in HIV lymphoma research published in 2009 through January 2010. Recent findings The majority of investigation in this field has been in diffuse large B-cell lymphoma, with infusional therapy remaining promising. Rituximab likely improves complete response and possibly overall survival, but may be associated with increased infections in a subset of patients with very low CD4 cell counts. Risk factors associated with the development of lymphoma include low CD4 cell count and likely cumulative HIV viremia. Biologic insights have been realized regarding pathogenesis. Summary Overall, the outcome for HIV lymphoma continues to improve as insights into the pathophysiology and treatment advance.

566 Background: IBM Watson for Oncology (WFO), trained by Memorial Sloan Kettering (MSK), is a cognitive computing system designed to apply machine learning, informed by MSK expertise, to enhance c...

11001 Background: Obesity is a poor prognostic factor for breast cancer (BC) survivors. White adipose tissue (WAT) inflammation (WATi) occurs in the breasts of most obese/overweight individuals, an...

e11608 Background: Human Epidermal growth factor Receptor-2 (HER2) is a member of the epidermal growth factor (EGFR) family of transmembrane receptors and is overexpressed in ~20% of breast cancers...

Background: Metabolic syndrome is associated with increased breast cancer (BC) risk. After menopause, obesity is associated with increased risk of hormone receptor (HR)-positive breast cancer. We demonstrated an obesity → inflammation → aromatase axis in breast white adipose tissue (WAT) where inflammation is defined by the presence of crown-like structures (CLS) consisting of a dead or dying adipocyte encircled by macrophages. CLS in the breast (CLS-B) are associated with elevated body mass index (BMI), postmenopausal status, increased adipocyte size, and increased tissue levels of proinflammatory mediators and aromatase. As obesity is a component of the metabolic syndrome and is associated with inflammation, we compared levels of relevant circulating factors in women with and without breast WAT inflammation. Methods: We prospectively collected paired WAT and fasting serum and plasma from women undergoing mastectomy at MSKCC. WAT inflammation was detected by CD68 immunohistochemistry to identify CLS-B by light microscopy. Plasma levels of glucose, insulin, hsCRP, leptin, adiponectin, and IL-6 were measured by ELISA. Serum levels of total cholesterol, triglycerides (TG), HDL and LDL cholesterol were determined. Insulin resistance (IR) was assessed using fasting plasma glucose and insulin levels via the updated Homeostasis Model Assessment (HOMA2-IR). Associations between CLS-B and clinicopathologic features, including medication usage, were analyzed by logistic regression and Fisher’s exact test. Differences in serum/plasma endpoints between subjects with and without CLS-B were evaluated using Student t-test and nonparametric Wilcoxon rank-sum test. Results: From 11/2011 – 3/2013 we accrued 100 patients (pts); median age 47 years (range 27 – 70). Overall, CLS-B were found in 52/100 (52%) pts: 18/19 (95%) obese pts, 17/33 (52%) overweight pts, and 17/48 (35%) normal BMI pts. A clinical diagnosis of dyslipidemia was present in 14/52 (27%) pts with CLS-B and 1/48 (2%) pts without CLS-B (P Fasting level, mean (SD)No CLS-B, N=48CLS-B +, N=52PGlucose, mg/dL73.2 (8.0)84.3 (37.6)0.04Insulin, mU/L4.3 (2.1)5.6 (2.9)0.01LDL cholesterol, mg/dL105.9 (31.0)119.4 (32.4)0.04HDL cholesterol, mg/dL71.9 (15.8)62.1 (16.1)0.003Triglycerides, mg/dL69.2 (26.3)104.9 (50.6) Conclusions: Breast WAT inflammation, which we have previously linked to increased aromatase activity, is associated with biochemical changes that occur in the metabolic syndrome, a risk factor for BC. Statin use is more common in patients with breast WAT inflammation and metabolic syndrome. Clinically, statin use may be a surrogate identifier of a population that is at increased baseline risk of BC. These findings may account for the variability in results of prior studies examining statin use and breast cancer risk due to elevated risk in users compared to non-users. Citation Format: Neil M Iyengar, Ayca Gucalp, Xi K Zhou, Louise R Howe, Patrick G Morris, Dilip Giri, Kotha Subbaramaiah, Priya Bhardwaj, Samuel S Park, Michael Pollak, Monica Morrow, Clifford A Hudis, Andrew J Dannenberg. Both metabolic syndrome and statin use are more common in women with breast inflammation [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-04-12.

Background TNBCs are a heterogeneous group characterized by lack of ER/PR/HER2 expression. Doane et al described a subgroup of TNBC associated with AR-dependent growth. While expression of EGFR and p53 are common in TNBC, their role in AR+ TNBC is less clear. We report the rates of EGFR and p53 expression and clinicopathologic features of AR+ TNBC from a retrospective cohort at MSKCC. Methods We identified 1,032 patients (pts) with resectable, TNBC (ER/PR 1 cm) with each tumor represented by 3 cores. AR was tested with DAKO Clone AR441, dilution (dil) 1:500; ratio of DAB nuclear staining to hematoxylin signal >1 SD above mean was defined as AR+. EGFR and p53 were tested with Thermo-Scientific Clone EP38Y, dil 1:50 and DAKO Clone D07, dil 1:50 respectively. Scoring: 0-1+ negative, 2-3+ positive. Fisher's exact test used to evaluate correlation between AR with EGFR and p53. RFS and OS evaluated using Kaplan-Meier methods. Clinicopathologic variables by AR status were compared using Chi-square/t-tests. Results 166 pts had adequate cores for AR testing. 10% were AR+ (17/166). 160 pts were evaluable for EGFR and 164 pts for p53. Median (med) followup: AR + =6 years (y), AR- = 5.6y. Adjuvant chemotherapy received: AR+ 82%, AR- 87%, P = 0.40. EGFR was expressed more frequently in AR- than AR+ TNBCs (111/143 (78%) vs 9/17 (53%); P =0.04). p53 expression was similar in AR- and AR+ TNBC (82/147 (56%) vs 7/17 (41%); P =0.30). Clinicopathologic variables based on AR and EGFR status appeared similar. 3y RFS and OS data are below. Conclusion Consistent with published reports, loss of AR expression correlates with EGFR expression. In contrast, no association was observed with p53 and AR. These data are hypothesis generating regarding the mechanism of interaction of AR and EGFR in TNBC. -3 year RFS (95% CI) -3 year OS (95% CI) AR+ 76% (47-90) 88% (59-97) AR- 81% (74-87) 93% (87-96) AR+ EGFR+ (n = 9) 67% (39-98) 78% (36-94) AR+ EGFR- (n = 8) 88% (39-98) 100% AR- EGFR+ (n = 111) 82% (73-88) 91% (84-95) AR_ EGFR- (n = 32) 81% (61-92) 97% (80-100) Disclosure All authors have declared no conflicts of interest.

TPS1615 Background: Obesity is a risk factor for the development of BC and is associated with poorer cancer outcomes irrespective of BC subtype. Obesity is associated with diffuse white adipose tis...

6601 Background: With an increasing complexity and number of endocrine, molecularly-targeted and immunotherapeutic clinical trial and standard-of-care therapies available for patients with metastat...