Ishwaria M. Subbiah

Cardiovascular Toxicity Profiles of Vascular-Disrupting Agents

BACKGROUND Vascular-disrupting agents (VDAs) represent a new class of chemotherapeutic agent that targets the existing vasculature in solid tumors. Preclinical and early-phase trials have demonstrated the promising therapeutic benefits of VDAs but have also uncovered a distinctive toxicity profile highlighted by cardiovascular events. METHODS We reviewed all preclinical and prospective phase I-III clinical trials published up to August 2010 in MEDLINE and the American Association of Cancer Research and American Society of Clinical Oncology meeting abstracts of small-molecule VDAs, including combretastatin A4 phosphate (CA4P), combretastatin A1 phosphate (CA1P), MPC-6827, ZD6126, AVE8062, and ASA404. RESULTS Phase I and II studies of CA1P, ASA404, MPC-6827, and CA4P all reported cardiovascular toxicities, with the most common cardiac events being National Cancer Institute Common Toxicity Criteria (version 3) grade 1-3 hypertension, tachyarrhythmias and bradyarrhythmias, atrial fibrillation, and myocardial infarction. Cardiac events were dose-limiting toxicities in phase I trials with VDA monotherapy and combination therapy. CONCLUSIONS Early-phase trials of VDAs have revealed a cardiovascular toxicity profile similar to that of their vascular-targeting counterparts, the angiogenesis inhibitors. As these agents are added to the mainstream chemotherapeutic arsenal, careful identification of baseline cardiovascular risk factors would seem to be a prudent strategy. Close collaboration with cardiology colleagues for early indicators of serious cardiac adverse events will likely minimize toxicity while optimizing the therapeutic potential of VDAs and ultimately enhancing patient outcomes.

Validation and Development of a Modified Breast Graded Prognostic Assessment As a Tool for Survival in Patients With Breast Cancer and Brain Metastases

PURPOSE Several indices have been developed to predict overall survival (OS) in patients with breast cancer with brain metastases, including the breast graded prognostic assessment (breast-GPA), comprising age, tumor subtype, and Karnofsky performance score. However, number of brain metastases-a highly relevant clinical variable-is less often incorporated into the final model. We sought to validate the existing breast-GPA in an independent larger cohort and refine it integrating number of brain metastases. PATIENTS AND METHODS Data were retrospectively gathered from a prospectively maintained institutional database. Patients with newly diagnosed brain metastases from 1996 to 2013 were identified. After validating the breast-GPA, multivariable Cox regression and recursive partitioning analysis led to the development of the modified breast-GPA. The performances of the breast-GPA and modified breast-GPA were compared using the concordance index. RESULTS In our cohort of 1,552 patients, the breast-GPA was validated as a prognostic tool for OS (P < .001). In multivariable analysis of the breast-GPA and number of brain metastases (> three v ≤ three), both were independent predictors of OS. We therefore developed the modified breast-GPA integrating a fourth clinical parameter. Recursive partitioning analysis reinforced the prognostic significance of these four factors. Concordance indices were 0.78 (95% CI, 0.77 to 0.80) and 0.84 (95% CI, 0.83 to 0.85) for the breast-GPA and modified breast-GPA, respectively (P < .001). CONCLUSION The modified breast-GPA incorporates four simple clinical parameters of high prognostic significance. This index has an immediate role in the clinic as a formative part of the clinicians discussion of prognosis and direction of care and as a potential patient selection tool for clinical trials.

Prognostic indicators and treatment outcome in 94 cases of fibrolamellar hepatocellular carcinoma.

Objective: Fibrolamellar hepatocellular carcinoma (FLHCC) is a rare variant of HCC. We report an analysis of the clinicopathologic features, treatment outcomes, and prognostic indicators of 94 cases. Methods: We retrospectively collected clinicopathologic and treatment outcome data from 94 FLHCC patients (48 males and 46 females). Median overall survival (OS) and recurrence-free survival (RFS) were calculated using Kaplan-Meier curves, and survival rates were compared by the log-rank test. The Cox proportional hazard model was used for univariate and multivariate estimation of hazard risk ratios and 95% confidence intervals (CI) for factors that correlated with survival and disease recurrence after resection. Results: Median age was 23 years (14-75); median OS was 57.2 months (95% CI, 36.4-77.9), and median RFS was 13.9 months (95% CI, 8.8-18.9). White race, female gender, early tumor stage, and tumor resection including metastasectomy were positively associated with longer OS, while female gender was the only significant positive predictor of longer RFS. Finally, the 5-fluorouracil-interferon combination was the most frequently used systemic therapy. Conclusions: Our analyses indicate that surgical approaches including metastasectomy as the first-line treatment in FLHCC correlated with better outcome. Multimodality approaches, including neoadjuvant and adjuvant therapies, prolonged patient survival.

STUMP un“stumped”: anti-tumor response to anaplastic lymphoma kinase (ALK) inhibitor based targeted therapy in uterine inflammatory myofibroblastic tumor with myxoid features harboring DCTN1-ALK fusion

BackgroundRecurrent, metastatic mesenchymal myxoid tumors of the gynecologic tract present a management challenge as there is minimal evidence to guide systemic therapy. Such tumors also present a diagnostic dilemma, as myxoid features are observed in leiomyosarcomas, inflammatory myofibroblastic tumors (IMT), and mesenchymal myxoid tumors. Comprehensive genomic profiling was performed in the course of clinical care on a case of a recurrent, metastatic myxoid uterine malignancy (initially diagnosed as smooth muscle tumor of uncertain malignant potential (STUMP)), to guide identify targeted therapeutic options. To our knowledge, this case represents the first report of clinical response to targeted therapy in a tumor harboring a DCTN1-ALK fusion protein.MethodsHybridization capture of 315 cancer-related genes plus introns from 28 genes often rearranged or altered in cancer was applied to >50 ng of DNA extracted from this sample and sequenced to high, uniform coverage. Therapy was given in the context of a phase I clinical trial ClinicalTrials.gov Identifier: (NCT01548144).ResultsImmunostains showed diffuse positivity for ALK1 expression and comprehensive genomic profiling identified an in frame DCTN1-ALK gene fusion. The diagnosis of STUMP was revised to that of an IMT with myxoid features. The patient was enrolled in a clinical trial and treated with an anaplastic lymphoma kinase (ALK) inhibitor (crizotinib/Xalkori®) and a multikinase VEGF inhibitor (pazopanib/Votrient®). The patient experienced an ongoing partial response (6+ months) by response evaluation criteria in solid tumors (RECIST) 1.1 criteria.ConclusionsFor myxoid tumors of the gynecologic tract, comprehensive genomic profiling can identify clinical relevant genomic alterations that both direct treatment targeted therapy and help discriminate between similar diagnostic entities.

Exceptional responders: in search of the science behind the miracle cancer cures

Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 455, Houston, TX77030, USA Division of Pediatrics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 455, Houston, TX 77030, USA *Author for correspondence: vsubbiah@mdanderson.org part of

Comprehensive genomic profiling of clinically advanced medullary thyroid carcinoma

Objective: The aim of this study was to determine the genomic alterations of cancer-related genes in advanced medullary thyroid carcinoma during the course of clinical care. Methods: Hybrid-capture-based comprehensive genomic profiling was performed on 34 consecutive medullary thyroid carcinoma cases to identify all four classes of genomic alterations, and outcome for an index patient was collected. Results:RET was mutated in 88% (30/34) of cases, with RET M918T being responsible for 70% (21/30) of the RET alterations. The other RET alterations were RET E632_L633del, C634R, C620R, C618G/R/S, V804M, and RET amplification. Two of the four RET wild-type patients harbored mutations in KRAS or HRAS (1/34 each). The next most frequent genomic alterations were amplifications of CCND1, FGF3, and FGF19 and alterations in CDKN2A (3/34 each). One case with a RET M918T mutation developed acquired resistance to progressively dose-escalated vandetanib. When the mTOR inhibitor everolimus was added to continued vandetanib treatment, the patient achieved a second 25% reduction of tumor volume (RECIST 1.1) for 8 months. Conclusions: Comprehensive genomic profiling identified the full breadth of RET alterations in metastatic medullary thyroid carcinoma and possible cooperating oncogenic driver alterations. This approach may refine the use of targeted therapy for these patients.

Killing two birds with one stone: BRAF V600E inhibitor therapy for hairy cell leukemia and Langerhans/dendritic cell sarcoma

Dear Editor, We read with great interest the article published in Annals of Hematology on a patient with Langerhans/dendritic cell sarcoma arising from hairy cell leukemia with both lesions demonstrating almost identical karyotypes and identical clonal immunoglobulin gene rearrangements [1]. This case is very interesting in light of fresh data on BRAF V600E mutations in several different tumor types [2]. Whole exome sequencing of patients with hairy cell leukemia has revealed BRAF V600E mutation [3]. This BRAFV600E mutation has been described as a diseasedefining event [3] in hairy cell leukemia and has been implicated in the pathogenesis of hairy cell leukemia. Langerhans cell histiocytoses have also been reported to harbor the BRAFV600E mutation [4]. Histiocytoses are extremely rare diseases with variable clinical syndromes and BRAFV600E mutations have been reported in multiple histiocytoses subtypes including Erdheim–Chester disease [5]. In the light of these results, the case reported is very fascinating [1]. It may be interesting to profile the BRAFV600E status of the hairy cell leukemic clone and the histiocytic/dendritic sarcoma clone. If confirmed, this could suggest clonality and may also indicate a common origin of these diverse rare diseases. Moreover, for this particular patient this may have implications for targeted therapy. Vemurafenib, a BRAF inhibitor has been recently Food and Drug Administration approved for the therapy of BRAFV600E mutant metastatic melanoma [6]. Although hairy cell leukemia is a treatable disease with standard regimens, rare relapsed patients could still benefit from BRAF inhibitor targeted therapy and a proof of concept study has already been reported [7]. Some patients with Langerhans cell histocytoses may have an aggressive clinical course and patients with refractory disease may have few options. BRAF inhibitor-targeted therapy may be the way to kill two birds with one stone such as in this patient if BRAFV600E mutation is confirmed.

Exploring response signals and targets in aggressive unresectable hepatocellular carcinoma: an analysis of targeted therapy phase 1 trials.

PURPOSE Patients with advanced hepatocellular carcinoma (HCC) have limited effective therapeutic options. Given the rapid advanced in drug development and emergence of novel agents, we analyzed the characteristics and outcomes of HCC patients treated on early phase trials with an emphasis on targeted therapies. METHODS We reviewed the records of consecutive HCC patients evaluated in the Phase I Clinical Trials Program at MD Anderson from March 2004. RESULTS Thirty-nine patients were not treated due to poor performance status (n = 22, 56%) and decision to pursue alternate therapies (n = 10, 27%). Of 61 treated patients (median age, 60 years; median prior therapies, 3), eight patients (13%) attained stable disease lasting ≥6 months; four (7%) had a partial response, mainly with anti-angiogenic or multikinase inhibitors. Median Phase I progression-free survival (PFS) was 2.6 months versus 4.4 months (p 0.019) and 4.1 months (p 0.27) for their first-, and second-line FDA-approved therapy. Molecular analysis showed frequent PTEN loss (10/19 patients, 53%) and P53 mutation (4/4 patients tested). On multivariate analysis, independent factors predicting shorter survival were white ethnicity/race (p 0.031), cirrhosis (p 0.016), and serum sodium (p 0.0013). CONCLUSIONS In our heavily-pretreated HCC patients, the phase I PFS was comparable to that of 2nd-line therapy, highlighting a potential role for clinical trials after progression on first-line therapy. The response rate (SD>6 months/PR) of 20% was observed with early signals of activity in regimens combining inhibitors of angiogenesis, multiple kinases and mTOR with preliminary molecular analysis revealing prevalence of PTEN loss.

Outcomes of patients ≥65 years old with advanced cancer treated on phase I trials at MD Anderson Cancer Center.

Patients ≥65 years with cancer remain underrepresented in clinical trials, particularly in phase I clinical trials. We analyzed the clinical course of patients ≥65 years treated on phase I clinical trials with particular emphasis on toxicities. We identified 347 consecutive patients ≥65 years with advanced cancer in our phase I clinic from 01/2004‐12/2009 and analyzed disease characteristics, toxicities, survival and response. Overall, 251 patients received a targeted agent, of whom 241 (96%) received an investigational, non‐FDA‐approved drug. Clinical benefit (complete response + partial response + stable disease ≥ 6 months) was noted in 61 patients (18%). Eighty‐nine patients (26%) had grade 3/4 toxicity, commonly hematologic, including 6 dose‐limiting toxicities and 1 treatment‐related death (<0.01%). Median overall survival from first Phase I Clinic visit was 8.8 months (95% CI: 7.8–10.6); median time to treatment failure was 1.9 months (95% CI: 1.8–2.1). Multivariable analyses revealed 4 indicators of lack of clinical benefit (liver metastases, performance status [PS] >1, prior radiation, ≥5 prior treatments; p <0.0001). Patients age 70–79 years had a greater risk of grade 3/4 toxicities when treated with combinations (≥2 drugs) compared to monotherapy (p = 0.006). Predictors of shorter time to treatment failure and overall survival included PS >1, thrombocytosis, >2 metastatic sites, and elevated lactate dehydrogenase (p <0.05). Our results suggest that phase I clinical trials are well tolerated in patients ≥65 years. Additionally, we identified risk factors that may facilitate patient selection for clinical trial participation.

Abstract 4700: One size does not fit all: Fingerprinting advanced carcinoma of unknown primary through comprehensive profiling identifies aberrant activation of the PI3K and MAPK signaling cascades in concert with impaired cell cycle arrest

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Background: Carcinoma of unknown primary (CUP) represents a heterogeneous group of cancers without an identifiable primary disease site where staining for a vast array of immunohistochemical markers is undertaken to identify tumor lineage. Given rapid advances in characterizing cancer genomes, we sought to describe the molecular profiles of patients with advanced CUP treated with novel targeted therapies on phase I clinical trials to identify pathways of interest to drive future therapeutic strategies. Methods: Of patients with advanced malignancies seen in the Phase I clinic, we identified 16 CUP patients on whom adequate tissue was available to perform next-generation sequencing (NGS) from FFPE sections using a targeted NGS assay in a CLIA laboratory (Foundation One, MA). Over 2000 exons of 186 cancer-related genes plus over 30 introns from 14 genes often rearranged in cancer were fully sequenced for point mutations, insertions/deletions, copy number alterations (CNAs) and select gene fusions. Results: Of 16 tumor specimen, 14 demonstrated genomic alterations with a median of 4 aberrations within each specimen (range 0 - 10, total of 69 alterations); two patients did not demonstrate any tested changes. All patients with detected mutations possessed an exclusive unique molecular profile of aberrations with no two patients demonstrating an identical panel of mutations. A total of 69 alterations were identified of which 18 (26%) led to aberrant cell signaling within the PI3K/AKT/MTOR (including 4 with PIK3CA mutations) or the MAPK signaling cascades, primarily KRAS mutations in 3 patients. Also noted were 13 (19%) alterations impairing cell cycle arrest most commonly affecting cyclin dependent kinases, 10 (14%) impacting epigenetic regulation and DNA methylation, 10 (14%) affecting known tumor suppressor genes including TP53 in 8 patients, and 10 (14%) unique alternations in transcriptional regulators. Conclusion: With thorough molecular profiling, we can identify the unique fingerprint of potential actionable aberrations in a subset of advanced CUP patients. Herein we identified activation of the PI3K/AKT/MTOR and RAS/RAF/MEK signaling pathways combined with impaired cell cycle arrest in 8 of 16 (50%) tested patients, suggesting that a combination of PI3K and MAPK cascade inhibitors in combination with a cell cycle inhibitor may be of therapeutic value to these patients. Further matching patients to these actionable aberrations is underway, thereby translating these therapeutic targets to the bedside with the development of novel targeted therapies. Note: This abstract was not presented at the meeting. Citation Format: Ishwaria M. Subbiah, Gauri Varadhachary, Apostolia M. Tsimberidou, Jennifer J. Wheler, Vivek Subbiah, Filip Janku, Sinchita Roy Chowdhury, Ralph Zinner, Funda Meric-Bernstam, David S. Hong. One size does not fit all: Fingerprinting advanced carcinoma of unknown primary through comprehensive profiling identifies aberrant activation of the PI3K and MAPK signaling cascades in concert with impaired cell cycle arrest. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4700. doi:10.1158/1538-7445.AM2014-4700