Jame Abraham

Adjuvant Chemotherapy for Breast Cancer: Effects on Cerebral White Matter Seen in Diffusion Tensor Imaging

PURPOSE The purpose of this study was to examine the effect of adjuvant chemotherapy on normal-appearing white matter in women with breast cancer. PATIENTS AND METHODS Ten patients with early-stage breast cancer who were treated with adjuvant chemotherapy and 9 age-, education-, and IQ-matched healthy controls were studied with magnetic resonance imaging. Diffusion tensor imaging was used to calculate fractional anisotropy (FA), a measure of white matter integrity. Measurements were made in the genu and splenium of the corpus callosum. Participants also completed measures of processing speed, depression, and anxiety. RESULTS Relative to controls, patients had slower processing speed and lower FA in the genu. Processing speed was positively correlated with FA in the genu. CONCLUSION The results of this pilot study suggest that adjuvant chemotherapy affects normal-appearing white matter in the genu of the corpus callosum and that this is related to the cognitive deficits experienced by patients.

Lapatinib in the treatment of breast cancer

Within the past 2 years, four separate groups have reported marked improvement in relapse-free survival when trastuzumab was added to adjuvant chemotherapy in patients with HER2-overexpressing breast cancer. These results add further credence to the relevance of this receptor as a tumor target. Despite the significant benefits observed in early and advanced HER2-positive breast cancer, overexpression of the receptor is still associated with a poorer prognosis and an increased risk of disease relapse, even in patients with primary operable disease. Besides cytotoxic chemotherapy, and possibly hormonal therapy, patients whose tumors exhibit resistance to trastuzumab have few molecular-targeted options available. Recently, lapatinib, a small molecule dual inhibitor of both HER2 and EGF receptors, has been developed to expand the options for treating HER-positive breast cancer.

A Phase I Study of the P-Glycoprotein Antagonist Tariquidar in Combination with Vinorelbine

Purpose: P-glycoprotein (Pgp) antagonists have had unpredictable pharmacokinetic interactions requiring reductions of chemotherapy. We report a phase I study using tariquidar (XR9576), a potent Pgp antagonist, in combination with vinorelbine. Experimental Design: Patients first received tariquidar alone to assess effects on the accumulation of 99mTc-sestamibi in tumor and normal organs and rhodamine efflux from CD56+ mononuclear cells. In the first cycle, vinorelbine pharmacokinetics was monitored after the day 1 and 8 doses without or with tariquidar. In subsequent cycles, vinorelbine was administered with tariquidar. Tariquidar pharmacokinetics was studied alone and with vinorelbine. Results: Twenty-six patients were enrolled. Vinorelbine 20 mg/m2 on day 1 and 8 was identified as the maximum tolerated dose (neutropenia). Nonhematologic grade 3/4 toxicities in 77 cycles included the following: abdominal pain (4 cycles), anorexia (2), constipation (2), fatigue (3), myalgia (2), pain (4) and dehydration, depression, diarrhea, ileus, nausea, and vomiting, (all once). A 150-mg dose of tariquidar: (1) reduced liver 99mTc-sestamibi clearance consistent with inhibition of liver Pgp; (2) increased 99mTc-sestamibi retention in a majority of tumor masses visible by 99mTc-sestamibi; and (3) blocked Pgp-mediated rhodamine efflux from CD56+ cells over the 48 hours examined. Tariquidar had no effects on vinorelbine pharmacokinetics. Vinorelbine had no effect on tariquidar pharmacokinetics. One patient with breast cancer had a minor response, and one with renal carcinoma had a partial remission. Conclusions: Tariquidar is a potent Pgp antagonist, without significant side effects and much less pharmacokinetic interaction than previous Pgp antagonists. Tariquidar offers the potential to increase drug exposure in drug-resistant cancers.

Epothilones: A Novel Class of Non-taxane Microtubule-stabilizing Agents

The epothilones are a novel class of non-taxane microtubule-stabilizing agents obtained from the fermentation of the cellulose degrading myxobacteria, Sorangium cellulosum. Preclinical studies have shown that the epothilones are more potent than the taxanes and active in some taxane-resistant models. Similar to paclitaxel and other taxanes, the epothilones block cells in mitosis, resulting in cell death. The chief components of the fermentation process are epothilones A and B, with epothilones C and D found in smaller amounts. Trace amounts of other epothilones have also been detected. Pre-clinical studies have shown that epothilone B is the most active form, exhibiting significantly higher antitumor activity than paclitaxel and docetaxel. Several phase I and phase II clinical trials are ongoing with epothilone B and BMS 247550, an epothilone B analog. Preliminary reports indicate these agents are active against human cancers in heavily pre-treated patients. The epothilones appear to be well tolerated, with a side effect profile that is similar to that reported with the taxanes. This article will review some basic aspects of epothilone chemistry and biology, and pre-clinical and preliminary clinical experience with epothilone B and its analog, BMS 247550.

Increased risk of brain metastases in patients with HER-2/neu-positive breast carcinoma

Preliminary data have indicated that overexpression of HER-2/neu is correlated with more aggressive disease, an increased metastatic potential, and a poorer prognosis in patients with breast carcinoma. Trastuzumab, a humanized anti-HER-2 antibody, reportedly is unable to penetrate the blood– brain-barrier and to our knowledge its efficacy in patients with brain metastases remains unclear. – 6 We conducted a retrospective study to evaluate whether patients with HER-2/neu-positive breast carcinoma have an increased risk of developing brain metastases. After approval from the institutional review board of West Virginia University, the pathology reports of 703 breast carcinoma patients who were diagnosed between April 1998 and January 2003 were reviewed. Based on immunohistochemistry or fluorescence in situ hybridization positivity, all patients who were positive for HER-2/neu were identified and their medical charts reviewed with regard to their course of disease and sites of metastases. Of the 703 patients studied, 164 (23%) were found to be positive for HER-2/neu; a sufficient oncologic history was available for 102 patients. Thirty-one patients (30%) developed distant metastases (95% confidence interval [95% CI], 0.223– 0.399) during follow-up lasting a median of 57 months. Brain metastases were reported to have developed in 15 of these 31 patients (48%)(95% CI, 0.320 – 0.652). A proportional hazards model was fit to the data to explore the association between patient age and time to the development of metastases. A significantly positive association (P 0.01) was found to exist between the two variables. Other models for censored data (Weibul, log-normal, and exponential models) were fitted and were found to produce nearly identical P values (Fig. 1). The results of this small retrospective study demonstrate that younger women with HER-2/neu-positive breast carcinoma may have a higher risk of developing brain metastases than previously reported for the general metastatic breast carcinoma patient population. This 442

Biological mechanisms of bevacizumab-associated adverse events

The perception that inhibition of cancer-associated angiogenesis would be an effective treatment strategy was based on the fundamental difference in cell cycle activity between neoplastic and normal endothelial cells. Selective targeting of tumor vessels could have additional benefits, such as circumventing development of acquired resistance to these types of agents, overcoming intrinsic tumor resistance, exhibiting broad anti-tumor activity and decreasing normal tissue toxicity. Successful translation of anti-angiogenic therapy into the clinical setting was achieved only 5 years ago with the approval of bevacizumab for metastatic colorectal cancer. Although the benefits demonstrated in clinical trials led to the approval of bevacizumab for treatment of colorectal, lung and breast cancers, and most recently glioblastoma, a number of serious soft-tissue and vascular toxicities have also been observed in patients receiving this anti-angiogenic agent. This review assesses the relationship between inhibition of VEGF and toxicity, and proposes the pathogenic mechanisms that lead to the adverse events.

Effect of a Scalp Cooling Device on Alopecia in Women Undergoing Chemotherapy for Breast Cancer: The SCALP Randomized Clinical Trial

Importance Chemotherapy may induce alopecia. Although scalp cooling devices have been used to prevent this alopecia, efficacy has not been assessed in a randomized clinical trial. Objectives To assess whether a scalp cooling device is effective at reducing chemotherapy-induced alopecia and to assess adverse treatment effects. Design, Setting, and Participants Multicenter randomized clinical trial of women with breast cancer undergoing chemotherapy. Patients were enrolled from December 9, 2013, to September 30, 2016. One interim analysis was planned to allow the study to stop early for efficacy. Data reported are from the interim analysis. This study was conducted at 7 sites in the United States, and 182 women with breast cancer requiring chemotherapy were enrolled and randomized. Interventions Participants were randomized to scalp cooling (n = 119) or control (n = 63). Scalp cooling was done using a scalp cooling device. Main Outcomes and Measures The primary efficacy end points were successful hair preservation assessed using the Common Terminology Criteria for Adverse Events version 4.0 scale (grade 0 [no hair loss] or grade 1 [<50% hair loss not requiring a wig] were considered to have hair preservation) at the end of 4 cycles of chemotherapy by a clinician unaware of treatment assignment, and device safety. Secondary end points included wig use and scores on the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire–Core 30, Hospital Anxiety and Depression Scale, and a summary scale of the Body Image Scale. Results At the time of the interim analysis, 142 participants were evaluable. The mean (SD) age of the patients was 52.6 (10.1) years; 36% (n = 51) received anthracycline-based chemotherapy and 64% (n = 91) received taxane-based chemotherapy. Successful hair preservation was found in 48 of 95 women with cooling (50.5%; 95% CI, 40.7%-60.4%) compared with 0 of 47 women in the control group (0%; 95% CI, 0%-7.6%) (success rate difference, 50.5%; 95% CI, 40.5%-60.6%). Because the 1-tailed P value from the Fisher exact test was <.001, which crossed the superiority boundary (P = .0061), the data and safety monitoring board recommended study termination on September 26, 2016. There were no statistically significant differences in changes in any of the scales of quality of life from baseline to chemotherapy cycle 4 among the scalp cooling and control groups. Only adverse events related to device use were collected; 54 adverse events were reported in the cooling group, all grades 1 and 2. There were no serious adverse device events. Conclusions and Relevance Among women with stage I to II breast cancer receiving chemotherapy with a taxane, anthracycline, or both, those who underwent scalp cooling were significantly more likely to have less than 50% hair loss after the fourth chemotherapy cycle compared with those who received no scalp cooling. Further research is needed to assess longer-term efficacy and adverse effects. Trial Registration clinicaltrials.gov Identifier: NCT01986140

Population-Based Molecular Prognosis of Breast Cancer by Transcriptional Profiling

Purpose: The purpose of this study is to predict breast cancer recurrence and metastases and to identify gene signatures indicative of clinicopathologic characteristics using gene expression patterns derived from cDNA microarray. Experimental Design: Expression profiles of 7,650 genes were investigated on an unselected group of 99 node-negative and node-positive breast cancer patients to identify prognostic gene signature of recurrence and metastases. The identified gene signature was validated on independent 78 patients with primary invasive carcinoma (T1/T2 and N0) and on 58 patients with locally advanced breast cancer (T3/T4 and/or N2). The gene predictors were identified using a combination of random forests and linear discriminant analysis function. Results: This study identified a new 28-gene signature that achieved highly accurate disease-free survival and overall survival (both at P < 0.001, time-dependent receiver operating characteristic analysis) in individual breast cancer patients. Patients categorized into high-risk, intermediate-risk, and low-risk groups had distinct disease-free survival (P < 0.005, Kaplan-Meier analysis, log-rank test) in three patient cohorts. A strong association (P < 0.05) was identified between risk groups and tumor size, tumor grade, estrogen receptor and progesterone receptor status, and HER2/neu overexpression in the studied cohorts. We also identified 14-gene predictors of nodal status and 9-gene predictors of tumor grade. Conclusions: This study has established a population-based approach to predicting breast cancer outcomes at the individual level exclusively based on gene expression patterns. The 28-gene recurrence signature has been validated as quantifying the probability of recurrence and metastases in patients with heterogeneous histology and disease stage.

Prospective Clinical Study of Precision Oncology in Solid Tumors

Systematic studies evaluating clinical benefit of tumor genomic profiling are lacking. We conducted a prospective study in 250 patients with select solid tumors at the Cleveland Clinic. Eligibility required histopathologic diagnosis, age of 18 years or older, Eastern Cooperative Oncology Group performance status 0-2, and written informed consent. Tumors were sequenced using FoundationOne (Cambridge, MA). Results were reviewed at the Cleveland Clinic Genomics Tumor Board. Outcomes included feasibility and clinical impact. Colorectal (25%), breast (18%), lung (13%), and pancreatobiliary (13%) cancers were the most common diagnoses. Median time from consent to result was 25 days (range = 3-140). Of 223 evaluable samples, 49% (n = 109) of patients were recommended a specific therapy, but only 11% (n = 24) received such therapy: 12 on clinical trials, nine off-label, three on-label. Lack of clinical trial access (n = 49) and clinical deterioration (n = 29) were the most common reasons for nonrecommendation/nonreceipt of genomics-driven therapy.

Barriers to recruitment of rural patients in cancer clinical trials.

PURPOSE The National Cancer Institute estimates that less than 5% of adult patients with cancer participate in clinical trials. This statistic has to improve in order for clinical trials to be more accurate and generalizable. Several studies have looked into the barriers to accrual among various patient subgroups. However, there are scant data regarding factors that act as barriers to accrual of rural patients. Our study aims to identify these barriers. PATIENTS AND METHODS Among patients seen at the Mary Babb Randolph Cancer Center at West Virginia University, 1,000 were randomly selected to receive a questionnaire by mail. Data obtained consisted of demographic and clinical information, as well as awareness about clinical trials, willingness to participate, and factors influencing participation. Patients had 6 weeks to respond. RESULTS Two hundred forty-one (24.1%) patients responded to the survey. Of these, 66.9% had heard about clinical trials, 19.6% reported that their health care team had discussed clinical trials, and 9.1% had participated in clinical trials. Respondents were more likely to be willing to participate in cancer prevention/screening trials than therapeutic trials. Regarding the decision not to participate in a clinical trial, patients cited discouragement from their oncologist, monetary burden, discouragement from family physician, commute, and lack of information as strongly or extremely influential factors. CONCLUSION Our findings specify the need for patient and physician education through community outreach programs. Oncologists should be trained to discuss clinical trials and to address concerns regarding their availability, utility, and accessibility. Financial counseling may play an important role in improving accrual rates as well.