Publications by authors named "Roisin M Connolly"

44 Publications

A randomized intervention involving family to improve communication in breast cancer care.

NPJ Breast Cancer 2021 Feb 12;7(1):14. Epub 2021 Feb 12.

The Johns Hopkins University School of Medicine, Baltimore, MD, USA.

We examined the effects of a communication intervention to engage family care partners on patient portal (MyChart) use, illness understanding, satisfaction with cancer care, and symptoms of anxiety in a single-blind randomized trial of patients in treatment for breast cancer. Patient-family dyads were recruited and randomly assigned a self-administered checklist to clarify the care partner role, establish a shared visit agenda, and facilitate MyChart access (n = 63) or usual care (n = 55). Interviews administered at baseline, 3, 9 (primary endpoint), and 12 months assessed anxiety (GAD-2), mean FAMCARE satisfaction, and complete illness understanding (4 of 4 items correct). Time-stamped electronic interactions measured MyChart use. By 9 months, more intervention than control care partners registered for MyChart (77.8 % vs 1.8%; p < 0.001) and logged into the patient's account (61.2% vs 0% of those registered; p < 0.001), but few sent messages to clinicians (6.1% vs 0%; p = 0.247). More intervention than control patients viewed clinical notes (60.3% vs 32.7%; p = 0.003). No pre-post group differences in patient or care partner symptoms of anxiety, satisfaction, or complete illness understanding were found. Intervention patients whose care partners logged into MyChart were more likely to have complete illness understanding at 9 months (changed 70.0% to 80.0% vs 69.7% to 54.6%; p = 0.03); symptoms of anxiety were numerically lower (16.7% to 6.7% vs 15.2% to 15.2%; p = 0.24) and satisfaction numerically higher (15.8-16.2 vs 18.0-17.4; p = 0.25). A brief, scalable communication intervention led to greater care partner MyChart use and increased illness understanding among patients with more engaged care partners (NCT03283553).
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http://dx.doi.org/10.1038/s41523-021-00217-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7881185PMC
February 2021

Phase I and Pharmacokinetic Study of Romidepsin in Patients with Cancer and Hepatic Dysfunction: A National Cancer Institute Organ Dysfunction Working Group Study.

Clin Cancer Res 2020 Oct 14;26(20):5329-5337. Epub 2020 Aug 14.

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

Purpose: Romidepsin dosing recommendations for patients with malignancy and varying degrees of hepatic dysfunction was lacking at the time of regulatory approval for T-cell lymphoma. We conducted a multicenter phase I clinical trial (ETCTN-9008) via the NCI Organ Dysfunction Working Group to investigate safety, first cycle MTD, and pharmacokinetic profile of romidepsin in this setting.

Patients And Methods: Patients with select advanced solid tumors or hematologic malignancies were stratified according to hepatic function. Romidepsin was administered intravenously on days 1, 8, and 15 of a 28-day cycle and escalation followed a 3 + 3 design in moderate and severe impairment cohorts. Blood samples for detailed pharmacokinetic analyses were collected after the first dose.

Results: Thirty-one patients received one dose of romidepsin and were evaluable for pharmacokinetic analyses in normal ( = 12), mild ( = 8), moderate ( = 5), and severe ( = 6) cohorts. Adverse events across cohorts were similar, and dose-limiting toxicity occurred in two patients (mild and severe impairment cohorts). The MTD was not determined because the geometric mean AUC values of romidepsin in moderate (7 mg/m) and severe (5 mg/m) impairment cohort were 114% and 116% of the normal cohort (14 mg/m).

Conclusions: Data from the ETCTN-9008 trial led to changes in the romidepsin labeling to reflect starting dose adjustment for patients with cancer and moderate and severe hepatic impairment, with no adjustment for mild hepatic impairment.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-1412DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7572570PMC
October 2020

Management of Breast Cancer During the COVID-19 Pandemic: A Stage- and Subtype-Specific Approach.

JCO Oncol Pract 2020 Oct 30;16(10):665-674. Epub 2020 Jun 30.

The Johns Hopkins University School of Medicine, Baltimore, MD.

The COVID-19 pandemic has rapidly changed delivery of cancer care. Many nonurgent surgeries are delayed to preserve hospital resources, and patient visits to health care settings are limited to reduce exposure to SARS-CoV-2. Providers must carefully weigh risks and benefits of delivering immunosuppressive therapy during the pandemic. For breast cancer, a key difference is increased use of neoadjuvant systemic therapy due to deferral of many breast surgeries during the pandemic. In some cases, this necessitates increased use of genomic tumor profiling on core biopsy specimens to guide neoadjuvant therapy decisions. Breast cancer treatment during the pandemic requires multidisciplinary input and varies according to stage, tumor biology, comorbidities, age, patient preferences, and available hospital resources. We present here the Johns Hopkins Women's Malignancies Program approach to breast cancer management during the COVID-19 pandemic. We include algorithms based on tumor biology and extent of disease that guide management decisions during the pandemic. These algorithms emphasize medical oncology treatment decisions and demonstrate how we have operationalized the general treatment recommendations during the pandemic proposed by national groups, such as the COVID-19 Pandemic Breast Cancer Consortium. Our recommendations can be adapted by other institutions and medical oncology practices in accordance with local conditions and resources. Guidelines such as these will be important as we continue to balance treatment of breast cancer against risk of SARS-CoV-2 exposure and infection until approval of a vaccine.
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http://dx.doi.org/10.1200/OP.20.00364DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564133PMC
October 2020

Best Foot Forward: Neoadjuvant Systemic Therapy as Standard of Care in Triple-Negative and HER2-Positive Breast Cancer.

Am Soc Clin Oncol Educ Book 2020 Mar;40:1-16

Department of Surgery, Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX.

Neoadjuvant systemic treatment of early-stage breast cancer has been used to improve resectability and reduce the extent of breast and axillary surgery. More recently, several other merits of neoadjuvant systemic treatment have emerged, including the ability to tailor clinically available adjuvant systemic therapy options based on pathologic response and to serve as a platform for early assessment of novel agents and response biomarkers and as an avenue for treatment optimization investigations (local and systemic therapy escalation and de-escalation trials guided by pathologic response). Attainment of a pathologic complete response (pCR) is associated with excellent long-term outcomes; conversely, the presence of residual disease is associated with a high risk of recurrence for patients with HER2-positive breast cancer and triple-negative breast cancer (TNBC). Treatment strategies in early-stage HER2-positive breast cancer include regimens incorporating trastuzumab, pertuzumab, ado-trastuzumab emtansine, and neratinib, resulting in high pCR rates and overall excellent long-term outcomes. Currently available cytotoxic regimens yield pCR for 35% to 55% of patients with TNBC, and immune checkpoint inhibition is showing early promise for this subtype. New drug and predictive biomarker evaluations in the neoadjuvant setting aim to develop optimal treatment strategies for the individual patient, with the ultimate goal of maximizing efficacy and minimizing toxicity. Research efforts involving novel agents are being undertaken to address the high risk of recurrence for patients with residual disease. Omission of breast surgery following neoadjuvant chemotherapy requires further development of imaging and biopsy techniques to accurately assess the extent of residual disease before clinical application.
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http://dx.doi.org/10.1200/EDBK_281381DOI Listing
March 2020

Conducting a Virtual Clinical Trial in HER2-Negative Breast Cancer Using a Quantitative Systems Pharmacology Model With an Epigenetic Modulator and Immune Checkpoint Inhibitors.

Front Bioeng Biotechnol 2020 25;8:141. Epub 2020 Feb 25.

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

The survival rate of patients with breast cancer has been improved by immune checkpoint blockade therapies, and the efficacy of their combinations with epigenetic modulators has shown promising results in preclinical studies. In this prospective study, we propose an ordinary differential equation (ODE)-based quantitative systems pharmacology (QSP) model to conduct an virtual clinical trial and analyze potential predictive biomarkers to improve the anti-tumor response in HER2-negative breast cancer. The model is comprised of four compartments: central, peripheral, tumor, and tumor-draining lymph node, and describes immune activation, suppression, T cell trafficking, and pharmacokinetics and pharmacodynamics (PK/PD) of the therapeutic agents. We implement theoretical mechanisms of action for checkpoint inhibitors and the epigenetic modulator based on preclinical studies to investigate their effects on anti-tumor response. According to model-based simulations, we confirm the synergistic effect of the epigenetic modulator and that pre-treatment tumor mutational burden, tumor-infiltrating effector T cell (Teff) density, and Teff to regulatory T cell (Treg) ratio are significantly higher in responders, which can be potential biomarkers to be considered in clinical trials. Overall, we present a readily reproducible modular model to conduct virtual clinical trials on patient cohorts of interest, which is a step toward personalized medicine in cancer immunotherapy.
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http://dx.doi.org/10.3389/fbioe.2020.00141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7051945PMC
February 2020

The Effects of a Remote-based Weight Loss Program on Adipocytokines, Metabolic Markers, and Telomere Length in Breast Cancer Survivors: the POWER-Remote Trial.

Clin Cancer Res 2020 06 18;26(12):3024-3034. Epub 2020 Feb 18.

Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Purpose: We initiated a clinical trial to determine the proportion of breast cancer survivors achieving ≥5% weight loss using a remotely delivered weight loss intervention (POWER-remote) or a self-directed approach, and to determine the effects of the intervention on biomarkers of cancer risk including metabolism, inflammation, and telomere length.

Experimental Design: Women with stage 0-III breast cancer, who completed local therapy and chemotherapy, with a body mass index ≥25 kg/m were randomized to a 12-month intervention (POWER-remote) versus a self-directed approach. The primary objective was to determine the number of women who achieved at least 5% weight loss at 6 months. We assessed baseline and 6-month change in a panel of adipocytokines (adiponectin, leptin, resistin, HGF, NGF, PAI1, TNFα, MCP1, IL1β, IL6, and IL8), metabolic factors (insulin, glucose, lipids, hs-CRP), and telomere length in peripheral blood mononuclear cells.

Results: From 2013 to 2015, 96 women were enrolled, and 87 were evaluable for the primary analysis; 45 to POWER-remote and 42 to self-directed. At 6 months, 51% of women randomized to POWER-remote lost ≥5% of their baseline body weight, compared with 12% in the self-directed arm [OR, 7.9; 95% confidence interval (CI), 2.6-23.9; = 0.0003]; proportion were similar at 12 months (51% vs 17%, respectively, = 0.003). Weight loss correlated with significant decreases in leptin, and favorable modulation of inflammatory cytokines and lipid profiles. There was no significant change in telomere length at 6 months.

Conclusions: A remotely delivered weight loss intervention resulted in significant weight loss in breast cancer survivors, and favorable effects on several biomarkers.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-2935DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7299780PMC
June 2020

Association of Tumor-Infiltrating Lymphocytes with Homologous Recombination Deficiency and Status in Patients with Early Triple-Negative Breast Cancer: A Pooled Analysis.

Clin Cancer Res 2020 06 3;26(11):2704-2710. Epub 2019 Dec 3.

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

Purpose: Patients with triple-negative breast cancer (TNBC) with homologous recombination deficient tumors achieve significantly higher pathologic complete response (pCR) rates when treated with neoadjuvant platinum-based therapy. Tumor-infiltrating lymphocytes (TIL) are prognostic and predictive of chemotherapy benefit in early stage TNBC. The relationship between TILs, mutation status, and homologous recombination deficiency (HRD) status in TNBC remains unclear.

Experimental Design: We performed a pooled analysis of five phase II studies that included patients with TNBC treated with neoadjuvant platinum-based chemotherapy to evaluate the association of TILs with HRD status (Myriad Genetics) and tumor mutation status. Furthermore, the relationship between pathologic response assessed using the residual cancer burden (RCB) index and HRD status with adjustment for TILs was evaluated.

Results: Among 161 patients, stromal TIL (sTIL) density was not significantly associated with HRD status ( = 0.107) or tumor mutation status ( = 0.391). In multivariate analyses, sTIL density [OR, 1.23; 95% confidence interval (CI), 0.94-1.61; = 0.139] was not associated with pCR, but was associated with RCB 0/I status (OR 1.62; 95% CI, 1.20-2.28; = 0.001). HRD was significantly associated with both pCR (OR 12.09; 95% CI, 4.11-44.29; = 7.82 × 10) and RCB 0/I (OR 10.22; 95% CI, 4.11-28.75; = 1.09 × 10) in these models.

Conclusions: In patients with TNBC treated with neoadjuvant platinum-based therapy, TIL density was not significantly associated with either tumor mutation status or HRD status. In this pooled analysis, HRD and sTIL density were independently associated with treatment response, with HRD status being the strongest predictor.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-0664DOI Listing
June 2020

Pre- and Postoperative Neratinib for HER2-Positive Breast Cancer Brain Metastases: Translational Breast Cancer Research Consortium 022.

Clin Breast Cancer 2020 04 22;20(2):145-151.e2. Epub 2019 Aug 22.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.

Purpose: This pilot study was performed to test our ability to administer neratinib monotherapy before clinically recommended craniotomy in patients with HER2-positive metastatic breast cancer to the central nervous system, to examine neratinib's central nervous system penetration at craniotomy, and to examine postoperative neratinib maintenance.

Patients And Methods: Patients with HER2-positive brain metastases undergoing clinically indicated cranial resection of a parenchymal tumor received neratinib 240 mg orally once a day for 7 to 21 days preoperatively, and resumed therapy postoperatively in 28-day cycles. Exploratory evaluations of time to disease progression, survival, and correlative tissue, cerebrospinal fluid (CSF), and blood-based analyses examining neratinib concentrations were planned. The study was registered at ClinicalTrials.gov under number NCT01494662.

Results: We enrolled 5 patients between May 22, 2013, and October 18, 2016. As of March 1, 2019, patients had remained on the study protocol for 1 to 75+ postoperative cycles pf therapy. Two patients had grade 3 diarrhea. Evaluation of the CSF showed low concentrations of neratinib; nonetheless, 2 patients continued to receive therapy without disease progression for at least 13 cycles, with one on-study treatment lasting for nearly 6 years. Neratinib distribution in surgical tissue was variable for 1 patient, while specimens from 2 others did not produce conclusive results as a result of limited available samples.

Conclusion: Neratinib resulted in expected rates of diarrhea in this small cohort, with 2 of 5 patients receiving the study treatment for durable periods. Although logistically challenging, we were able to test a limited number of CSF- and parenchymal-based neratinib concentrations. Our findings from resected tumor tissue in one patient revealed heterogeneity in drug distribution and tumor histopathology.
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http://dx.doi.org/10.1016/j.clbc.2019.07.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7035200PMC
April 2020

Reply to E. Hindié et al.

J Clin Oncol 2019 08 28;37(23):2092-2093. Epub 2019 Jun 28.

Roisin M. Connolly, MB, BCh, MD, Johns Hopkins University School of Medicine, Baltimore, MD; Chiung-Yu Huang, PhD, University of California, San Francisco, San Francisco, CA; Vered Stearns, MD, Johns Hopkins University School of Medicine, Baltimore, MD; and Richard L. Wahl, MD, Washington University School of Medicine, St Louis, MO.

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http://dx.doi.org/10.1200/JCO.19.01078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6879311PMC
August 2019

Sharing in care: engaging care partners in the care and communication of breast cancer patients.

Breast Cancer Res Treat 2019 Aug 4;177(1):127-136. Epub 2019 Jun 4.

The Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Purpose: Family is often overlooked in cancer care. We developed a patient-family agenda setting intervention to engage family in cancer care communication.

Methods: We conducted a pilot randomized controlled trial (NCT03283553) of patients on active treatment for breast cancer and their family "care partner." Intervention dyads (n = 69) completed a self-administered checklist to clarify care partner roles, establish a shared visit agenda, and facilitate MyChart patient portal access. Control dyads (n = 63) received usual care. We assessed intervention acceptability and initial effects from post-visit surveys and MyChart utilization at 6 weeks.

Results: At baseline, most patients (89.4%) but few care partners (1.5%) were registered for MyChart. Most patients (79.4%) wanted their care partner to have access to their records and 39.4% of care partners reported accessing MyChart. In completing the checklist, patients and care partners endorsed active communication roles for the care partner and identified a similar visit agenda: most (> 90%) reported the checklist was easy, useful, and recommended it to others. At 6 weeks, intervention (vs control) care partners were more likely to be registered for MyChart (75.4% vs 1.6%; p < 0.001), to have logged in (43.5% vs 0%; p < 0.001) and viewed clinical notes (30.4% vs 0%; p < 0.001), but were no more likely to exchange direct messages with clinicians (1.5% vs 0%; p = 0.175). No differences in patients' MyChart use were observed, but intervention patients more often viewed clinical notes (50.7% vs 9.5%; p < 0.001).

Conclusions: A patient-family agenda setting intervention was acceptable and affected online practices of cancer patients and care partners.
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http://dx.doi.org/10.1007/s10549-019-05306-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6640103PMC
August 2019

TBCRC 022: A Phase II Trial of Neratinib and Capecitabine for Patients With Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer and Brain Metastases.

J Clin Oncol 2019 05 12;37(13):1081-1089. Epub 2019 Mar 12.

1 Dana-Farber Cancer Institute, Boston, MA.

Purpose: Evidence-based treatments for metastatic, human epidermal growth factor receptor 2 (HER2)-positive breast cancer to the CNS are limited. We previously reported modest activity of neratinib monotherapy for HER2-positive breast cancer brain metastases. Here we report the results from additional study cohorts.

Patients And Methods: Patients with measurable, progressive, HER2-positive brain metastases (92% after receiving CNS surgery and/or radiotherapy) received neratinib 240 mg orally once per day plus capecitabine 750 mg/m twice per day for 14 days, then 7 days off. Lapatinib-naïve (cohort 3A) and lapatinib-treated (cohort 3B) patients were enrolled. If nine or more of 35 (cohort 3A) or three or more of 25 (cohort 3B) had CNS objective response rates (ORR), the drug combination would be deemed promising. The primary end point was composite CNS ORR in each cohort separately, requiring a reduction of 50% or more in the sum of target CNS lesion volumes without progression of nontarget lesions, new lesions, escalating steroids, progressive neurologic signs or symptoms, or non-CNS progression.

Results: Forty-nine patients enrolled in cohorts 3A (n = 37) and 3B (n = 12; cohort closed for slow accrual). In cohort 3A, the composite CNS ORR = 49% (95% CI, 32% to 66%), and the CNS ORR in cohort 3B = 33% (95% CI, 10% to 65%). Median progression-free survival was 5.5 and 3.1 months in cohorts 3A and 3B, respectively; median survival was 13.3 and 15.1 months. Diarrhea was the most common grade 3 toxicity (29% in cohorts 3A and 3B).

Neratinib plus capecitabine is active against refractory, HER2-positive breast cancer brain metastases, adding additional evidence that the efficacy of HER2-directed therapy in the brain is enhanced by chemotherapy. For optimal tolerance, efforts to minimize diarrhea are warranted.
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http://dx.doi.org/10.1200/JCO.18.01511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6494354PMC
May 2019

TBCRC026: Phase II Trial Correlating Standardized Uptake Value With Pathologic Complete Response to Pertuzumab and Trastuzumab in Breast Cancer.

J Clin Oncol 2019 03 5;37(9):714-722. Epub 2019 Feb 5.

1 Johns Hopkins University School of Medicine, Baltimore, MD.

Purpose: Predictive biomarkers to identify patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer who may benefit from targeted therapy alone are required. We hypothesized that early measurements of tumor maximum standardized uptake values corrected for lean body mass (SULmax) on [F]fluorodeoxyglucose positron emission tomography/computed tomography would predict pathologic complete response (pCR) to neoadjuvant pertuzumab and trastuzumab (PT).

Patients And Methods: Patients with stage II/III, estrogen receptor-negative, HER2-positive breast cancer received four cycles of neoadjuvant PT. [F]Fluorodeoxyglucose positron emission tomography/computed tomography was performed at baseline and 15 days after PT initiation (C1D15). Eighty evaluable patients were required to test the null hypothesis that the area under the curve of percentage of change in SULmax by C1D15 predicting pCR is less than or equal to 0.65, with a one-sided type I error rate of 10%.

Results: Eighty-eight women were enrolled (83 evaluable), and 85% (75 of 88) completed all four cycles of PT. pCR after PT alone was 34%. Receiver operating characteristic analysis yielded an area under the curve of 0.76 (90% CI, 0.67 to 0.85), which rejected the null hypothesis. Between patients who obtained pCR versus not, a significant difference in median percent reduction in SULmax by C1D15 was observed (63.8% v 33.5%; P < .001), an SULmax reduction greater than or equal to 40% was more prevalent (86% v 46%; P < .001; negative predictive value, 88%; positive predictive value, 49%), and a significant difference in median C1D15 SULmax (1.6 v 3.9; P < .001) and higher proportion of C1D15 SULmax less than or equal to 3 (93% v 38%; P < .001; negative predictive value, 94%; positive predictive value, 55%) were observed.

Conclusion: Early changes in SULmax predict response to four cycles of PT in estrogen receptor-negative, HER2-positive breast cancer. Once optimized, this quantitative imaging strategy may facilitate a more tailored approach to therapy in this setting.
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http://dx.doi.org/10.1200/JCO.2018.78.7986DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6424139PMC
March 2019

Entinostat Converts Immune-Resistant Breast and Pancreatic Cancers into Checkpoint-Responsive Tumors by Reprogramming Tumor-Infiltrating MDSCs.

Cancer Immunol Res 2018 12 19;6(12):1561-1577. Epub 2018 Oct 19.

Viragh Center for Pancreatic Clinical Research and Care, Bloomberg Kimmel Institute for Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Immune-checkpoint inhibition (ICI) has revolutionized treatment in cancers that are naturally immunogenic by enabling infiltration of T cells into the tumor microenvironment (TME) and promoting cytotoxic signaling pathways. Tumors possessing complex immunosuppressive TMEs such as breast and pancreatic cancers present unique therapeutic obstacles as response rates to ICI remain low. Such tumors often recruit myeloid-derived suppressor cells (MDSCs), whose functioning prohibits both T-cell activation and infiltration. We attempted to sensitize these tumors to ICI using epigenetic modulation to target MDSC trafficking and function to foster a less immunosuppressive TME. We showed that combining a histone deacetylase inhibitor, entinostat (ENT), with anti-PD-1, anti-CTLA-4, or both significantly improved tumor-free survival in both the HER2/neu transgenic breast cancer and the Panc02 metastatic pancreatic cancer mouse models. Using flow cytometry, gene-expression profiling, and functional assays, we characterized populations of tumor-infiltrating lymphocytes (TILs) and MDSCs, as well as their functional capabilities. We showed that addition of ENT to checkpoint inhibition led to significantly decreased suppression by granulocytic MDSCs in the TME of both tumor types. We also demonstrated an increase in activated granzyme-B-producing CD8 T effector cells in mice treated with combination therapy. Gene-expression profiling of both MDSCs and TILs identified significant changes in immune-related pathways. In summary, addition of ENT to ICI significantly altered infiltration and function of innate immune cells, allowing for a more robust adaptive immune response. These findings provide a rationale for combination therapy in patients with immune-resistant tumors, including breast and pancreatic cancers.
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http://dx.doi.org/10.1158/2326-6066.CIR-18-0070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6279584PMC
December 2018

A phase II study evaluating the efficacy of zoledronic acid in prevention of aromatase inhibitor-associated musculoskeletal symptoms: the ZAP trial.

Breast Cancer Res Treat 2018 Aug 11;171(1):121-129. Epub 2018 May 11.

Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA.

Purpose: Aromatase inhibitor-associated musculoskeletal symptoms (AIMSS) are common adverse events of AIs often leading to drug discontinuation. We initiated a prospective clinical trial to evaluate whether bisphosphonates are associated with reduced incidence of AIMSS.

Methods: In the single-arm trial, the Zoledronic Acid Prophylaxis (ZAP) trial, we compared the incidence of AIMSS against historical controls from the Exemestane and Letrozole Pharmacogenomics (ELPh) trial. Eligible women were postmenopausal with stage 0-III breast cancer planning to receive adjuvant AIs. AIMSS was assessed using the Health Assessment Questionnaire and Visual Analog Scale over 12 months in both trials. Participants in the ZAP trial received zoledronic acid prior to initiating letrozole and after 6 months; ELPh participants included in the analysis were taking letrozole but not bisphosphonates. We analyzed patient-reported outcomes (PROs) and bone density in the ZAP trial using mixed-effects linear regression models and paired t tests, respectively.

Results: From 2011 to 2013, 59 postmenopausal women enrolled in ZAP trial. All 59 (100%) women received baseline and 52 (88%) received 6-month zoledronic acid, and had similar characteristics to historical controls from the ELPh trial (n = 206). Cumulatively during the first year of AI, 37 and 67% of ZAP and ELPh participants reported AIMSS (p < 0.001), respectively. Within the ZAP trial, we did not observe significant changes in other PROs; however, we report improvements in bone mineral density.

Conclusions: Compared to historical controls, zoledronic acid administered concomitantly with adjuvant AIs was associated with a reduced incidence of AIMSS. A randomized controlled trial is required to confirm these findings.
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http://dx.doi.org/10.1007/s10549-018-4811-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6432628PMC
August 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

E2112: randomized phase iii trial of endocrine therapy plus entinostat/placebo in patients with hormone receptor-positive advanced breast cancer.

NPJ Breast Cancer 2018 11;4. Epub 2018 Jan 11.

7Johns Hopkins University, Baltimore, MD USA.

Endocrine therapies are effective in the treatment of hormone receptor (HR)-positive breast cancer, however, de novo or acquired treatment resistance is a significant clinical problem. A potential mechanism of resistance involves changes in gene expression secondary to epigenetic modifications, which might be reversed with the use of histone deacetylase (HDAC) inhibitors such as entinostat. The ENCORE 301 phase II randomized, placebo-controlled study demonstrated a significant improvement in progression-free survival (PFS) and overall survival (OS), with the addition of entinostat to exemestane in patients with HR-positive advanced breast cancer with disease progression after prior non-steroidal aromatase inhibitor (AI). These results prompted the development of E2112, a phase III registration trial which is investigating entinostat/placebo in combination with exemestane in patients with locally advanced or metastatic breast cancer who have experienced disease progression after a non-steroidal AI. E2112 aims to validate the preclinical and clinical findings supporting the role of HDAC inhibitors in overcoming resistance to endocrine therapy in breast cancer, and ultimately improve outcomes for patients with advanced breast cancer.
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http://dx.doi.org/10.1038/s41523-017-0053-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5765007PMC
January 2018

Tumor and serum DNA methylation in women receiving preoperative chemotherapy with or without vorinostat in TBCRC008.

Breast Cancer Res Treat 2018 01 16;167(1):107-116. Epub 2017 Sep 16.

Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, 1650 Orleans St., Baltimore, MD, 21287, USA.

Background: Methylated gene markers have shown promise in predicting breast cancer outcomes and treatment response. We evaluated whether baseline and changes in tissue and serum methylation levels would predict pathological complete response (pCR) in patients with HER2-negative early breast cancer undergoing preoperative chemotherapy.

Methods: The TBCRC008 trial investigated pCR following 12 weeks of preoperative carboplatin and albumin-bound paclitaxel + vorinostat/placebo (n = 62). We measured methylation of a 10-gene panel by quantitative multiplex methylation-specific polymerase chain reaction and expressed results as cumulative methylation index (CMI). We evaluated association between CMI level [baseline, day 15 (D15), and change] and pCR using univariate and multivariable logistic regression models controlling for treatment and hormone receptor (HR) status, and performed exploratory subgroup analyses.

Results: In univariate analysis, one log unit increase in tissue CMI levels at D15 was associated with 40% lower chance of obtaining pCR (odds ratio, OR 0.60, 95% CI 0.37-0.97; p = 0.037). Subgroup analyses suggested a significant association between tissue D15 CMI levels and pCR in vorinostat-treated [OR 0.44 (0.20, 0.93), p = 0.03], but not placebo-treated patients.

Conclusion: In this study investigating the predictive roles of tissue and serum CMI levels in patients with early breast cancer for the first time, we demonstrate that high D15 tissue CMI levels may predict poor response. Larger studies and improved analytical procedures to detect methylated gene markers in early stage breast cancer are needed. TBCRC008 is registered on ClinicalTrials.gov (NCT00616967).
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http://dx.doi.org/10.1007/s10549-017-4503-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5793219PMC
January 2018

Whole-Exome Sequencing of Metaplastic Breast Carcinoma Indicates Monoclonality with Associated Ductal Carcinoma Component.

Clin Cancer Res 2017 Aug 19;23(16):4875-4884. Epub 2017 Apr 19.

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

Although most human cancers display a single histology, there are unusual cases where two or more distinct tissue types present within a primary tumor. One such example is metaplastic breast carcinoma, a rare but aggressive cancer with a heterogeneous histology, including squamous, chondroid, and spindle cells. Metaplastic carcinomas often contain an admixed conventional ductal invasive or mammary carcinoma component, and are typically triple-negative for estrogen receptor, progesterone receptor, and HER-2 amplification/overexpression. An unanswered question is the origin of metaplastic breast cancers. While they may arise independently from their ductal components, their close juxtaposition favors a model that postulates a shared origin, either as two derivatives from the same primary cancer or one histology as an outgrowth of the other. Understanding the mechanism of development of these tumors may inform clinical decisions. We performed exome sequencing for paired metaplastic and adjacent conventional invasive ductal carcinomas in 8 patients and created a pipeline to identify somatic variants and predict their functional impact, without having normal tissue. We then determined the genetic relationships between the histologically distinct compartments. In each case, the tumor components have nearly identical landscapes of somatic mutation, implying that the differing histologies do not derive from genetic clonal divergence. A shared origin for tumors with differing histologies suggests that epigenetic or noncoding changes may mediate the metaplastic phenotype and that alternative therapeutic approaches, including epigenetic therapies, may be required for metaplastic breast cancers. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-0108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5559334PMC
August 2017

Entinostat: a promising treatment option for patients with advanced breast cancer.

Future Oncol 2017 Jun 9;13(13):1137-1148. Epub 2017 Mar 9.

Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD, USA.

Entinostat is a synthetic benzamide derivative histone deacetylase (HDAC) inhibitor, which potently and selectively inhibits class I and IV HDAC enzymes. This action promotes histone hyperacetylation and transcriptional activation of specific genes, with subsequent inhibition of cell proliferation, terminal differentiation and apoptosis. This oral HDAC inhibitor has been evaluated in Phase I and II trials in patients with advanced malignancies, and is in general well tolerated. Entinostat does not currently have regulatory approval for clinical use; however promising preclinical and clinical data exist in hormone-resistant breast cancer. An ECOG-ACRIN Phase III registration study is ongoing in advanced breast cancer (E2112, NCT02115282) and aims to confirm the overall survival advantage observed with the combination of exemestane and entinostat/placebo in the Phase II setting (ENCORE301 trial). This article provides an overview of the chemistry, pharmacokinetics/pharmacodynamics and available clinical data for entinostat with a focus on advanced breast cancer.
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http://dx.doi.org/10.2217/fon-2016-0526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5618943PMC
June 2017

Personalized Medicine in the Oncology Clinic: Implementation and Outcomes of the Johns Hopkins Molecular Tumor Board.

JCO Precis Oncol 2017 31;2017. Epub 2017 May 31.

The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD.

Purpose: Tumor genomic profiling for personalized oncology therapy is being widely applied in clinical practice even as it is being evaluated more formally in clinical trials. Given the complexities of genomic data and its application to clinical use, molecular tumor boards with diverse expertise can provide guidance to oncologists and patients seeking to implement personalized genetically targeted therapy in practice.

Methods: A multidisciplinary molecular tumor board reviewed tumor molecular profiling reports from consecutive referrals at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins over a 3-year period. The tumor board weighed evidence for actionability of genomic alterations identified by molecular profiling and provided recommendations including US Food and Drug Administration-approved drug therapy, clinical trials of matched targeted therapy, off-label use of such therapy, and additional tumor or germline genetic testing.

Results: One hundred fifty-five patients were reviewed. Actionable genomic alterations were identified in 132 patients (85%). Off-label therapies were recommended in 37 patients (24%). Eleven patients were treated off-label, and 13 patients were enrolled onto clinical trials of matched targeted therapies. Median progression-free survival of patients treated with matched therapies was 5 months (95% CI, 2.9 months to not reached), and the progression-free survival probability at 6 months was 43%(95% CI, 26% to 71%). Lack of locally available clinical trials was the major limitation on clinical actionability of tumor profiling reports.

Conclusion: The molecular tumor board recommended off-label targeted therapies for a quarter of all patients reviewed. Outcomes were heterogeneous, although 43% of patients receiving genomically matched therapy derived clinical benefit lasting at least 6 months. Until more data become available from precision oncology trials, molecular tumor boards can help guide appropriate use of tumor molecular testing to direct therapy.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6039131PMC
http://dx.doi.org/10.1200/PO.16.00046DOI Listing
May 2017

Optimizing the Use of Gene Expression Profiling in Early-Stage Breast Cancer.

J Clin Oncol 2016 12 31;34(36):4390-4397. Epub 2016 Oct 31.

Hyun-seok Kim, Christopher B. Umbricht, Peter B. Illei, Ashley Cimino-Mathews, Soonweng Cho, Nivedita Chowdhury, Maria Cristina Figueroa-Magalhaes, Catherine Pesce, Stacie C. Jeter, Deborah K. Armstrong, Roisin M. Connolly, John H. Fetting, Ben Ho Park, Vered Stearns, Antonio C. Wolff, and Leslie Cope, The Johns Hopkins University School of Medicine; Kala Visvanathan, The Johns Hopkins University Bloomberg School of Public Health, Baltimore; Charles Mylander, Martin Rosman, and Lorraine Tafra, Anne Arundel Medical Center, Annapolis, MD; Bradley M. Turner, David G. Hicks, University of Rochester Medical Center, Rochester, NY; Robert S. Miller, American Society of Clinical Oncology, Alexandria, VA; and Tyler A. Jensen and Dylan V. Miller, Intermountain Healthcare, Salt Lake City, UT.

Purpose Gene expression profiling assays are frequently used to guide adjuvant chemotherapy decisions in hormone receptor-positive, lymph node-negative breast cancer. We hypothesized that the clinical value of these new tools would be more fully realized when appropriately integrated with high-quality clinicopathologic data. Hence, we developed a model that uses routine pathologic parameters to estimate Oncotype DX recurrence score (ODX RS) and independently tested its ability to predict ODX RS in clinical samples. Patients and Methods We retrospectively reviewed ordered ODX RS and pathology reports from five institutions (n = 1,113) between 2006 and 2013. We used locally performed histopathologic markers (estrogen receptor, progesterone receptor, Ki-67, human epidermal growth factor receptor 2, and Elston grade) to develop models that predict RS-based risk categories. Ordering patterns at one site were evaluated under an integrated decision-making model incorporating clinical treatment guidelines, immunohistochemistry markers, and ODX. Final locked models were independently tested (n = 472). Results Distribution of RS was similar across sites and to reported clinical practice experience and stable over time. Histopathologic markers alone determined risk category with > 95% confidence in > 55% (616 of 1,113) of cases. Application of the integrated decision model to one site indicated that the frequency of testing would not have changed overall, although ordering patterns would have changed substantially with less testing of estimated clinical risk-high or clinical risk-low cases and more testing of clinical risk-intermediate cases. In the validation set, the model correctly predicted risk category in 52.5% (248 of 472). Conclusion The proposed model accurately predicts high- and low-risk RS categories (> 25 or ≤ 25) in a majority of cases. Integrating histopathologic and molecular information into the decision-making process allows refocusing the use of new molecular tools to cases with uncertain risk.
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http://dx.doi.org/10.1200/JCO.2016.67.7195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5455310PMC
December 2016

Combination Epigenetic Therapy in Advanced Breast Cancer with 5-Azacitidine and Entinostat: A Phase II National Cancer Institute/Stand Up to Cancer Study.

Clin Cancer Res 2017 Jun 15;23(11):2691-2701. Epub 2016 Dec 15.

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

In breast cancer models, combination epigenetic therapy with a DNA methyltransferase inhibitor and a histone deacetylase inhibitor led to reexpression of genes encoding important therapeutic targets, including the estrogen receptor (ER). We conducted a multicenter phase II study of 5-azacitidine and entinostat in women with advanced hormone-resistant or triple-negative breast cancer (TNBC). Patients received 5-azacitidine 40 mg/m (days 1-5, 8-10) and entinostat 7 mg (days 3, 10) on a 28-day cycle. Continuation of epigenetic therapy was offered with the addition of endocrine therapy at the time of progression [optional continuation (OC) phase]. Primary endpoint was objective response rate (ORR) in each cohort. We hypothesized that ORR would be ≥20% against null of 5% using Simon two-stage design. At least one response was required in 1 of 13 patients per cohort to continue accrual to 27 per cohort (type I error, 4%; power, 90%). There was one partial response among 27 women with hormone-resistant disease (ORR = 4%; 95% CI, 0-19), and none in 13 women with TNBC. One additional partial response was observed in the OC phase in the hormone-resistant cohort ( = 12). Mandatory tumor samples were obtained pre- and posttreatment (58% paired) with either up- or downregulation of ER observed in approximately 50% of posttreatment biopsies in the hormone-resistant, but not TNBC cohort. Combination epigenetic therapy was well tolerated, but our primary endpoint was not met. OC phase results suggest that some women benefit from epigenetic therapy and/or reintroduction of endocrine therapy beyond progression, but further study is needed. .
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http://dx.doi.org/10.1158/1078-0432.CCR-16-1729DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5457329PMC
June 2017

Individualized Molecular Analyses Guide Efforts (IMAGE): A Prospective Study of Molecular Profiling of Tissue and Blood in Metastatic Triple-Negative Breast Cancer.

Clin Cancer Res 2017 Jan 3;23(2):379-386. Epub 2016 Aug 3.

The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Purpose: The clinical utility of next-generation sequencing (NGS) in breast cancer has not been demonstrated. We hypothesized that we could perform NGS of a new biopsy from patients with metastatic triple-negative breast cancer (TNBC) in a clinically actionable timeframe.

Experimental Design: We planned to enroll 40 patients onto a prospective study, Individualized Molecular Analyses Guide Efforts (IMAGE), to evaluate the feasibility of obtaining a new biopsy of a metastatic site, perform NGS (FoundationOne), and convene a molecular tumor board to formulate treatment recommendations within 28 days. We collected blood at baseline and at time of restaging to assess cell-free circulating plasma tumor DNA (ptDNA).

Results: We enrolled 26 women with metastatic TNBC who had received ≥1 line of prior chemotherapy, and 20 (77%) underwent NGS of a metastatic site biopsy. Twelve (60%) evaluable patients received treatment recommendations within 28 days of consent. The study closed after 20 patients underwent NGS, based on protocol-specified interim futility analysis. Three patients went on to receive genomically directed therapies. Twenty-four of 26 patients had genetic alterations successfully detected in ptDNA. Among 5 patients, 4 mutations found in tumor tissues were not identified in blood, and 4 mutations found in blood were not found in corresponding tumors. In 9 patients, NGS of follow-up blood samples showed 100% concordance with baseline blood samples.

Conclusions: This study demonstrates challenges of performing NGS on prospective tissue biopsies in patients with metastatic TNBC within 28 days, while also highlighting the potential use of blood as a more time-efficient and less invasive method of mutational assessment. Clin Cancer Res; 23(2); 379-86. ©2016 AACR.
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http://dx.doi.org/10.1158/1078-0432.CCR-16-1543DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5241251PMC
January 2017

FDG-PET/CT and MRI for Evaluation of Pathologic Response to Neoadjuvant Chemotherapy in Patients With Breast Cancer: A Meta-Analysis of Diagnostic Accuracy Studies.

Oncologist 2016 08 8;21(8):931-9. Epub 2016 Jul 8.

Russell H. Morgan Department of Radiology and Radiological Sciences Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, Maryland, USA Department of Radiology, University of Texas Southwestern Medical Center, Dallas, Texas, USA Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, Texas, USA Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, Texas, USA Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas, USA

Introduction: This study compared the diagnostic test accuracy of magnetic resonance imaging (MRI) with that of (18)F-fluoro-2-glucose-positron emission tomography/computed tomography (FDG-PET/CT) imaging in assessment of response to neoadjuvant chemotherapy (NAC) in breast cancer.

Methods: A systematic search was performed in PubMed and EMBASE (last updated in June 2015). Studies investigating the performance of MRI and FDG-PET or FDG-PET/CT imaging during or after completion of NAC in patients with histologically proven breast cancer were eligible for inclusion. We considered only studies reporting a direct comparison between these imaging modalities to establish precise summary estimates in the same setting of patients. Pathologic response was considered as the reference standard. Two authors independently screened and selected studies that met the inclusion criteria and extracted the data.

Results: A total of 10 studies were included. The pooled estimates of sensitivity and specificity across all included studies were 0.71 and 0.77 for FDG-PET/CT (n = 535) and 0.88 and 0.55 for MRI (n = 492), respectively. Studies were subgrouped according to the time of therapy assessment. In the intra-NAC setting, FDG-PET/CT imaging outperformed MRI with fairly similar pooled sensitivity (0.91 vs. 0.89) and higher specificity (0.69 vs. 0.42). However, MRI appeared to have higher diagnostic accuracy than FDG-PET/CT imaging when performed after the completion of NAC, with significantly higher sensitivity (0.88 vs. 0.57).

Conclusion: Analysis of the available studies of patients with breast cancer indicates that the timing of imaging for NAC-response assessment exerts a major influence on the estimates of diagnostic accuracy. FDG-PET/CT imaging outperformed MRI in intra-NAC assessment, whereas the overall performance of MRI was higher after completion of NAC, before surgery.

Implications For Practice: The timing of therapy assessment imaging exerts a major influence on overall estimates of diagnostic accuracy. (18)F-fluoro-2-glucose-positron emission tomography (FDG-PET)/computed tomography (CT) imaging outperformed magnetic resonance imaging (MRI) in intra-neoadjuvant chemotherapy assessment with fairly similar pooled sensitivity and higher specificity. However, MRI appeared to be more accurate than FDG-PET/CT in predicting pathologic response when used in the post-therapy setting.
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http://dx.doi.org/10.1634/theoncologist.2015-0353DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4978549PMC
August 2016

A Clinicopathologic Analysis of 45 Patients With Metaplastic Breast Carcinoma.

Am J Clin Pathol 2016 Mar 19;145(3):365-72. Epub 2016 Feb 19.

Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD; and

Objectives: Metaplastic breast carcinomas (MBCs) are rare, aggressive cancers lacking targeted therapy. Here, we review the clinicopathologic features, treatment, and outcomes of patients with MBC treated at our institution.

Methods: We searched clinical and pathology databases for patients with histologically confirmed MBC from 1999 to 2012. We estimated survival probabilities using the Kaplan-Meier method and evaluated prognostic factors using Cox regression.

Results: Forty-five cases were identified, including chondroid (24%), spindled (20%), sarcomatoid (16%), squamous (11%), and mixed (29%) histologic subtypes. Median tumor size was 3 cm, with 86% grade III and 69% triple-negative for estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2. Most had negative lymph nodes, and two patients had metastases at diagnosis. Six patients received neoadjuvant therapy, with one pathologic complete response. All patients underwent surgery, 60% received adjuvant radiation, and 58% had adjuvant chemotherapy. Five-year recurrence-free survival was 64%; 5-year overall survival was 69%. Tumor size, history of breast cancer, and mixed histology were associated with inferior outcomes.

Conclusions: We report one of the largest single-institution series of patients with MBC. MBC is associated with a poor prognosis, despite low nodal involvement. Most patients in this series had high-grade, triple-negative tumors and were treated with optimal therapy.
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http://dx.doi.org/10.1093/ajcp/aqv097DOI Listing
March 2016

Translational Breast Cancer Research Consortium (TBCRC) 022: A Phase II Trial of Neratinib for Patients With Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer and Brain Metastases.

J Clin Oncol 2016 Mar 1;34(9):945-52. Epub 2016 Feb 1.

Rachel A. Freedman, Rebecca S. Gelman, Christina Herold, Nicole Ryabin, Sarah Farooq, Elizabeth Lawler, Ian E. Krop, Eric P. Winer, and Nancy U. Lin, Dana-Farber Cancer Institute; Beverly Moy, Massachusetts General Hospital; Alarice Lowe and Nathalie Y.R. Agar, Brigham and Women's Hospital, Boston, MA; Jeffrey S. Wefel, Kenneth R. Hess, and Nuhad Ibrahim, The University of Texas MD Anderson Cancer Center; Polly A. Niravath and Mothaffar F. Rimawi, Baylor College of Medicine, Houston, TX; Michelle E. Melisko, University of California, San Francisco, San Francisco, CA; Roisin M. Connolly and Antonio C. Wolff, Johns Hopkins University, Baltimore, MD; Catherine H. Van Poznak, University of Michigan, Ann Arbor, MI; Shannon L. Puhalla, University of Pittsburgh Cancer Institute and Magee-Women's Hospital, Pittsburgh, PA; Kimberly L. Blackwell, Duke University Medical Center, Durham, NC; and Minetta C. Liu, Mayo Clinic, Rochester, MN.

Purpose: Evidence-based treatments for metastatic, human epidermal growth factor receptor 2 (HER2)-positive breast cancer in the CNS are limited. Neratinib is an irreversible inhibitor of erbB1, HER2, and erbB4, with promising activity in HER2-positive breast cancer; however, its activity in the CNS is unknown. We evaluated the efficacy of treatment with neratinib in patients with HER2-positive breast cancer brain metastases in a multicenter, phase II open-label trial.

Patients And Methods: Eligible patients were those with HER2-positive brain metastases (≥ 1 cm in longest dimension) who experienced progression in the CNS after one or more line of CNS-directed therapy, such as whole-brain radiotherapy, stereotactic radiosurgery, and/or surgical resection. Patients received neratinib 240 mg orally once per day, and tumors were assessed every two cycles. The primary endpoint was composite CNS objective response rate (ORR), requiring all of the following: ≥ 50% reduction in volumetric sum of target CNS lesions and no progression of non-target lesions, new lesions, escalating corticosteroids, progressive neurologic signs/symptoms, or non-CNS progression--the threshold for success was five of 40 responders.

Results: Forty patients were enrolled between February 2012 and June 2013; 78% of patients had previous whole-brain radiotherapy. Three women achieved a partial response (CNS objective response rate, 8%; 95% CI, 2% to 22%). The median number of cycles received was two (range, one to seven cycles), with a median progression-free survival of 1.9 months. Five women received six or more cycles. The most common grade ≥ 3 event was diarrhea (occurring in 21% of patients taking prespecified loperamide prophylaxis and 28% of those without prophylaxis). Patients in the study experienced a decreased quality of life over time.

Conclusion: Although neratinib had low activity and did not meet our threshold for success, 12.5% of patients received six or more cycles. Studies combining neratinib with chemotherapy in patients with CNS disease are ongoing.
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http://dx.doi.org/10.1200/JCO.2015.63.0343DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5070554PMC
March 2016

Combined Treatment with Epigenetic, Differentiating, and Chemotherapeutic Agents Cooperatively Targets Tumor-Initiating Cells in Triple-Negative Breast Cancer.

Cancer Res 2016 04 19;76(7):2013-2024. Epub 2016 Jan 19.

Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Efforts to induce the differentiation of cancer stem cells through treatment with all-trans retinoic acid (ATRA) have yielded limited success, partially due to the epigenetic silencing of the retinoic acid receptor (RAR)-β The histone deacetylase inhibitor entinostat is emerging as a promising antitumor agent when added to the standard-of-care treatment for breast cancer. However, the combination of epigenetic, cellular differentiation, and chemotherapeutic approaches against triple-negative breast cancer (TNBC) has not been investigated. In this study, we found that combined treatment of TNBC xenografts with entinostat, ATRA, and doxorubicin (EAD) resulted in significant tumor regression and restoration of epigenetically silenced RAR-β expression. Entinostat and doxorubicin treatment inhibited topoisomerase II-β (TopoII-β) and relieved TopoII-β-mediated transcriptional silencing of RAR-β Notably, EAD was the most effective combination in inducing differentiation of breast tumor-initiating cells in vivo Furthermore, gene expression analysis revealed that the epithelium-specific ETS transcription factor-1 (ESE-1 or ELF3), known to regulate proliferation and differentiation, enhanced cell differentiation in response to EAD triple therapy. Finally, we demonstrate that patient-derived metastatic cells also responded to treatment with EAD. Collectively, our findings strongly suggest that entinostat potentiates doxorubicin-mediated cytotoxicity and retinoid-driven differentiation to achieve significant tumor regression in TNBC. Cancer Res; 76(7); 2013-24. ©2016 AACR.
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http://dx.doi.org/10.1158/0008-5472.CAN-15-1619DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4873448PMC
April 2016

TBCRC 008: early change in 18F-FDG uptake on PET predicts response to preoperative systemic therapy in human epidermal growth factor receptor 2-negative primary operable breast cancer.

J Nucl Med 2015 Jan 4;56(1):31-7. Epub 2014 Dec 4.

From the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, Maryland

Unlabelled: Epigenetic modifiers, including the histone deacetylase inhibitor vorinostat, may sensitize tumors to chemotherapy and enhance outcomes. We conducted a multicenter randomized phase II neoadjuvant trial of carboplatin and nanoparticle albumin-bound paclitaxel (CP) with vorinostat or placebo in women with stage II/III, human epidermal growth factor receptor 2 (HER2)-negative breast cancer, in which we also examined whether change in maximum standardized uptake values corrected for lean body mass (SUL(max)) on (18)F-FDG PET predicted pathologic complete response (pCR) in breast and axillary lymph nodes.

Methods: Participants were randomly assigned to 12 wk of preoperative carboplatin (area under the curve of 2, weekly) and nab-paclitaxel (100 mg/m(2) weekly) with vorinostat (400 mg orally daily, days 1-3 of every 7-d period) or placebo. All patients underwent (18)F-FDG PET and research biopsy at baseline and on cycle 1 day 15. The primary endpoint was the pCR rate. Secondary objectives included correlation of change in tumor SUL(max) on (18)F-FDG PET by cycle 1 day 15 with pCR and correlation of baseline and change in Ki-67 with pCR.

Results: In an intent-to-treat analysis (n = 62), overall pCR was 27.4% (vorinostat, 25.8%; placebo, 29.0%). In a pooled analysis (n = 59), we observed a significant difference in median change in SUL(max) 15 d after initiating preoperative therapy between those achieving pCR versus not (percentage reduction, 63.0% vs. 32.9%; P = 0.003). Patients with 50% or greater reduction in SUL(max) were more likely to achieve pCR, which remained statistically significant in multivariable analysis including estrogen receptor status (odds ratio, 5.1; 95% confidence interval, 1.3-22.7; P = 0.023). Differences in baseline and change in Ki-67 were not significantly different between those achieving pCR versus not.

Conclusion: Preoperative CP with vorinostat or placebo is associated with similar pCR rates. Early change in SUL(max) on (18)F-FDG PET 15 d after the initiation of preoperative therapy has potential in predicting pCR in patients with HER2-negative breast cancer. Future studies will further test (18)F-FDG PET as a potential treatment-selection biomarker.
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http://dx.doi.org/10.2967/jnumed.114.144741DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4352313PMC
January 2015

Pertuzumab and its accelerated approval: evolving treatment paradigms and new challenges in the management of HER2-positive breast cancer.

Oncology (Williston Park) 2014 Mar;28(3):186-94, 196

The addition of trastuzumab, a monoclonal antibody to human epidermal growth factor receptor 2 (HER2), to standard chemotherapy in patients with HER2-positive breast cancer has resulted in major improvements in breast cancer outcomes, including improved survival, in both the adjuvant and metastatic settings. However, some patients experience disease relapse despite adjuvant trastuzumab-containing therapy, and resistance to trastuzumab develops in the majority of patients in the metastatic setting. An understanding of the molecular mechanisms underlying trastuzumab resistance has aided the development of novel HER2-targeted therapies. In June 2012, the HER2 dimerization inhibitor pertuzumab was approved by the US Food and Drug Administration (FDA) for use with chemotherapy and trastuzumab in the first-line treatment of metastatic HER2-positive breast cancer. In September 2013, accelerated approval was granted for use of pertuzumab in the neoadjuvant setting, representing a landmark decision by the FDA. This article discusses the development of pertuzumab to date, with a particular focus on the accelerated approval decision. We highlight the need to identify reliable biomarkers of sensitivity and resistance to HER2-targeted therapy, which would make possible the individualization of treatment for patients with HER2-positive breast cancer.
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March 2014