PurposeAndrogen receptor (AR) is frequently detected in breast cancers, and AR-targeted therapies are showing activity in AR-positive (AR+) breast cancer. However, the role of AR in breast cancers is still not fully elucidated and the biology of AR in breast cancer remains incompletely understood. Circulating tumor cells (CTCs) can serve as prognostic and diagnostic tools, prompting us to measure AR protein expression and conduct genomic analyses on CTCs in patients with metastatic breast cancer.MethodsBlood samples from patients with metastatic breast cancer were deposited on glass slides, subjected to nuclear staining with DAPI, and reacted with fluorescent-labeled antibodies to detect CD45, cytokeratin (CK), and biomarkers of interest (AR, estrogen receptor [ER], and HER2) on all nucleated cells. The stained slides were scanned and enumerated by non-enrichment-based non-biased approach independent of cell surface epithelial cell adhesion molecule (EpCAM) using the Epic Sciences CTC platform. Data were analyzed using established digital pathology algorithms.ResultsOf 68 patients, 51 (75%) had at least 1 CTC, and 49 of these 51 (96%) had hormone-receptor-positive (HR+)/HER2-negative primary tumors. AR was expressed in CK+ CTCs in 10 patients. Of these 10 patients, 3 also had ER expression in CK+ CTCs. Single cell genomic analysis of 78 CTCs from 1 of these 3 patients identified three distinct copy number patterns. AR+ cells had a lower frequency of chromosomal changes than ER+ and HER2+ cells.ConclusionsCTC enumeration and analysis using no enrichment or selection provides a non-biased approach to detect AR expression and chromosomal aberrations in CTCs in patients with metastatic breast cancer. The heterogeneity of intrapatient AR expression in CTCs leads to the new hypothesis that patients with AR+ CTCs have heterogeneous disease with multiple drivers. Further studies are warranted to investigate the clinical applicability of AR+ CTCs and their heterogeneity.

In patients with pulmonary emphysema, studies have reported 2-3% of individuals with severe a 1 -Pi deficiency. The aims of this study were to evaluate the accuracy of a new method for quantifying a 1 -Pi through phenotyping from dried blood spots (DBS) and to test the hypothesis that the screening of a population at risk increases the detection rate for severe a 1 -Pi deficiency.The accuracy of phenotyping results from DBS was compared to conventional methods in a total of 555 individuals. In a prospective study 1,060 patients with chronic lung disease were screened for a 1 -Pi deficiency using DBS.The validation of the phenotyping method from DBS showed an accuracy of 100%. Out of 1,060 tested patients, none had a severe PiZ deficiency and only 3 had PiSZ, whilst 36 (3.34%) individuals were identified as heterozygous for PiMS and 39 (3.68%) for PiMZ.No patients with severe a 1 -Pi deficiency could be detected in this population and the frequency of PiMS or PiMZ detected was similar to that of the normal population. Thus, the screening of an unselected population of chronic obstructive pulmonary disease and asthma patients may not detect a large number of individuals with severe a 1 -Pi deficiency.

Talimogene laherparepvec (T-VEC) is an immunotherapy that generates local tumor lysis and systemic antitumor immune response. We studied the efficacy of intratumoral administration of T-VEC as monotherapy for inoperable locoregional recurrence of breast cancer. T-VEC was injected intratumorally at 106 PFU/mL on day 1 (cycle 1), 108 PFU/mL on day 22 (cycle 2), and 108 PFU/mL every 2 weeks thereafter (cycles ≥ 3). Nine patients were enrolled, 6 with only locoregional disease and 3 with both locoregional and distant disease. No patient completed the planned 10 cycles or achieved complete or partial response. The median number of cycles administered was 4 (range, 3–8). Seven patients withdrew prematurely because of uncontrolled disease progression, 1 withdrew after cycle 3 because of fatigue, and 1 withdrew after cycle 4 for reasons unrelated to study treatment. Median progression-free survival and overall survival were 77 days (95% CI, 63–NA) and 361 days (95% CI, 240–NA). Two patients received 8 cycles with clinically stable disease as the best response. The most common grade 2 or higher adverse event was injection site reaction (n = 7, 78%). Future studies could examine whether combining intratumoral T-VEC with concurrent systemic therapy produces better outcomes.

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Background: IBCs that do not completely respond to chemotherapy often have dysregulated immune pathways, and novel therapies are needed to improve outcomes in recurrent/metastatic disease. One-third of IBCs express the atezolizumab target PD-L1, and cobimetinib increases PD-L1 expression; thus, we hypothesize that atezolizumab and cobimetinib may act synergistically in IBC. The FDA-approved agent eribulin is active in IBC and has anti-stem cell activity and can reverse the IBC phenotype of epithelial-to-mesenchymal transition. Hence the use of eribulin as a chemotherapy backbone in combination with other novel agents is well justified. Trial Design: This single-arm, open-label trial is enrolling patients with recurrent IBC or de novo metastatic IBC that has progressed on at least 1 line of standard chemotherapy. During a 4-week pharmacodynamic window, patients have an upfront biopsy, receive atezolizumab and cobimetinib treatment for 4 weeks, and have a second biopsy. Triple-combination treatment then commences, with standard eribulin dosing. After 4 cycles of eribulin, patients receive maintenance targeted therapy until disease progression or intolerable toxicity. Eligibility Criteria: Patients with metastatic IBC of any molecular subtype must have measurable disease (per RECIST 1.1) amenable to biopsy. Patients with HER2+ disease must have received both pertuzumab and T-DM1. Patients with treated stable brain metastases are allowed. Patients must have recovered from the acute effects of any prior therapies and have adequate hematologic, organ, and cardiac function. Patients with autoimmune diseases or a history of pneumonitis are ineligible. Specific Aims: The primary objective is to determine the overall response rate (ORR) of the combination therapy. Secondary objectives include determining the safety and tolerability, clinical benefit rate, response duration, progression-free survival, 2-year overall survival rate and predictive biomarker analyses. Statistical Methods: The trial will enroll up to 9 patients in its phase I/safety lead-in portion and up to 33 patients total. A Bayesian optimal interval design is used to efficiently determine the maximum tolerated cobimetinib dose in phase I. Patients start cobimetinib at the FDA-approved dose of 60 mg/day with a target toxicity rate is 0.3. Phase II will enroll 24 patients to determine the efficacy of the triple-combination therapy. The historical ORR in metastatic IBC is 10%; our sample size provides 80% power to detect an ORR improvement to 25%. Accrual: The trial has enrolled 7 patients since its start in August 2017. Citation Format: Alexander A, Marx AN, Reddy SM, Reuben JM, Le-Petross HC, Lane D, Huang ML, Krishnamurthy S, Gong Y, Gombos DS, Patel N, Tung CI, Allen RC, Kandl TJ, Wu J, Liu S, Patel AB, Futreal A, Wistuba I, Layman RM, Valero V, Tripathy D, Ueno NT, Lim B. Phase II study of atezolizumab, cobimetinib, and eribulin in patients with recurrent or metastatic inflammatory breast cancer (IBC) [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 OT3-05-04.