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ABSTRACT: Overcoming endocrine resistance is a 21st century hurdle in the treatment of hormone receptor-positive breast cancers. Estrogen plays a role in the growth of 70% of breast cancers. There are many strategies evolved to overcome estrogen resistance. Established strategies include using drugs such as tamoxifen, a selective estrogen receptor modulator to selectively block estrogen receptors and aromatase inhibitors to decrease the synthesis of estrogen. However, endocrine resistance is commonly encountered in treating patients with standard single-therapy regimens. Recently, the role of the PI3K and the mTOR pathways has been targeted to overcome resistance. The mTOR pathway is a complex pathway regulating cell metabolism, growth and apoptosis. Novel agents such as mTOR inhibitors, PI3K inhibitors and Akt inhibitors are transitioning from bench-top research to clinical application with promising results. This article reviews the common mechanisms of endocrine resistance, and combination therapies that utilize the mTOR/PI3K pathways to overcome resistance.
Expert Review of Anti-infective Therapy 02/2013; 13(2):143-7. · 2.65 Impact Factor
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Clinical advances in hematology & oncology: H&O 09/2012; 10(9):611-3.
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Expert Review of Anti-infective Therapy 09/2012; 12(9):1113-5. · 2.65 Impact Factor
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Immunotherapy 05/2012; 4(5):473-5. · 1.85 Impact Factor
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ABSTRACT: As mortality in breast cancer patients has improved, morbidity of treatment has become increasingly important. Cognitive dysfunction has been considered as a morbid condition that may possibly result from aromatase inhibitor therapy, the standard treatment in postmenopausal, estrogen/progesterone receptor-positive breast cancer patients. Chemotherapy has been associated with cognitive dysfunction through neuropsychological testing and neurological functional imaging, but the relationship between estrogen and cognition remains largely unexplained. In focusing on aromatase inhibitor therapy, most of the studies yielding mixed results have been limited by confounders and small numbers of populations studied. This article briefly summarizes the major studies evaluating aromatase inhibitor therapy and cognitive dysfunction while considering new directions in future study design.
Expert Review of Anti-infective Therapy 08/2011; 11(8):1277-82. · 2.65 Impact Factor
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ABSTRACT: 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.
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.
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.
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.
Journal of Oncology Practice 05/2011; 7(3):172-7.
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Mehdi Hamadani,
Michael Craig,
Gary S Phillips, Jame Abraham,
William Tse,
Aaron Cumpston,
Laura Gibson,
Scot C Remick,
Pamela Bunner,
Sonia Leadmon,
Patrick Elder,
Craig Hofmeister,
Sam Penza,
Yvonne Efebera,
Leslie Andritsos,
Ramiro Garzon,
Don M Benson,
William Blum,
Steven M Devine
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ABSTRACT: We evaluated the impact of busulfan dose intensity in patients undergoing reduced toxicity/intensity conditioning allogeneic transplantation in a multicenter retrospective study of 112 consecutive patients. Seventy-five patients were conditioned with busulfan (0.8 mg/kg/dose IV × 8 doses), fludarabine (30 mg/m(2) /day, days -7 to -3), and 6 mg/kg of ATG [reduced intensity conditioning (RIC) group], while 37 patients received a more-intense conditioning with busulfan (130 mg/m(2) /day IV, days -6 to -3), fludarabine (40 mg/m(2) /day, days -6 to -3) and 6 mg/kg of ATG [reduced toxicity conditioning (RTC) group]. At baseline both groups were matched for median age, unrelated donor allografts, and human leukocyte antigen-mismatched allografts. More patients in RIC group had high-risk disease, and higher median comorbidity index. There were no graft rejections. Median time to neutrophil (17 days vs. 15 days; p = 0.003) and platelet engraftment (16 days vs. 11 days; p < 0.001) was significantly longer in the RIC group. RTC group had significantly more bacterial (62.2% vs. 32%; p = 0.004) and fungal infections (13.5% vs. 1.3% p = 0.01). For RIC and RTC groups rates of grades II-IV acute GVHD (34% vs. 40%; p-value = 0.54), and chronic GVHD (45% vs. 57%; p-value = 0.30) were not significantly different. In similar order at 1 year the cumulative-incidence of non-relapse mortality (NRM; 12% vs. 21%; p-value = 0.21) and relapse rates (38% vs. 39%; p = 0.96) were not significantly different. Patients in RIC and RTC groups had similar 1-year overall survival (61% vs. 50%, p = 0.11) and progression-free survival (50% vs. 36%, p-value = 0.39). Our data suggest that the merits of higher busulfan dose intensity in the context of fludarabine/busulfan-based RTC may be offset by higher early morbidity.
Hematological Oncology 02/2011; 29(4):202-10. · 2.47 Impact Factor
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ABSTRACT: The goal of this initial clinical study was to test a new positron emission/tomography imager and biopsy system (PEM/PET) in a small group of selected subjects to assess its clinical imaging capabilities. Specifically, the main task of this study is to determine whether the new system can successfully be used to produce images of known breast cancer and compare them to those acquired by standard techniques.
The PEM/PET system consists of two pairs of rotating radiation detectors located beneath a patient table. The scanner has a spatial resolution of ∼2 mm in all three dimensions. The subjects consisted of five patients diagnosed with locally advanced breast cancer ranging in age from 40 to 55 years old scheduled for pre-treatment, conventional whole body PET imaging with F-18 Fluorodeoxyglucose (FDG). The primary lesions were at least 2 cm in diameter.
The images from the PEM/PET system demonstrated that this system is capable of identifying some lesions not visible in standard mammograms. Furthermore, while the relatively large lesions imaged in this study where all visualised by a standard whole body PET/CT scanner, some of the morphology of the tumours (ductal infiltration, for example) was better defined with the PEM/PET system. Significantly, these images were obtained immediately following a standard whole body PET scan.
The initial testing of the new PEM/PET system demonstrated that the new system is capable of producing good quality breast-PET images compared standard methods.
Journal of Medical Imaging and Radiation Oncology 02/2011; 55(1):58-64. · 0.87 Impact Factor
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ABSTRACT: Over the past two decades, since the discovery of the human EGF receptor 2 (HER2) oncogene, the oncoprotein has become one of the best known and intensively studied tumor targets in oncology. In fact, laboratory findings were the basis for clinical proof-of-principle studies, whose results not only confirmed the relationship between gene amplification and an aggressive tumor phenotype but also demonstrated that the poor prognosis associated with receptor overexpression could be improved. Indeed, the success in treating patients with HER2-positive breast cancer extends to those with early as well as advanced disease. Nonetheless, not all tumors respond to treatment targeting the receptor; disease progression also occurs after initially responding to anti-HER2 therapy. This article focuses on the biology of HER2 and three novel agents currently in clinical trials that target HER2 beyond disease progression.
Expert Review of Anti-infective Therapy 09/2010; 10(9):1497-509. · 2.65 Impact Factor
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ABSTRACT: Physicians consistently overestimate survival for patients with cancer. The "surprise" question--"Would I be surprised if this patient died in the next year?"--improves end-of-life care by identifying patients with a poor prognosis. It has not been previously studied in patients with cancer.
To determine the efficacy of the surprise question in patients with cancer.
Prospective cohort study.
Academic cancer center.
853 consecutive patients with breast, lung, or colon cancer.
Surprise question classification and patient status at 12 months, alive or dead, by surprise question response.
Oncologists classified 826 of 853 prospective patients with cancer (97%) with 131 (16%) classified into the "No" group and 695 (84%) into the "Yes" group. In multivariate analysis, a "No" response identified patients with cancer who had a seven times greater hazard of death in the next year compared to patients in the "Yes" group (HR 7.787, p < 0.001).
Single center study.
The surprise question is a simple, feasible, and effective tool to identify patients with cancer who have a greatly increased risk of 1-year mortality.
Journal of palliative medicine 07/2010; 13(7):837-40. · 1.84 Impact Factor
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ABSTRACT: Most deaths from breast cancer are from metastatic disease. Tests that predict an individual's risk of developing metastatic disease could be useful. There is growing evidence that circulating tumor cells (CTC) could help predict recurrence and effectiveness of therapy. However, there are unresolved issues with CTC detection methods and their implementation in the community. The utility of CTC testing in the management of breast cancer is unclear based on current studies. This article reviews the role of CTC testing in the management of early and metastatic breast cancer.
Clinical Breast Cancer 06/2010; 10(3):209-16. · 2.38 Impact Factor
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ABSTRACT: Over 60% of the American population meets the criteria for obesity, and obesity is very common in patients with breast cancer. Many studies have shown that obese patients with breast cancer have a worse prognosis compared to normal weight individuals. Tumor characteristics and other factors contribute to this. Exercise could reverse some of the pathophysiologic factors that contribute to this increased risk, and has been shown in some studies to improve survival in patients with breast cancer. In addition to administering anticancer therapy, cancer clinicians should make concerted attempts to get patients to enroll in weight management and exercise programs, which could improve survival in patients with breast cancer.
Oncology (Williston Park, N.Y.) 04/2010; 24(4):342-6. · 1.03 Impact Factor
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ABSTRACT: It remains a critical issue to improve the survival rate in patients with recurrent or metastatic breast cancer. This study sought to develop a prognostic scheme based on a 28-gene signature in a broad patient population, including those with advanced disease. Clinically annotated transcriptional profiles of 1,734 breast cancer patients were obtained to validate the 28-gene signature in prognostic categorization. The 28-gene signature generated significant patient stratification with regard to breast cancer disease-free survival (log-rank P<0.0001; n=1,337) and overall survival (log-rank P<0.0001; n=806) in Kaplan-Meier analyses. The gene expression signature provides refined prognosis of disease-free survival (log-rank P<0.006; Kaplan-Meier analysis) within each classic clinicopathologic factor-defined subgroup, including LN-, LN+, ER-, ER+ and tumor grade II. Furthermore, it was investigated whether this gene signature predicts chemoresponse to drugs commonly used to treat breast cancer. The mRNA expression levels of this gene signature in NCI-60 cell lines were used to predict chemoresponse to CMF, tamoxifen, paclitaxel, docetaxel, and doxorubicin (adriamycin). The 28-gene prognostic signature accurately (P<0.02) predicted chemotherapeutic response to the studied drugs. This study confirmed the prognostic applicability of the breast cancer gene signature in a broad clinical setting. This prognostic signature is also predictive of drug response in cancer cell lines.
International Journal of Oncology 03/2010; 36(3):607-16. · 2.40 Impact Factor
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Jame Abraham,
James Keresztury,
John Azar,
Manish Monga,
Timothy Bowers,
Mathew Page Jones,
Maria Tria Tirona,
Jondavid Pollock,
Craig Coonley,
Steven Jubelirer,
James Frame,
Patti Fogg,
Molly Getto,
Shannon Filburn,
John Naim,
Dan Lucas,
William Petros,
Sharon Hall,
Scot C Remick
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ABSTRACT: In the United States, mortality rates have been declining for certain tumors, For the majority of advanced stage cancer types, cure is unattainable but treatment is still evolving. Advances in the treatment of cancer can be achieved by enrolling patients in cancer clinical trials. Presently, less than 3% of adult cancer patients participate on clinical trials in the United States. Providing cancer care and access to clinical trials are a challenge in a rural state, with a dispersed population base, such as West Virginia. Building upon recognition of barriers to clinical trials awareness and access, oncology leaders in the state are in the formative stages of developing a statewide cancer clinical trials network. Realization of this network will have an enormous impact on cancer care in our state and perhaps can serve as a model for other community and physician teams for other diseases.
The West Virginia medical journal 10/2009; 105 Spec No:6-11.
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ABSTRACT: In 2007, the American Cancer Society ranked West Virginia 43rd in breast cancer incidence rates for individual states. Despite our improvements in medical care, the advanced pathological characteristics of breast cancer at diagnosis receive little attention. Consequently, we compared the changing pattern of early breast cancer in several cohort studies conducted at regional medical centers in West Virginia. The data used in this analysis was derived from 320 women presenting at West Virginia University Hospital (WVUH) in Morgantown between 1999 and 2004, with a diagnosis of invasive breast cancer. Details of age, tumor size and axillary lymph node status were compared with tumor registry information published from a cohort study of 191 patients from the Charleston Area Medical Center (CAMC) between 1990 and 1991. Only histologically documented adenocarcinomas of the breast were included. Tumor size was characterized using the TNM system and staged according to AJCC criteria. For comparative purposes, details from the two regional centers were compared with tumor characteristics from a large longitudinal cohort of 2,484 breast cancers from the Women's Health Initiative (WHI) study. Baseline median age at diagnosis of women screened at WVUH was younger than patients at CAMC (52 vs. 60). Women diagnosed with triple-negative breast cancer at WVUH and CAMC had similar age distributions. Within the triple-negative patients at WVUH, 44% of patients were less than 50 years of age and 20% were less than 40 years of age. At CAMC, 35% were less than 50 years of age and 7% were less than 40 years of age. For women at WVUH, 61.5% presented with T1 tumors compared to 65.5% at CAMC. These figures were lower than the WHI average of 80.3%. In contrast, more women presented with larger T2 tumors at our medical centers compared with the national study, 32.6% versus 17.4% respectively. At WVUH, 2.3% of women had T3 tumors (> or =5 cm) compared with 1% at CAMC. Similar to the WHI study, 35-42% of women at WVUH and CAMC were diagnosed at the T1c stage. Approximately, 30% were diagnosed with positive lymph nodes, compared to 23% in the national study. Combined breast cancer data from our medical centers show an increase in more advanced tumors and positive regional lymph node involvement at the time of diagnosis compared to national reports. Other factors such as obesity, diabetes, poverty and access to mammography screening could be influencing the poorer outcomes for women with breast cancer in West Virginia.
The West Virginia medical journal 10/2009; 105 Spec No:54-9.
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ABSTRACT: 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.
Expert Review of Anti-infective Therapy 08/2009; 9(7):999-1007. · 2.65 Impact Factor
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Jame Abraham,
Maureen Edgerly,
Richard Wilson,
Clara Chen,
Ann Rutt,
Susan Bakke,
Rob Robey,
Andrew Dwyer,
Barry Goldspiel,
Frank Balis,
Olaf Van Tellingen,
Susan E Bates,
Tito Fojo
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ABSTRACT: 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.
Patients first received tariquidar alone to assess effects on the accumulation of (99m)Tc-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.
Twenty-six patients were enrolled. Vinorelbine 20 mg/m(2) 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 (99m)Tc-sestamibi clearance consistent with inhibition of liver Pgp; (2) increased (99m)Tc-sestamibi retention in a majority of tumor masses visible by (99m)Tc-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.
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.
Clinical Cancer Research 06/2009; 15(10):3574-82. · 7.74 Impact Factor
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ABSTRACT: Positron-emission tomography (PET) scan is a widely used imaging modality in the management of various malignancies. There is considerable controversy regarding its use in breast cancer diagnosis and treatment. In this review, we discuss published data on the use of 2-[18F]-fluoro-2-deoxy-D-glucose (FDG-PET) in the staging workup of locally advanced breast cancer, and management of locally recurrent and metastatic breast cancer. FDG-PET is a useful tool in staging advanced breast cancer and assessing the extent of disease involvement when metastasis is suspected. It might also aid in assessing early response to therapy. Future goals of improving PET scan accuracy in the management of breast cancer will be achieved through utilizing radiotracers, based on a better understanding of tumor biology and improvement in breast-specific PET scans.
Oncology (Williston Park, N.Y.) 04/2009; 23(3):255-61. · 1.03 Impact Factor
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Clinical advances in hematology & oncology: H&O 04/2009; 7(3):180-2.
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ABSTRACT: Smoking is a well-recognized risk factor for several cancers including cancers of the lung, bladder, and head and neck. Studies have shown that smoking can adversely affect the outcomes of different modalities of cancer treatment. This study examines smoking behaviors among cancer survivors to collect information necessary to create successful smoking cessation interventions.
For this observational clinical study, questionnaires were sent to 1,000 randomly selected patients diagnosed with cancer between 2003 and 2007 in one cancer center. Data were statistically analyzed to determine the likelihood of a patient quitting smoking after being diagnosed with cancer.
We received 187 responses from the 1,000 surveys sent (18.7%). Of these, 166 were usable for analysis. The mean age of respondents was 64 (± 13) years. Men were more likely than women to be past smokers (55% of men and 32% of women respectively, P = .003). Fifty-two percent of respondents reported having a history of smoking. However, only 20% of patients reported having been active smokers at the time they were diagnosed with cancer. Furthermore, only 44% of these reported having quit smoking after their diagnosis with cancer. Only 62% of all respondents reported that they had been informed of the dangers of smoking by their health care provider during cancer treatment.
In our study sample, less than one half (44%) of smoking cancer patients quit smoking after their cancer diagnosis, and only 62% of smoking cancer patients received smoking cessation counseling from their physicians. Intervention programs are needed to help cancer survivors to quit smoking. Prospective clinical trials may help identify the ideal intervention for smoking cessation.
Journal of Oncology Practice 01/2009; 5(1):6-9.
