Publications by authors named "Leisha A Emens"

101 Publications

Outcomes After Sentinel Lymph Node Biopsy and Radiotherapy in Older Women With Early-Stage, Estrogen Receptor-Positive Breast Cancer.

JAMA Netw Open 2021 Apr 1;4(4):e216322. Epub 2021 Apr 1.

Women's Cancer Research Center, UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania.

Importance: Overtreatment of early-stage breast cancer with favorable tumor biology in older patients may be harmful without affecting recurrence and survival. Guidelines that recommend deimplementation of sentinel lymph node biopsy (SLNB) (Choosing Wisely) and radiotherapy (RT) (National Comprehensive Cancer Network) have been published.

Objective: To describe the use rates and association with disease recurrence of SLNB and RT in older women with breast cancer.

Design, Setting, And Participants: This cohort study obtained patient and clinical data from an integrated cancer registry and electronic health record of a single health care system in Pennsylvania. The cohort was composed of consecutive female patients 70 years or older who were diagnosed with early-stage, estrogen receptor-positive, ERBB2 (formerly HER2)-negative, clinically node-negative breast cancer from January 1, 2010, to December 31, 2018, who were treated at 15 community and academic hospitals within the health system.

Exposures: Sentinel lymph node biopsy and adjuvant RT.

Main Outcomes And Measures: Primary outcomes were 5-year locoregional recurrence-free survival (LRFS) rate and disease-free survival (DFS) rate after SLNB and after RT. Secondary outcomes included recurrence rate, subgroups that may benefit from SLNB or RT, and use rate of SLNB and RT over time. Propensity scores were used to create 2 cohorts to separately evaluate the association of SLNB and RT with recurrence outcomes. Cox proportional hazards regression model was used to estimate hazard ratios (HRs).

Results: From 2010 to 2018, a total of 3361 women 70 years or older (median [interquartile range {IQR}] age, 77.0 [73.0-82.0] years) with estrogen receptor-positive, ERBB2-negative, clinically node-negative breast cancer were included in the study. Of these women, 2195 (65.3%) received SLNB and 1828 (54.4%) received adjuvant RT. Rates of SLNB steadily increased (1.0% per year), a trend that persisted after the 2016 adoption of the Choosing Wisely guideline. Rates of RT decreased slightly (3.4% per year). To examine patient outcomes and maximize follow-up time, the analysis was limited to cases from 2010 to 2014, identifying 2109 patients with a median (IQR) follow-up time of 4.1 (2.5-5.7) years. In the propensity score-matched cohorts, no association was found between SLNB and either LRFS (HR, 1.26; 95% CI, 0.37-4.30; P = .71) or DFS (HR, 1.92; 95% CI, 0.86-4.32; P = .11). In addition, RT was not associated with LRFS (HR, 0.33; 95% CI, 0.09-1.24; P = .10) or DFS (HR, 0.99; 95% CI, 0.46-2.10; P = .97). Subgroup analysis showed that stratification by tumor grade or comorbidity was not associated with LRFS or DFS. Low absolute rates of recurrence were observed when comparing the groups that received SLNB (3.5%) and those that did not (4.5%) as well as the groups that received RT (2.7%) and those that did not (5.5%).

Conclusions And Relevance: This study found that receipt of SLNB or RT was not associated with improved LRFS or DFS in older patients with ER-positive, clinically node-negative breast cancer. Despite limited follow-up time and wide 95% CIs, this study supports the continued deimplementation of both SLNB and RT in accordance with the Choosing Wisely and National Comprehensive Cancer Network guidelines.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.6322DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8050744PMC
April 2021

Predictive Biomarkers: Progress on the Road to Personalized Cancer Immunotherapy.

Authors:
Leisha A Emens

J Natl Cancer Inst 2021 Apr 6. Epub 2021 Apr 6.

University of Pittsburgh Department of Medicine and UPMC Hillman Cancer Center, Pittsburgh, PA, USA.

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http://dx.doi.org/10.1093/jnci/djab068DOI Listing
April 2021

Quantitative systems pharmacology model predictions for efficacy of atezolizumab and nab-paclitaxel in triple-negative breast cancer.

J Immunother Cancer 2021 Feb;9(2)

Department of Biomedical Engineering, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.

Background: Immune checkpoint blockade therapy has clearly shown clinical activity in patients with triple-negative breast cancer, but less than half of the patients benefit from the treatments. While a number of ongoing clinical trials are investigating different combinations of checkpoint inhibitors and chemotherapeutic agents, predictive biomarkers that identify patients most likely to benefit remains one of the major challenges. Here we present a modular quantitative systems pharmacology (QSP) platform for immuno-oncology that incorporates detailed mechanisms of immune-cancer cell interactions to make efficacy predictions and identify predictive biomarkers for treatments using atezolizumab and nab-paclitaxel.

Methods: A QSP model was developed based on published data of triple-negative breast cancer. With the model, we generated a virtual patient cohort to conduct in silico virtual clinical trials and make retrospective analyses of the pivotal IMpassion130 trial that led to the accelerated approval of atezolizumab and nab-paclitaxel for patients with programmed death-ligand 1 (PD-L1) positive triple-negative breast cancer. Available data from clinical trials were used for model calibration and validation.

Results: With the calibrated virtual patient cohort based on clinical data from the placebo comparator arm of the IMpassion130 trial, we made efficacy predictions and identified potential predictive biomarkers for the experimental arm of the trial using the proposed QSP model. The model predictions are consistent with clinically reported efficacy endpoints and correlated immune biomarkers. We further performed a series of virtual clinical trials to compare different doses and schedules of the two drugs for simulated therapeutic optimization.

Conclusions: This study provides a QSP platform, which can be used to generate virtual patient cohorts and conduct virtual clinical trials. Our findings demonstrate its potential for making efficacy predictions for immunotherapies and chemotherapies, identifying predictive biomarkers, and guiding future clinical trial designs.
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http://dx.doi.org/10.1136/jitc-2020-002100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7883871PMC
February 2021

Atezolizumab and nab-Paclitaxel in Advanced Triple-Negative Breast Cancer: Biomarker Evaluation of the IMpassion130 Study.

J Natl Cancer Inst 2021 Feb 1. Epub 2021 Feb 1.

Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.

Background: Understanding the impact of the tumor immune microenvironment and BRCA-related DNA repair deficiencies on the clinical activity of immune checkpoint inhibitors may help optimize both patient and treatment selection in metastatic triple-negative breast cancer (mTNBC). In this substudy from the phase 3 IMpassion130 trial, immune biomarkers and BRCA alterations were evaluated for association with clinical benefit with atezolizumab (A) + nab-paclitaxel (nP) vs placebo + nP in unresectable locally advanced or mTNBC.

Methods: Patients were randomized 1:1 to nab-paclitaxel 100 mg/m2 (days 1, 8, and 15 of a 28-day cycle) + atezolizumab 840 mg every 2 weeks or placebo until progression or toxicity. Progression-free survival (PFS) and overall survival (OS) were evaluated based on programmed death-ligand 1 (PD-L1) expression on immune cells (IC) and tumor cells (TC), intratumoral CD8, stromal tumor-infiltrating lymphocytes (sTILs), and BRCA1/2 mutations.

Results: PD-L1 IC+ in either primary or metastatic tumor tissue was linked to PFS and OS benefit with A+nP. PD-L1 IC+ low (26.9%; 243 of 902 patients) and high (13.9%; 125 of 902 patients) populations had improved outcomes that were comparable. Intratumoral CD8 and sTILs positivity were associated with PD-L1 IC+ status; A+nP vs P+nP improved outcomes were observed only in CD8+ and sTIL+ patients who were also PD-L1 IC+. BRCA1/2 mutations (occurring in 14.5% [89 of 612 patients]) were not associated with PD-L1 IC status, and PD-L1 IC+ patients benefited from A+nP regardless of BRCA1/2 mutation status.

Conclusions: Although A+nP was more efficacious in patients with richer tumor immune microenvironment, clinical benefit was only observed in patients whose tumors were PD-L1 IC+.S.
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http://dx.doi.org/10.1093/jnci/djab004DOI Listing
February 2021

Immunotherapy in Triple-Negative Breast Cancer.

Authors:
Leisha A Emens

Cancer J 2021 Jan-Feb 01;27(1):59-66

From the University of Pittsburgh Department of Medicine and UPMC Hillman Cancer Center, Pittsburgh, PA.

Abstract: Triple-negative breast cancer (TNBC) is an aggressive subtype of mammary carcinoma. A subset of TNBC is immune activated, suggesting that immunotherapy may be a viable treatment strategy. Phase III clinical trials have shown that atezolizumab or pembrolizumab is well-tolerated in combination with chemotherapy, with progression-free survival benefit in metastatic programmed death ligand-1 (PD-L1)-positive TNBC patients treated first line. Based on IMpassion130, the combination of atezolizumab and nab-paclitaxel is now considered a standard of care for the treatment of PD-L1-positive advanced TNBC. In early TNBC, pembrolizumab and atezolizumab have been tested in combination with standard neoadjuvant chemotherapy, resulting in a higher complete pathologic response rate than standard neoadjuvant chemotherapy alone, regardless of disease PD-L1 status. These findings establish proof of principle for immunotherapy in both early and advanced TNBC. High priorities for the field include developing more active immunotherapy combination regimens and more refined biomarkers that optimally identify patients most likely to benefit from immunotherapy.
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http://dx.doi.org/10.1097/PPO.0000000000000497DOI Listing
January 2021

Robust antigen-specific CD8 T cell tolerance to a model prostate cancer neoantigen.

Oncoimmunology 2020 09 6;9(1):1809926. Epub 2020 Sep 6.

Columbia Center for Translational Immunology, Columbia University Irving Medical Center, New York, NY, USA.

Immunotherapy has shown limited success in prostate cancer; this may be partially explained by its immunosuppressive tumor microenvironment (TME). Although androgen-deprivation therapy (ADT), the most common treatment for prostate cancer, initially promotes a robust T cell infiltrate, T cell responses are later attenuated. Based on the castration-sensitive Myc-CaP model, we developed an antigen-specific system to study CD8 T cell tolerance to prostate tumors. This model is unique in that CD8 T cells recognize a bona-fide tumor antigen (Her-2/neu), rather than an overexpressed xenogenic antigen like chicken ovalbumin or influenza hemagglutinin. Using this novel model, we demonstrate robust tolerance that is not alleviated by TLR agonists or ADT. This model may serve as a novel and useful tool to further interrogate methods by which to augment anti-tumor cancer immune responses to prostate cancer.

Significance: Prostate cancer is a leading cause of cancer-related death in men worldwide, with an estimated 33,000 deaths projected in the U.S. in 2020. Although primary (localized) tumors can be cured by surgery or radiation, approximately 40% of patients eventually develop recurrent disease. While initially responsive to androgen-deprivation, many patients with recurrent prostate cancer eventually progress to a more advanced disease state known as metastatic castration-resistant prostate cancer (mCRPC); this is the lethal phenotype. These studies describe a novel androgen-responsive murine cell line that expresses a bona-fide tumor antigen (Her-2/neu). Pre-clinical work with this model shows robust and antigen-specific CD8 T cell tolerance, providing a novel preclinical model to study CD8 T cell tolerance to prostate tumors.
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http://dx.doi.org/10.1080/2162402X.2020.1809926DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7781773PMC
September 2020

Perspectives in immunotherapy: meeting report from the "Immunotherapy Bridge" (December 4th-5th, 2019, Naples, Italy).

J Transl Med 2021 01 6;19(1):13. Epub 2021 Jan 6.

Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.

Over the last few years, numerous clinical trials and real-world experience have provided a large amount of evidence demonstrating the potential for long-term survival with immunotherapy agents across various malignancies, beginning with melanoma and extending to other tumours. The clinical success of immune checkpoint blockade has encouraged increasing development of other immunotherapies. It has been estimated that there are over 3000 immuno-oncology trials ongoing, targeting hundreds of disease and immune pathways. Evolving topics on cancer immunotherapy, including the state of the art of immunotherapy across various malignancies, were the focus of discussions at the Immunotherapy Bridge meeting (4-5 December, 2019, Naples, Italy), and are summarised in this report.
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http://dx.doi.org/10.1186/s12967-020-02627-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7789268PMC
January 2021

Digital Pathology Analysis Quantifies Spatial Heterogeneity of CD3, CD4, CD8, CD20, and FoxP3 Immune Markers in Triple-Negative Breast Cancer.

Front Physiol 2020 19;11:583333. Epub 2020 Oct 19.

Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, United States.

Overwhelming evidence has shown the significant role of the tumor microenvironment (TME) in governing the triple-negative breast cancer (TNBC) progression. Digital pathology can provide key information about the spatial heterogeneity within the TME using image analysis and spatial statistics. These analyses have been applied to CD8+ T cells, but quantitative analyses of other important markers and their correlations are limited. In this study, a digital pathology computational workflow is formulated for characterizing the spatial distributions of five immune markers (CD3, CD4, CD8, CD20, and FoxP3) and then the functionality is tested on whole slide images from patients with TNBC. The workflow is initiated by digital image processing to extract and colocalize immune marker-labeled cells and then convert this information to point patterns. Afterward invasive front (IF), central tumor (CT), and normal tissue (N) are characterized. For each region, we examine the intra-tumoral heterogeneity. The workflow is then repeated for all specimens to capture inter-tumoral heterogeneity. In this study, both intra- and inter-tumoral heterogeneities are observed for all five markers across all specimens. Among all regions, IF tends to have higher densities of immune cells and overall larger variations in spatial model fitting parameters and higher density in cell clusters and hotspots compared to CT and N. Results suggest a distinct role of IF in the tumor immuno-architecture. Though the sample size is limited in the study, the computational workflow could be readily reproduced and scaled due to its automatic nature. Importantly, the value of the workflow also lies in its potential to be linked to treatment outcomes and identification of predictive biomarkers for responders/non-responders, and its application to parameterization and validation of computational immuno-oncology models.
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http://dx.doi.org/10.3389/fphys.2020.583333DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7604437PMC
October 2020

Trastuzumab emtansine plus atezolizumab versus trastuzumab emtansine plus placebo in previously treated, HER2-positive advanced breast cancer (KATE2): a phase 2, multicentre, randomised, double-blind trial.

Lancet Oncol 2020 10;21(10):1283-1295

Division of Research, Peter MacCallum Cancer Center, Melbourne, VIC, Australia. Electronic address:

Background: HER2-positive metastatic breast cancer is incurable and new treatments are needed. Addition of atezolizumab to trastuzumab emtansine might potentiate anticancer immunity and enhance the HER2-targeted cytotoxic activity of trastuzumab emtansine. We aimed to test this combination in HER2-positive advanced breast cancer that had progressed after previous treatment with trastuzumab and a taxane.

Methods: The KATE2 study is a randomised, double-blind, placebo-controlled, phase 2 study at 68 centres from nine countries across Asia, Australia, North America, and western Europe. Eligible patients were adults (aged ≥18 years) with an Eastern Cooperative Oncology Group performance status of 0 or 1 and centrally confirmed, measurable, HER2-positive advanced breast cancer previously treated with trastuzumab and a taxane. Patients were randomly assigned (2:1) either trastuzumab emtansine (3·6 mg/kg of bodyweight) plus atezolizumab (1200 mg) or trastuzumab emtansine plus placebo; all study drugs were administered by intravenous infusion every 3 weeks. Randomisation was done via an interactive voice and web response system using a permuted block scheme (block size of six) and was stratified by PD-L1 status, world region, and liver metastases. Patients, investigators, and study team members were masked to treatment allocation. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT02924883, and the study has been completed.

Findings: Between Sept 26, 2016, and Aug 7, 2017, 330 patients were screened for the study, of whom 202 were randomly allocated either atezolizumab (n=133) or placebo (n=69). At the recommendation of the independent data monitoring committee, treatment assignment was unmasked on Dec 11, 2017, due to futility and the numerically higher frequency of adverse events among patients assigned atezolizumab. This date was set as the clinical cutoff for the primary analysis. Median follow-up was 8·5 months (IQR 6·1-11·5) for patients assigned atezolizumab and 8·4 months (5·3-11·1) for those assigned placebo. Median progression-free survival was 8·2 months (95% CI 5·8-10·7) for patients assigned atezolizumab versus 6·8 months (4·0-11·1) for those assigned placebo (stratified hazard ratio 0·82, 95% CI 0·55-1·23; p=0·33). The most common grade 3 or worse adverse events were thrombocytopenia (17 [13%] among 132 patients who received atezolizumab vs three [4%] among 68 who received placebo), increased aspartate aminotransferase (11 [8%] vs two [3%]), anaemia (seven [5%] vs 0), neutropenia (six [5%] vs three [4%]), and increased alanine aminotransferase (six [5%] vs two [3%]). Serious adverse events occurred in 43 (33%) of 132 patients who received atezolizumab and 13 (19%) of 68 patients who received placebo. One patient who received atezolizumab died due to a treatment-related adverse event (haemophagocytic syndrome).

Interpretation: Addition of atezolizumab to trastuzumab emtansine did not show a clinically meaningful improvement in progression-free survival and was associated with more adverse events. Further study of trastuzumab emtansine plus atezolizumab is warranted in a subpopulation of patients with PD-L1-positive, HER2-positive advanced breast cancer.

Funding: F Hoffman-La Roche.
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http://dx.doi.org/10.1016/S1470-2045(20)30465-4DOI Listing
October 2020

Current and emerging biologic therapies for triple negative breast cancer.

Expert Opin Biol Ther 2020 Aug 9:1-12. Epub 2020 Aug 9.

Department of Medicine, Division of Hematology and Oncology, University of Pittsburgh, Pittsburgh, PA, USA.

Introduction: Triple negative breast cancer, defined by a lack of estrogen receptor, progesterone receptor, or human epidermal growth factor2, accounts for approximately 15% of breast cancer patients. Treatment options have historically been limited to chemotherapy, which has significant toxicity and a suboptimal impact on the five-year relapse rate and survival.

Areas Covered: Transcriptomic analyses reveal that TNBC is biologically heterogenous. Predictive biomarkers based on the distinct biology of the different subtypes of TNBC should identify patients that will derive the greatest benefit from a specifically targeted therapeutic agent. Two biomarker-driven treatments have recently been approved: poly-ADP ribose polymerase inhibitors for patients with germline mutations and atezolizumab in combination with -paclitaxel for patients expressing PD-L1 on tumor-infiltrating immune cells.

Expert Opinion: Identifying informative predictive biomarkers is critical for the optimal development of targeted drugs for TNBC. Some targeted agents, such as the antibody-drug conjugate sacituzumab govitecan-hziy and the precision medicines capivasertib and ipatisertib, have already shown promising results in early clinical trials, and the results of definitive phase 3 trials are eagerly awaited. Additionally, testing novel immunotherapies and other targeted agents in earlier stages of disease, particularly the neoadjuvant setting, is a high priority.
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http://dx.doi.org/10.1080/14712598.2020.1801627DOI Listing
August 2020

The evolving management of metastatic triple negative breast cancer.

Semin Oncol 2020 Aug 28;47(4):229-237. Epub 2020 May 28.

University of Pittsburgh Department of Medicine, UPMC Hillman Cancer Center, Pittsburgh, PA. Electronic address:

Advanced triple negative breast cancer (TNBC) is an incurable disease classified by its lack of expression of the estrogen receptor, progesterone receptor, and human epidermal growth factor receptor-2. Due to its lack of therapeutic targets, it has historically been treated with single agent chemotherapy, with combination cytotoxic therapy typically reserved for patients with high disease burdens, symptomatic disease, and/or impending visceral crisis. Recent molecular analyses have revealed that this clinical group of TNBCs is in fact quite biologically heterogeneous, with multiple TNBC subtypes defined by distinct biology and clinical behavior. Building on this biology, 2 targeted strategies are now approved for selected patients with advanced TNBC: the poly (ADP-ribose) polymerase inhibitors for advanced TNBC with a germline mutation in BRCA1/2, and the combination of the programmed death ligand 1-specific antibody atezolizumab with nab-paclitaxel for advanced TNBC that expresses programmed death ligand 1 on immune cells within the tumor. These targeted agents tend to be associated with a more favorable side effect profile and longer disease control than standard chemotherapy. A number of other targeted therapies have shown promise in early clinical trials, and several are now in definitive phase 3 testing for advanced TNBC. These include the antiapoptotic kinase inhibitors ipatisertib and capivasertib, and the antibody-drug conjugate sacituzumab govitecan-hziy. Approved biomarker-driven treatment options for this disease are thus likely to expand in the near-term. Here we review current treatment options and emerging targeted therapies for advanced TNBC. For patients who do not meet criteria for approved targeted therapies, participation in clinical trials evaluating precision medicines with candidate predictive biomarkers in advanced TNBC should be encouraged.
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http://dx.doi.org/10.1053/j.seminoncol.2020.05.005DOI Listing
August 2020

Cytokine profiling of tumor-infiltrating T lymphocytes by flow cytometry.

Methods Enzymol 2020 18;631:1-20. Epub 2019 Oct 18.

Department of Medicine, UPMC Hillman Cancer Center, and UPMC Magee Women's Hospital, University of Pittsburgh, Pittsburgh, PA, United States. Electronic address:

Intracellular cytokine staining (ICS) utilizing fluorescently labeled, cytokine-specific antibodies is a powerful technique utilized to evaluate cytokine expression that provides resolution at the single cell level. Combined with multi-parameter flow cytometry, ICS can provide detailed information on complex cytokine profiles and cellular phenotypes within the tumor microenvironment, particularly for the CD4 T helper and CD8 cytotoxic T cell compartments. This technique provides critical information concerning tumor-infiltrating T cell function that is essential for evaluating existing or therapeutically-induced tumor antigen-specific T cell responses in both preclinical models and cancer patients. In this chapter we will discuss in detail the critical steps necessary for a successful ICS assay and outline common protocols for the evaluation of cytokine production from T cell subsets present within the tumor microenvironment.
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http://dx.doi.org/10.1016/bs.mie.2019.08.015DOI Listing
January 2021

Breast cancer vaccines: Heeding the lessons of the past to guide a path forward.

Cancer Treat Rev 2020 Mar 29;84:101947. Epub 2019 Nov 29.

UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, United States. Electronic address:

The ability of cancer immunotherapy to generate lasting responses in a broad spectrum of tumors has generated great enthusiasm in medical oncology. A number of new immune-based compounds have now been approved based on the recent success of immune checkpoint blockade, either administered as monotherapy or in combination with other agents. Because clinical activity is limited only to subsets of patients, two major goals of cancer immunotherapy are (1) to reliably identify responders to these current treatments, and (2) to increase the number of patients who can respond to immunotherapy by developing new strategies. These goals are critically important since the hallmark of immune-based therapies is the induction of durable immunologic and clinical responses that result in overall survival benefit. Innovative combination strategies have great potential for bringing the benefit of immunotherapy to more patients. The use of cancer vaccines to actively induce immune effectors together with other drugs, which may include immune checkpoint blockade, chemotherapy, and/or molecularly targeted agents, is a particularly attractive strategy. Cancer vaccines have been tested both to prevent or intercept the development of cancer, and to decrease established tumor burdens. No vaccine has yet been approved for either breast cancer treatment or prevention. Here, we review the history of breast cancer vaccine development, and highlight near-term opportunities for moving forward.
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http://dx.doi.org/10.1016/j.ctrv.2019.101947DOI Listing
March 2020

Atezolizumab plus nab-paclitaxel as first-line treatment for unresectable, locally advanced or metastatic triple-negative breast cancer (IMpassion130): updated efficacy results from a randomised, double-blind, placebo-controlled, phase 3 trial.

Lancet Oncol 2020 01 27;21(1):44-59. Epub 2019 Nov 27.

University of Pittsburgh Medical Center Hillman Cancer Center, Pittsburgh, PA, USA.

Background: Immunotherapy in combination with chemotherapy has shown promising efficacy across many different tumour types. We report the prespecified second interim overall survival analysis of the phase 3 IMpassion130 study assessing the efficacy and safety of atezolizumab plus nab-paclitaxel in patients with unresectable, locally advanced or metastatic triple-negative breast cancer.

Methods: In this randomised, placebo-controlled, double-blind, phase 3 trial, done in 246 academic centres and community oncology practices in 41 countries, patients aged 18 years or older, with previously untreated, histologically documented, locally advanced or metastatic triple-negative breast cancer, and Eastern Cooperative Oncology Group performance status of 0 or 1 were eligible. Patients were randomly assigned (1:1) using a permuted block method (block size of four) and an interactive voice-web response system. Randomisation was stratified by previous taxane use, liver metastases, and PD-L1 expression on tumour-infiltrating immune cells. Patients received atezolizumab 840 mg or matching placebo intravenously on day 1 and day 15 of every 28-day cycle and nab-paclitaxel 100 mg/m of body surface area intravenously on days 1, 8, and 15 until progression or unacceptable toxicity. Investigators, patients, and the funder were masked to treatment assignment. Coprimary endpoints were investigator-assessed progression-free survival per Response Evaluation Criteria in Solid Tumors version 1.1 and overall survival, assessed in the intention-to-treat population and in patients with PD-L1 immune cell-positive tumours (tumours with ≥1% PD-L1 expression). The final progression-free survival results were previously reported at the first interim overall survival analysis. The prespecified statistical testing hierarchy meant that overall survival in the subgroup of PD-L1 immune cell-positive patients could only be formally tested if overall survival was significantly different between the treatment groups in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT02425891.

Findings: Between June 23, 2015, and May 24, 2017, 902 patients were enrolled, of whom 451 were randomly assigned to receive atezolizumab plus nab-paclitaxel and 451 were assigned to receive placebo plus nab-paclitaxel (the intention-to-treat population). Six patients from each group did not receive treatment. At the second interim analysis (data cutoff Jan 2, 2019), median follow-up was 18·5 months (IQR 9·6-22·8) in the atezolizumab group and 17·5 months (8·4-22·4) in the placebo group. Median overall survival in the intention-to-treat patients was 21·0 months (95% CI 19·0-22·6) with atezolizumab and 18·7 months (16·9-20·3) with placebo (stratified hazard ratio [HR] 0·86, 95% CI 0·72-1·02, p=0·078). In the exploratory overall survival analysis in patients with PD-L1 immune cell-positive tumours, median overall survival was 25·0 months (95% CI 19·6-30·7) with atezolizumab versus 18·0 months (13·6-20·1) with placebo (stratified HR 0·71, 0·54-0·94]). As of Sept 3, 2018 (the date up to which updated safety data were available), the most common grade 3-4 adverse events were neutropenia (38 [8%] of 453 patients in the atezolizumab group vs 36 [8%] of 437 patients in the placebo group), peripheral neuropathy (25 [6%] vs 12 [3%]), decreased neutrophil count (22 [5%] vs 16 [4%]), and fatigue (17 [4%] vs 15 [3%]). Treatment-related deaths occurred in two (<1%) patients in the atezolizumab group (autoimmune hepatitis related to atezolizumab [n=1] and septic shock related to nab-paclitaxel [n=1]) and one (<1%) patient in the placebo group (hepatic failure). No new treatment-related deaths have been reported since the primary clinical data cutoff date (April 17, 2018).

Interpretation: Consistent with the first interim analysis, this second interim overall survival analysis of IMpassion130 indicates no significant difference in overall survival between the treatment groups in the intention-to-treat population but suggests a clinically meaningful overall survival benefit with atezolizumab plus nab-paclitaxel in patients with PD-L1 immune cell-positive disease. However, this positive result could not be formally tested due to the prespecified statistical testing hierarchy. For patients with PD-L1 immune cell-positive metastatic triple-negative breast cancer, atezolizumab plus nab-paclitaxel is an important therapeutic option in a disease with high unmet need.

Funding: F Hoffmann-La Roche and Genentech.
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http://dx.doi.org/10.1016/S1470-2045(19)30689-8DOI Listing
January 2020

Perspectives in immunotherapy: meeting report from the "Immunotherapy Bridge 2018" (28-29 November, 2018, Naples, Italy).

J Immunother Cancer 2019 11 29;7(1):332. Epub 2019 Nov 29.

Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA.

Immunotherapy is now widely established as a potent and effective treatment option across several types of cancer. However, there is increasing recognition that not all patients respond to immunotherapy, focusing attention on the immune contexture of the tumor microenvironment (TME), drivers of the immune response and mechanisms of tumor resistance to immunity. The development of novel immunotherapeutics and their use in combination with checkpoint inhibitors and other standard of care and novel treatment modalities is an area of particular attention across several tumor types, including melanoma, lung, ovarian, breast, pancreatic, renal, head and neck, brain and non-melanoma skin cancers. The 4th Immunotherapy Bridge meeting (28-29 November, 2018, Naples, Italy) focused on a wide range of evolving topics and trends in the field of cancer immunotherapy and key presentations from this meeting are summarised in this report.
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http://dx.doi.org/10.1186/s40425-019-0798-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6884742PMC
November 2019

Adenosine 2A Receptor Blockade as an Immunotherapy for Treatment-Refractory Renal Cell Cancer.

Cancer Discov 2020 01 15;10(1):40-53. Epub 2019 Nov 15.

Corvus Pharmaceuticals, Burlingame, California.

Adenosine mediates immunosuppression within the tumor microenvironment through triggering adenosine 2A receptors (A2AR) on immune cells. To determine whether this pathway could be targeted as an immunotherapy, we performed a phase I clinical trial with a small-molecule A2AR antagonist. We find that this molecule can safely block adenosine signaling . In a cohort of 68 patients with renal cell cancer (RCC), we also observe clinical responses alone and in combination with an anti-PD-L1 antibody, including subjects who had progressed on PD-1/PD-L1 inhibitors. Durable clinical benefit is associated with increased recruitment of CD8 T cells into the tumor. Treatment can also broaden the circulating T-cell repertoire. Clinical responses are associated with an adenosine-regulated gene-expression signature in pretreatment tumor biopsies. A2AR signaling, therefore, represents a targetable immune checkpoint distinct from PD-1/PD-L1 that restricts antitumor immunity. SIGNIFICANCE: This first-in-human study of an A2AR antagonist for cancer treatment establishes the safety and feasibility of targeting this pathway by demonstrating antitumor activity with single-agent and anti-PD-L1 combination therapy in patients with refractory RCC. Responding patients possess an adenosine-regulated gene-expression signature in pretreatment tumor biopsies...
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http://dx.doi.org/10.1158/2159-8290.CD-19-0980DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6954326PMC
January 2020

Tumor immune microenvironment and genomic evolution in a patient with metastatic triple negative breast cancer and a complete response to atezolizumab.

J Immunother Cancer 2019 10 23;7(1):274. Epub 2019 Oct 23.

School of Medicine, Oncology/Immunology, Johns Hopkins University, The Skip Viragh Outpatient Cancer Building, Floor 8, Viragh 8200-30, Box 11, 201 N Broadway, Baltimore, MD, 21287, USA.

Background: Metastatic TNBC (mTNBC) has a poor prognosis and few treatment options. The anti-PD-L1 antibody atezolizumab demonstrated clinical activity in mTNBC patients with PD-L1-positive tumor-infiltrating immune cells. The current study describes the tumor immune microenvironment (TiME) and genomic evolution across sequential therapies in a patient with a 31-year history of TNBC and a complete response (CR) to atezolizumab monotherapy.

Materials And Methods: In 1986, the patient had surgery and radiotherapy (XRT) for newly diagnosed TNBC, followed by surgery and adjuvant chemotherapy for two locoregional recurrences. She developed mTNBC in 2009 and was sequentially treated with capecitabine, gemcitabine-carboplatin-iniparib (GCI), XRT and an experimental vaccine. She experienced disease progression (PD) to all these therapies. In 2013, she had a PD-L1 positive tumor and enrolled in a phase 1 atezolizumab monotherapy study (PCD4989g; NCT01375842). She received atezolizumab for 1 year with initial pseudo-progression followed by a partial response. After 1 year without treatment she experienced PD, reinitiated atezolizumab and subsequently achieved CR. Tumor specimens were collected at numerous times between 2008 and 2015 and assessed by immunohistochemistry, RNA-seq and DNA-seq.

Results: TiME biomarkers, including CD8, ICs and PD-L1 on IC, increased after capecitabine and remained high after GCI, XRT and through pseudo-progression on atezolizumab. At PD post-atezolizumab exposure, TiME biomarkers decreased but PD-L1 status remained positive. Immune-related RNA signatures confirmed these findings. TNBC subtyping revealed evolution from luminal androgen receptor (LAR) to basal-like immune activated (BLIA). Genomic profiling showed truncal alterations in RB1 and TP53, while the presence of other genomic alterations varied over time. Tumor mutational burden peaked after XRT and declined after atezolizumab exposure.

Conclusions: This case report describes the evolution of TiME and TNBC molecular subtypes/genomics over time with sequential therapies in a TNBC patient with a CR to atezolizumab monotherapy. These data suggest the TiME is pliable and may be manipulated to maximize response to immunotherapy (NCT01375842, https://clinicaltrials.gov/ct2/show/NCT01375842?term=NCT01375842&rank=1 ).
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http://dx.doi.org/10.1186/s40425-019-0740-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6813065PMC
October 2019

Metastatic breast cancers have reduced immune cell recruitment but harbor increased macrophages relative to their matched primary tumors.

J Immunother Cancer 2019 10 18;7(1):265. Epub 2019 Oct 18.

Womens Cancer Research Center, UPMC Hillman Cancer Center, Magee Womens Research Institute, Pittsburgh, USA.

The interplay between the immune system and tumor progression is well recognized. However, current human breast cancer immunophenotyping studies are mostly focused on primary tumors with metastatic breast cancer lesions remaining largely understudied. To address this gap, we examined exome-capture RNA sequencing data from 50 primary breast tumors (PBTs) and their patient-matched metastatic tumors (METs) in brain, ovary, bone and gastrointestinal tract. We used gene expression signatures as surrogates for tumor infiltrating lymphocytes (TILs) and compared TIL patterns in PBTs and METs. Enrichment analysis and deconvolution methods both revealed that METs had a significantly lower abundance of total immune cells, including CD8+ T cells, regulatory T cells and dendritic cells. An exception was M2-like macrophages, which were significantly higher in METs across the organ sites examined. Multiplex immunohistochemistry results were consistent with data from the in-silico analysis and showed increased macrophages in METs. We confirmed the finding of a significant reduction in immune cells in brain METs (BRMs) by pathologic assessment of TILs in a set of 49 patient-matched pairs of PBT/BRMs. These findings indicate that METs have an overall lower infiltration of immune cells relative to their matched PBTs, possibly due to immune escape. RNAseq analysis suggests that the relative levels of M2-like macrophages are increased in METs, and their potential role in promoting breast cancer metastasis warrants further study.
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http://dx.doi.org/10.1186/s40425-019-0755-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6798422PMC
October 2019

The dawn of immunotherapy for breast cancer.

Authors:
Leisha A Emens

Clin Adv Hematol Oncol 2019 Jun;17(6):332-335

UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania.

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June 2019

Safety, clinical activity and biomarker assessments of atezolizumab from a Phase I study in advanced/recurrent ovarian and uterine cancers.

Gynecol Oncol 2019 08 14;154(2):314-322. Epub 2019 Jun 14.

UPMC Hillman Cancer Center, 300 Halket St, Suite 4628, Pittsburgh, PA 15213, United States. Electronic address:

Objective: Patients with advanced/recurrent epithelial ovarian and uterine cancers have limited treatment options beyond platinum chemotherapy. Both tumor types can express programmed death-ligand 1 (PD-L1), providing a potential therapeutic target for these patients. Here we present data from the ovarian and uterine cancer cohorts of the Phase I atezolizumab monotherapy study (PCD4989g).

Methods: This Phase I, multi-center, first-in-human, open-label, dose-escalation/expansion clinical trial investigated single-agent atezolizumab in cohorts of patients with recurrent epithelial ovarian or uterine cancer. The primary objective was to evaluate the safety and tolerability of single-agent atezolizumab. Anti-tumor activity and preliminary assessment of potential biomarkers were evaluated as secondary and exploratory objectives, respectively.

Results: The ovarian and uterine cancer cohorts enrolled 12 and 15 patients, respectively (10 [83%] and 5 [33%], respectively, had PD-L1 ≥ 5% on tumor-infiltrating immune cells). Atezolizumab was generally well tolerated with no new safety signals identified. The safety profiles in both cohorts were consistent with the known profile of atezolizumab monotherapy. Treatment-related adverse events (AEs) were mostly Grade ≤ 2, with no treatment-related Grade ≥ 4 AEs reported. Preliminary anti-tumor activity, with long durations of response, was observed in 2 patients from each cohort (ovarian cancer, 8.1 and 30.6+ months; uterine cancer, 7.3 and 16.6+ months). High microsatellite instability and tumor mutational burden were noted in the responders from the uterine cancer cohort.

Conclusions: Atezolizumab monotherapy was well tolerated in patients with epithelial ovarian or uterine cancer and may have clinical activity warranting further investigation.

Trial Registration: ClinicalTrials.gov identifier: NCT01375842.
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http://dx.doi.org/10.1016/j.ygyno.2019.05.021DOI Listing
August 2019

Development of [F]FPy-WL12 as a PD-L1 Specific PET Imaging Peptide.

Mol Imaging 2019 Jan-Dec;18:1536012119852189

1 Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University, Baltimore, MD, USA.

Expression of programmed cell death ligand 1 (PD-L1) within tumors is an important biomarker for guiding immune checkpoint therapies; however, immunohistochemistry-based methods of detection fail to provide a comprehensive picture of PD-L1 levels in an entire patient. To facilitate quantification of PD-L1 in the whole body, we developed a peptide-based, high-affinity PD-L1 imaging agent labeled with [F]fluoride for positron emission tomography (PET) imaging. The parent peptide, WL12, and the nonradioactive analog of the radiotracer, FPy-WL12, inhibit PD-1/PD-L1 interaction at low nanomolar concentrations (half maximal inhibitory concentration [IC], 26-32 nM). The radiotracer, [F]FPy-WL12, was prepared by conjugating 2,3,5,6-tetrafluorophenyl 6-[F]fluoronicotinate ([F]FPy-TFP) to WL12 and assessed for specificity in vitro in 6 cancer cell lines with varying PD-L1 expression. The uptake of the radiotracer reflected the PD-L1 expression assessed by flow cytometry. Next, we performed the in vivo evaluation of [F]FPy-WL12 in mice bearing cancer xenografts by PET imaging, ex vivo biodistribution, and blocking studies. In vivo data demonstrated a PD-L1-specific uptake of [F]FPy-WL12 in tumors that is reduced in mice receiving a blocking dose. The majority of [F]FPy-WL12 radioactivity was localized in the tumors, liver, and kidneys indicating the need for optimization of the labeling strategy to improve the in vivo pharmacokinetics of the radiotracer.
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http://dx.doi.org/10.1177/1536012119852189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6563393PMC
June 2020

Atezolizumab and Nab-Paclitaxel in Advanced Triple-Negative Breast Cancer. Reply.

N Engl J Med 2019 03;380(10):987-988

University of Pittsburgh Medical Center Hillman Cancer Center, Pittsburgh, PA.

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http://dx.doi.org/10.1056/NEJMc1900150DOI Listing
March 2019

Phase I Study of the Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitor Navoximod (GDC-0919) Administered with PD-L1 Inhibitor (Atezolizumab) in Advanced Solid Tumors.

Clin Cancer Res 2019 06 15;25(11):3220-3228. Epub 2019 Feb 15.

University of Colorado Cancer Center, Aurora, Colorado.

Purpose: IDO1 induces immune suppression in T cells through l-tryptophan (Trp) depletion and kynurenine (Kyn) accumulation in the local tumor microenvironment, suppressing effector T cells and hyperactivating regulatory T cells (Treg). Navoximod is an investigational small-molecule inhibitor of IDO1. This phase I study evaluated safety, tolerability, pharmacokinetics, and pharmacodynamics of navoximod in combination with atezolizumab, a PD-L1 inhibitor, in patients with advanced cancer.

Patients And Methods: The study consisted of a 3+3 dose-escalation stage ( = 66) and a tumor-specific expansion stage ( = 92). Navoximod was given orally every 12 hours continuously for 21 consecutive days of each cycle with the exception of cycle 1, where navoximod administration started on day -1 to characterize pharmacokinetics. Atezolizumab was administered by intravenous infusion 1,200 mg every 3 weeks on day 1 of each cycle.

Results: Patients ( = 157) received navoximod at 6 dose levels (50-1,000 mg) in combination with atezolizumab. The maximum administered dose was 1,000 mg twice daily; the MTD was not reached. Navoximod demonstrated a linear pharmacokinetic profile, and plasma Kyn generally decreased with increasing doses of navoximod. The most common treatment-related AEs were fatigue (22%), rash (22%), and chromaturia (20%). Activity was observed at all dose levels in various tumor types (melanoma, pancreatic, prostate, ovarian, head and neck squamous cell carcinoma, cervical, neural sheath, non-small cell lung cancer, triple-negative breast cancer, renal cell carcinoma, urothelial bladder cancer): 6 (9%) dose-escalation patients achieved partial response, and 10 (11%) expansion patients achieved partial response or complete response.

Conclusions: The combination of navoximod and atezolizumab demonstrated acceptable safety, tolerability, and pharmacokinetics for patients with advanced cancer. Although activity was observed, there was no clear evidence of benefit from adding navoximod to atezolizumab.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-2740DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7980952PMC
June 2019

Association of Cancer Immunotherapy With Acute Macular Neuroretinopathy and Diffuse Retinal Venulitis.

JAMA Ophthalmol 2019 01;137(1):96-100

Genentech Inc, South San Francisco, California.

Importance: Checkpoint inhibition in cancer immunotherapy related to T-cell-driven mechanisms of action associated with acute macular neuroretinopathy (AMN) and diffuse retinal venulitis, an adverse event not previously described, is reported here.

Objective: To describe 2 patients who developed ophthalmologic events after treatment with the programmed death 1 axis inhibitor, atezolizumab.

Design, Setting, And Participants: Retrospective review of 2 patients treated with atezolizumab for metastatic breast cancer and colon cancer, respectively, who presented with AMN and diffuse retinal venulitis conducted at 2 tertiary medical centers.

Main Outcomes And Measures: Multimodal imaging including near infrared, optical coherence tomography, and fluorescein angiography were used to characterize retinal vascular abnormalities.

Results: Based on optical coherence tomography and multimodal imaging findings, the clinical diagnosis of AMN associated with diffuse retinal venulitis was made in these 2 patients receiving atezolizumab.

Conclusions And Relevance: While only 2 cases of patients receiving the programmed death ligand 1 inhibitor atezolizumab who experienced AMN and diffuse retinal venulitis are described here, these findings suggest that patients receiving programmed death 1 axis inhibitor therapies may need to be monitored for unexpected immune-related ocular toxicity including abnormalities of the microvasculature and large retinal vessels. Further studies might investigate the potential mechanisms of retinal vascular changes associated with these therapies.
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http://dx.doi.org/10.1001/jamaophthalmol.2018.5191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6439799PMC
January 2019

Atezolizumab and Nab-Paclitaxel in Advanced Triple-Negative Breast Cancer.

N Engl J Med 2018 11 20;379(22):2108-2121. Epub 2018 Oct 20.

From the Barts Cancer Institute, Queen Mary University of London, London (P.S.); Perlmutter Cancer Center, New York University School of Medicine, New York (S.A.); the Department of Medicine, University of California, San Francisco, San Francisco (H.S.R.), and Genentech, South San Francisco (L.M., S.Y.C., R.F.) - both in California; University Hospital Heidelberg, Heidelberg, Germany (A.S.); Centro de Pesquisa em Oncologia, Hospital São Lucas, Pontifical Catholic University of Rio Grande do Sul, Porto Alegre (C.H.B.), and the University of São Paulo, São Paulo (R.H.) - both in Brazil; Aichi Cancer Center Hospital, Nagoya, Japan (H.I.); the Department of Medical Oncology, Institut Curie, Paris (V.D.); Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea (S.-A.I.); Florida Cancer Specialists and Research Institute, New Port Richey (G.S.W.); Roche, Basel, Switzerland (V.H., A.H.); Dana-Farber Cancer Institute, Boston (E.P.W.); Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, VIC, Australia (S.L.); and the Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore (L.A.E.).

Background: Unresectable locally advanced or metastatic triple-negative (hormone-receptor-negative and human epidermal growth factor receptor 2 [HER2]-negative) breast cancer is an aggressive disease with poor outcomes. Nanoparticle albumin-bound (nab)-paclitaxel may enhance the anticancer activity of atezolizumab.

Methods: In this phase 3 trial, we randomly assigned (in a 1:1 ratio) patients with untreated metastatic triple-negative breast cancer to receive atezolizumab plus nab-paclitaxel or placebo plus nab-paclitaxel; patients continued the intervention until disease progression or an unacceptable level of toxic effects occurred. Stratification factors were the receipt or nonreceipt of neoadjuvant or adjuvant taxane therapy, the presence or absence of liver metastases at baseline, and programmed death ligand 1 (PD-L1) expression at baseline (positive vs. negative). The two primary end points were progression-free survival (in the intention-to-treat population and PD-L1-positive subgroup) and overall survival (tested in the intention-to-treat population; if the finding was significant, then it would be tested in the PD-L1-positive subgroup).

Results: Each group included 451 patients (median follow-up, 12.9 months). In the intention-to-treat analysis, the median progression-free survival was 7.2 months with atezolizumab plus nab-paclitaxel, as compared with 5.5 months with placebo plus nab-paclitaxel (hazard ratio for progression or death, 0.80; 95% confidence interval [CI], 0.69 to 0.92; P=0.002); among patients with PD-L1-positive tumors, the median progression-free survival was 7.5 months and 5.0 months, respectively (hazard ratio, 0.62; 95% CI, 0.49 to 0.78; P<0.001). In the intention-to-treat analysis, the median overall survival was 21.3 months with atezolizumab plus nab-paclitaxel and 17.6 months with placebo plus nab-paclitaxel (hazard ratio for death, 0.84; 95% CI, 0.69 to 1.02; P=0.08); among patients with PD-L1-positive tumors, the median overall survival was 25.0 months and 15.5 months, respectively (hazard ratio, 0.62; 95% CI, 0.45 to 0.86). No new adverse effects were identified. Adverse events that led to the discontinuation of any agent occurred in 15.9% of the patients who received atezolizumab plus nab-paclitaxel and in 8.2% of those who received placebo plus nab-paclitaxel.

Conclusions: Atezolizumab plus nab-paclitaxel prolonged progression-free survival among patients with metastatic triple-negative breast cancer in both the intention-to-treat population and the PD-L1-positive subgroup. Adverse events were consistent with the known safety profiles of each agent. (Funded by F. Hoffmann-La Roche/Genentech; IMpassion130 ClinicalTrials.gov number, NCT02425891 .).
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http://dx.doi.org/10.1056/NEJMoa1809615DOI Listing
November 2018

Long-term Clinical Outcomes and Biomarker Analyses of Atezolizumab Therapy for Patients With Metastatic Triple-Negative Breast Cancer: A Phase 1 Study.

JAMA Oncol 2019 01;5(1):74-82

Centre for Experimental Cancer Medicine, Barts Cancer Institute, Queen Mary University of London, London, England.

Importance: Atezolizumab (anti-programmed cell death ligand 1 [PD-L1]) is well tolerated and clinically active in multiple cancer types. Its safety and clinical activity in metastatic triple-negative breast cancer (mTNBC) has not been reported.

Objective: To evaluate the safety, clinical activity, and biomarkers associated with the use of single-agent atezolizumab in patients with mTNBC.

Design, Setting, And Participants: Women with mTNBC (defined by investigator assessment) were enrolled between January 2013 and February 2016 in a multicohort open-label, phase 1 study at US and European academic medical centers. Median follow-up was 25.3 months (range, 0.4-45.6 months). Eligible patients regardless of line of therapy had measurable disease by Response Evaluation Criteria in Solid Tumors, version 1.1; Eastern Cooperative Oncology Group performance status of 0 to 1; and a representative tumor sample for assessment of immune cell (IC) PD-L1 expression.

Interventions: Atezolizumab was given intravenously every 3 weeks until unacceptable toxic effects or loss of clinical benefit.

Main Outcomes And Measures: Primary outcome was safety and tolerability. Activity and exploratory outcomes included objective response rate (ORR), duration of response, progression-free survival (PFS), and overall survival (OS). Outcomes were assessed in all patients and in key patient subgroups.

Results: Among 116 evaluable patients (median age, 53 years [range, 29-82 years]), treatment-related adverse events occurred in 73 (63%); 58 (79%) were grade 1 to 2. Most adverse events occurred within the first treatment year. The ORRs were numerically higher in first-line (5 of 21 [24%]) than in second-line or greater patients (6 of 94 [6%]). Median duration of response was 21 months (range, 3 to ≥38 months). Median PFS was 1.4 (95% CI, 1.3-1.6) months by RECIST and 1.9 (95% CI, 1.4-2.5) months by irRC. In first-line patients, median OS was 17.6 months (95% CI, 10.2 months to not estimable). Patients with PD-L1 expression of at least 1% tumor-infiltrating ICs had higher ORRs and longer OS (12% [11 of 91]; 10.1 [95% CI, 7.0-13.8] months, respectively) than those with less than 1% ICs (0 of 21; 6.0 [95% CI, 2.6-12.6] months, respectively). High levels of ICs (>10%) were independently associated with higher ORRs and longer OS.

Conclusions And Relevance: Single-agent atezolizumab was well tolerated and provided durable clinical benefit in patients with mTNBC with stable or responding disease and in earlier lines of treatment.

Trial Registration: ClinicalTrials.gov identifier: NCT01375842.
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http://dx.doi.org/10.1001/jamaoncol.2018.4224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6439773PMC
January 2019

STING signaling: a key to therapeutic tumor immunity.

Immunotherapy 2018 07;10(9):729-731

Department of Oncology, Bloomberg-Kimmel Institute at Johns Hopkins, Baltimore, MD 21287, USA.

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http://dx.doi.org/10.2217/imt-2018-0064DOI Listing
July 2018

Targeting adenosine for cancer immunotherapy.

J Immunother Cancer 2018 06 18;6(1):57. Epub 2018 Jun 18.

Bloomberg~Kimmel Institute for Cancer Immunotherapy, Sidney-Kimmel Comprehensive Cancer Center, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.

Immune checkpoint antagonists (CTLA-4 and PD-1/PD-L1) and CAR T-cell therapies generate unparalleled durable responses in several cancers and have firmly established immunotherapy as a new pillar of cancer therapy. To extend the impact of immunotherapy to more patients and a broader range of cancers, targeting additional mechanisms of tumor immune evasion will be critical. Adenosine signaling has emerged as a key metabolic pathway that regulates tumor immunity. Adenosine is an immunosuppressive metabolite produced at high levels within the tumor microenvironment. Hypoxia, high cell turnover, and expression of CD39 and CD73 are important factors in adenosine production. Adenosine signaling through the A2a receptor expressed on immune cells potently dampens immune responses in inflamed tissues. In this article, we will describe the role of adenosine signaling in regulating tumor immunity, highlighting potential therapeutic targets in the pathway. We will also review preclinical data for each target and provide an update of current clinical activity within the field. Together, current data suggest that rational combination immunotherapy strategies that incorporate inhibitors of the hypoxia-CD39-CD73-A2aR pathway have great promise for further improving clinical outcomes in cancer patients.
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http://dx.doi.org/10.1186/s40425-018-0360-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6006764PMC
June 2018

Racial disparities in the rate of cardiotoxicity of HER2-targeted therapies among women with early breast cancer.

Cancer 2018 05 30;124(9):1904-1911. Epub 2018 Jan 30.

Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, Maryland.

Background: Human epidermal growth factor receptor 2 (HER2)-targeted therapies are highly effective at preventing breast cancer recurrence but are associated with cardiotoxicity in some patients, and minimal data are available regarding racial disparities in the incidence of this toxicity. The authors conducted a retrospective study to analyze the association of black or white race with treatment-induced cardiotoxicity and incomplete therapy among patients with HER2-positive early breast cancer.

Methods: Women with HER2-positive, stage I through III breast cancer who initiated (neo)adjuvant HER2-targeted therapy (trastuzumab with or without pertuzumab) from January 2005 to March 2015 at the authors' institution were eligible. We analyzed differences in the incidence of cardiotoxicity (a decline in the left ventricular ejection fraction to <50% AND an absolute drop in the left ventricular ejection fraction of ≥10% from baseline) and incomplete therapy (<52 weeks of HER2-targeted therapy) between black and white women in univariate and multivariable analyses.

Results: The authors identified 59 black patients and 157 white patients who had a median follow-up 5.2 years. The median patient age was 53 years and was similar for black and white patients. The 1-year cardiotoxicity incidence was 12% overall (95% confidence interval [CI], 7%-16%), 24% in black women (95% CI, 12%-34%), and 7% in white women (95% CI, 3%-11%). Black patients had a significantly greater probability of incomplete therapy compared with white patients (odds ratio, 4.61; 95% CI, 1.70-13.07; P = .002). High correlation was observed between a cardiotoxicity event and incomplete therapy (96% concordance).

Conclusions: Black patients have a higher rate of cardiotoxicity and resultant incomplete adjuvant HER2-targeted therapy than white patients. This patient population may benefit from enhanced cardiac surveillance, cardioprotective strategies, and early referral to cardiology when appropriate. Cancer 2018;124:1904-11. © 2018 American Cancer Society.
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http://dx.doi.org/10.1002/cncr.31260DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5910274PMC
May 2018