Pavani Chalasani

Phase I trial of AEG35156 an antisense oligonucleotide to XIAP plus gemcitabine in patients with metastatic pancreatic ductal adenocarcinoma.

Objectives:AEG35156 is an antisense oligonucleotide (ASO) that targets the X-linked inhibitor of apoptosis mRNA. Preclinical studies showed potent activity of AEG35156 in combination with gemcitabine in pancreatic ductal adenocarcinoma (PDA). A phase I study was conducted to establish the maximum-tolerated dose, safety, and antitumor activity of AEG35156 plus gemcitabine in metastatic PDA. Methods:Fourteen patients with metastatic PDA were enrolled. Nine patients were treated at 350 mg IV and 5 patients at 500 mg IV of AEG35156, 3 weeks on/1 week off of a 28-day cycle. Gemcitabine was administered at 1000 mg/m2 IV over 30 minutes immediately after AEG35156 in both groups. Because of perceived neurotoxicity dose deescalation to 350 mg was recommended. Results:All 14 patients were evaluable for tolerability and toxicity. Toxicities include neutropenia (grade 3/4, 6 patients), thrombocytopenia (grade 3, 2 patients), peripheral neuropathy (grade 3, 2 patients), fatigue (grade 3, 4 patients), ascites (grade 3, 2 patients), and nausea/vomiting (grade 4, 2 patients). Five patients (45%) experienced stable disease with a median progression-free survival of 58 days (95% CI, 52-107 d). Conclusions:The maximum-tolerated dose is AEG35156 500 mg plus gemcitabine 1000 mg/m2 given on days 1, 8, and 15 every 28 days. AEG35156 plus gemcitabine failed to show significant clinical activity in advanced PDA.

Caring for the Breast Cancer Survivor: A Guide for Primary Care Physicians

Breast cancer accounts for more than 25% of cancers in women. Because of improved screening and treatment modalities, mortality has decreased significantly. Currently, over 2.5 million breast cancer survivors live in the US and receive care from a primary care provider. Providers need to be aware of common and serious complications of breast cancer treatment. In this review we discuss complications of local and systemic treatment for breast cancer, including lymphedema, osteoporosis, cardiovascular disease, and vasomotor symptoms. Current strategies for screening, monitoring, and treating these complications also are outlined.

A phase I clinical trial of bavituximab and paclitaxel in patients with HER2 negative metastatic breast cancer

Bavituximab is a chimeric monoclonal antibody that targets phosphatidylserine (PS). PS is externalized on cells in the tumor microenvironment when exposed to hypoxia and/or other physiological stressors. On attaching to PS, bavituximab is thought to promote antitumor immunity through its effects on PS receptors in monocytes, and myeloid‐derived suppressor cells, as well as trigger antitumor effects by inducing an antibody‐dependent cellular cytotoxicity on tumor‐associated endothelial cells. We conducted a phase I clinical trial of bavituximab in combination with paclitaxel in patients with HER2‐negative metastatic breast cancer. Patients were treated with weekly paclitaxel (80 mg/m2 for 3/4 weeks) and weekly bavituximab (3 mg/kg for 4/4 weeks). Correlative studies included the measurement of circulating microparticles, endothelial cells, and apoptotic tumor cells by flow cytometry. Fourteen patients with metastatic breast cancer were enrolled; all were evaluable for toxicity and 13 were evaluable for response. Treatment resulted in an overall response rate (RR) of 85% with a median progression‐free survival (PFS) of 7.3 months. Bone pain, fatigue, headache, and neutropenia were the most common adverse effects. Infusion‐related reactions were the most common adverse event related to bavituximab therapy. Correlative studies showed an increase in the PS‐expressing apoptotic circulating tumor cells in response to bavituximab, but not with paclitaxel. No changes in the number of circulating endothelial cells or apoptotic endothelial cells were observed with therapy. Platelet and monocyte‐derived microparticles decreased after initiation of bavituximab. Bavituximab in combination with paclitaxel is well tolerated for treatment of patients with metastatic breast cancer with promising results observed in terms of clinical RRs and PFS. The toxicity profile of bavituximab is notable for manageable infusion‐related reactions with no evidence for increased thrombogenicity. Recent preclinical data suggest that bavituximab can also promote antitumor immune activity that should be explored in future clinical trials.

A Pilot Study of Estradiol Followed by Exemestane for Reversing Endocrine Resistance in Postmenopausal Women With Hormone Receptor-Positive Metastatic Breast Cancer

BACKGROUND Endocrine resistance is a frequent complication, and strategies to reverse it are a high research priority for metastatic breast cancer (MBC) that is hormone receptor positive. Preclinical data suggest re-exposure to estrogen induces tumor regression in tamoxifen-resistant tumors. We conducted a pilot study to determine whether short-term estradiol exposure would reverse endocrine resistance and resensitize tumors METHODS Postmenopausal women with estrogen receptor-positive MBC whose disease had progressed after receiving at least one prior endocrine therapy were eligible for the study. Patients were initially treated with 6 mg/day estradiol, and those who had not progressed after 3 months were then switched to exemestane. RESULTS Thirteen patients were evaluable for toxicity and response. No grade 3 or 4 toxicities were observed. Of the 13 patients who initiated estradiol therapy, 6 patients (46%) had not experienced disease progression at month 3 and were switched to exemestane. On exemestane, disease progression was documented in five patients, with one having stable disease as best response. Median progression-free survival for all patients was 4.8 months (range: 0.6-9.5 months). CONCLUSION Treatment with an estrogen prior to resuming antiestrogen treatments was not effective at reversing hormone resistance; however, low-dose estradiol treatment had measurable clinical activity with minimal toxicity and should be considered as a therapeutic option for hormone-refractory MBC.

Clinical Translation of Tumor Acidosis Measurements with AcidoCEST MRI

PurposeWe optimized acido-chemical exchange saturation transfer (acidoCEST) magnetic resonance imaging (MRI), a method that measures extracellular pH (pHe), and translated this method to the radiology clinic to evaluate tumor acidosis.ProceduresA CEST-FISP MRI protocol was used to image a flank SKOV3 tumor model. Bloch fitting modified to include the direct estimation of pH was developed to generate parametric maps of tumor pHe in the SKOV3 tumor model, a patient with high-grade invasive ductal carcinoma, and a patient with metastatic ovarian cancer. The acidoCEST MRI results of the patient with metastatic ovarian cancer were compared with DCE MRI and histopathology.ResultsThe pHe maps of a flank model showed pHe measurements between 6.4 and 7.4, which matched with the expected tumor pHe range from past acidoCEST MRI studies in flank tumors. In the patient with metastatic ovarian cancer, the average pHe value of three adjacent tumors was 6.58, and the most reliable pHe measurements were obtained from the right posterior tumor, which favorably compared with DCE MRI and histopathological results. The average pHe of the kidney showed an average pHe of 6.73 units. The patient with high-grade invasive ductal carcinoma failed to accumulate sufficient agent to generate pHe measurements.ConclusionsOptimized acidoCEST MRI generated pHe measurements in a flank tumor model and could be translated to the clinic to assess a patient with metastatic ovarian cancer.

Circulating Carbonic Anhydrase IX and Antiangiogenic Therapy in Breast Cancer

Introduction. Carbonic anhydrase IX (CAIX) is a hypoxia regulated metalloenzyme integral to maintaining cellular pH. Increased CAIX expression is associated with poor prognosis in breast cancer. To explore CAIX as a biomarker for breast cancer therapies, we measured plasma CAIX levels in healthy control subjects and in breast cancer patients. Methods. In control subjects we evaluated plasma CAIX stability via commercially available ELISA. We then similarly quantified plasma CAIX levels in (1) locally advanced breast cancer (LABC) patients treated with neoadjuvant paclitaxel + sunitinib (T + S) followed by doxorubicin and cyclophosphamide (AC); (2) metastatic breast cancer (MBC) patients treated with systemic chemotherapy. Results. Plasma CAIX levels were stable at room temperature for at least 48 hours in control subjects. Mean baseline plasma CAIX levels were lower in controls compared to patients with LABC or MBC. In LABC, CAIX levels rose significantly in response to administration of antiangiogenic therapy (T + S) (p = 0.02) but not AC (p = 0.37). In patients with MBC treated without an antiangiogenic agent CAIX levels did not change with therapy. Conclusions. Our results suggest that CAIX may be an easily obtained, stable measure of tumor associated hypoxia as well as a useful pharmacodynamic biomarker for antiangiogenic therapy.

Abstract OT2-2-05: Metronomic eribulin in metastatic breast cancer

Introduction : Breast cancer is a common and curable malignancy. In the setting of late or early recurrence, improvement in therapy is indicated as overall survival (OS) has changed little over the past few decades. Eribulin mesylate is a non-taxane microtubule dynamics inhibitor FDA approved in salvage metastatic breast cancer (MBC) treatment based on improvements in OS. Eribulin mesylate is a synthetic analogue of halichondrin B, a product isolated from the marine sponge Halichondria okadai . Anti-tubulin therapy is an established cornerstone of chemotherapeutics for MBC. Work at our center and others has shown a favorable therapeutic index for weekly metronomic vinorelbine. The history of other effective and tolerable agents, including paclitaxel, capecitabine, and vinorelbine, suggests that a low dose metronomic schedule of eribulin could be effective, well tolerated and result in longer time to progression (TTP), and higher quality of life during therapy. In phase I studies, Eribulin showed activity at doses well below the maximally tolerated 1.4mg/m 2 given 2/3 weeks, suggesting a lower metronomic schedule would not compromise efficacy. A lower dose metronomic schedule will allow responding patients to remain on treatment, resulting in longer TTP and greater use of the drug in practice. Study Design : This is an open-label, multi-center, phase II study of eribulin for patients with MBC. HER2 positive patients may enroll with concomitant use of trastuzumab. Patients will receive eribulin 0.9 mg/m 2 administered intravenously over 2 to 5 minutes on Days 1¸ 8 and 15 of a 28-day cycle. Treatment will be continued until disease progression, unacceptable toxicity or withdrawal of patient consent. Eligibility Criteria : Patients with MBC whose disease has progressed following 1-6 prior regimens with prior exposure to a taxane, ECOG PS of 0 – 2, measurable disease per RECIST 1.1, normal marrow and organ function. Patients with known CNS metastases must have stable disease off steroids after treatment with surgery or radiation. Exclusion criteria: mild hepatic or renal impairment, grade > 2 peripheral neuropathy, significant cardiovascular impairment or other severe or uncontrolled medical disease or psychiatric or neurologic disorder. Specific Aims : The primary aim is to increase progression free survival (PFS). We hypothesize that metronomic dosing of eribulin will result in PFS of 4-6 months. Secondary aims include decreasing the frequency of alopecia to less than 50%, grade 3 or 4 neutropenia to less than 30% and sensory neuropathy (all grades) to less than 25% of subjects enrolled. An exploratory aim is to assess the role of circulating endothelial cell precursors (CEPs) and apoptotic circulating endothelial cells in predicting early response to treatment. Statistical Methods : PFS will be measured as the time from study enrollment until the earliest date of disease progression or death. The sample size of n=60 has 99% power for the lower bound of the confidence interval to be greater than 2.2 months (the median PFS in the physician’s discretion arm of the EMBRACE trial), assuming that the true median PFS is 4 months, comparable to or an incremental improvement over the median PFS for the eribulin arm of the EMBRACE trial (3.7 months). Currently 12 of 60 expected enrollments have occurred. Citation Format: Pavani Chalasani, Livingston B Robert, Thomas A Rado, Vijayakrishna K Gadi, Thomas D Kummet, Jennifer M Specht, Alison Stopeck, Hannah M Linden. Metronomic eribulin in metastatic breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr OT2-2-05.

Spontaneous Paraesophageal Hematoma

Spontaneous paraesophageal hematoma (SPH) likely shares a common etiology with spontaneous intramural esophageal hematoma (IEH). Patients with IEH typically present with hematemesis or melena leading to early detection and management, but patients with SPH do not have overt gastrointestinal bleeding on presentation. Management depends on the correction of the underlying causative factor. We present the first case of a spontaneous paraesophageal hematoma in a patient with hemophilia B. Awareness of this complication of hemophilia, its clinical manifestations, and imaging findings, allows for a timely diagnosis and appropriate management.

Optimizing Quality of Life in Patients with Hormone Receptor-Positive Metastatic Breast Cancer: Treatment Options and Considerations

The treatment landscape for hormone receptor-positive metastatic breast cancer continues to evolve as the molecular mechanisms of this heterogeneous disease are better understood and targeted treatment strategies are developed. Patients are now living for extended periods of time with this disease as they progress through sequential lines of treatment. With a rapidly expanding therapeutic armamentarium, the prevalence of metastatic breast cancer patients with prolonged survival is expected to increase, as is the duration of survival. Practice guidelines recommend endocrine therapy alone as first-line therapy for the majority of patients with metastatic hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer. The approval of new agents and expanded combination options has extended their use beyond first line, but endocrine therapy is not used as widely in clinical practice as recommended. As all treatments are palliative, even as survival is prolonged, optimizing and maintaining patient quality of life is crucial. This article surveys data relevant to the use of endocrine therapy in the setting of hormone receptor-positive metastatic breast cancer, including key clinical evidence regarding approved therapies and the impact of these therapies on patient quality of life.

Abstract 3728: Imaging biomarkers of aromatase-inhibitor induced joint pain

Estrogen receptor positive (ER+) breast cancer patients undergoing treatment with aromatase inhibitors (AI) tend to discontinue the supplement when to painful side effects appear. It is believed that women with AI-induced musculoskeletal syndrome (AIMSS) have specific physiological conditions that differentiate them from women with normal aging-related inflammatory processes (e.g., rheumatoid arthritis or RA). Ultrasound shear wave elastography (USWE) provides a real-time, quantitative assessment of the elastic modulus of soft tissue, which is a potential biomarker that is altered in women with AIMSS. Because USWE is a completely noninvasive technique available on state-of-the-art clinical ultrasound scanners, it can be readily applied to study patients who undergo AI treatment and help predict adverse effects during therapy. A Siemens s3000 clinical scanner and 9 MHz linear probe were used for USWE of the hands and wrists in postmenopausal women on AI, postmenopausal women with RA and healthy postmenopausal women. The scans included an evaluation of major wrist tendons, nerve, and joints with shear wave velocities ranging from 0.5 to 15 m/s, which are directly related to the local shear modulus – an absolute measure of tissue stiffness. The ultrasound images and raw shear wave data were then analyzed in MATLAB-TM using a custom graphical user interface (GUI) to calculate the distribution of velocities (or shear moduli) in a user-defined region of interest (ROI). The results were exported to a spreadsheet in Excel for further analysis and comparison among the different groups. Initial results suggest the shear wave velocity and estimated Young’s modulus (λ) were significantly higher in AI patients (14.6 ± 0.2 m/s, λ=642 ± 17 kPa) compared to RA (6.84 ± 1.1 m/s, λ=143 ± 43 kPa) and healthy (7.58 ± 0.9 m/s, λ=174 ± 42 kPa) patients. These values suggest that the mechanical properties of tendons in the wrist may change during treatment with AI and contribute to joint pain in these subjects. It is critical that ER+ patients on AI complete their full treatment. As a potential biomarker of AIMSS and associated pain, USWE may help predict which patients are most susceptible to these side effects, promote early intervention to reduce or eliminate symptoms, and help increase adherence to AI therapy. Citation Format: Brian A. Goldstein, Mihra Taljanovic, Pavani Chalasani, C. Kent Kwoh, Amanda Hadden, Russell Witte, Jessica Martinez. Imaging biomarkers of aromatase-inhibitor induced joint pain [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3728. doi:10.1158/1538-7445.AM2017-3728