Biomarker panel for early screening of trastuzumab -induced cardiotoxicity among breast cancer patients in west virginia.

Cardiotoxicity is a well-known pathophysiological consequence in breast cancer patients receiving trastuzumab. Trastuzumab related cardiotoxicity typically results in an overall decline in cardiac function, primarily characterized by reduction in left ventricular ejection fraction (LVEF) and development of symptoms associated with heart failure. Current strategies for the monitoring of cardiac function, during trastuzumab therapy, includes serial echocardiography, which is cost ineffective as well as offers limited specificity, while offering limited potential in monitoring early onset of cardiotoxicity. However, biomarkers have been shown to be aberrant prior to any detectable functional or clinical deficit in cardiac function. Hence, this study aims to develop a panel of novel biomarkers and circulating miRNAs for the early screening of trastuzumab induced cardiotoxicity. Patients with clinical diagnosis of invasive ductal carcinoma were enrolled in the study, with blood specimen collected and echocardiography performed prior to trastuzumab therapy initiation at baseline, 3- and 6-months post trastuzumab therapy. Following 6-months of trastuzumab therapy, about 18% of the subjects developed cardiotoxicity, as defined by reduction in LVEF. Our results showed significant upregulation of biomarkers and circulating miRNAs, specific to cardiac injury and remodeling, at 3- and 6-months post trastuzumab therapy. These biomarkers and circulating miRNAs significantly correlated with the cardiac injury specific markers, troponin I and T. The findings in the present study demonstrates the translational applicability of the proposed biomarker panel in early preclinical diagnosis of trastuzumab induced cardiotoxicity, further allowing management of cardiac function decline and improved health outcomes for breast cancer patients.

Effect of Tart Cherry on Aromatase Inhibitor-Induced Arthralgia (AIA) in Nonmetastatic Hormone-Positive Breast Cancer Patients: A Randomized Double-Blind Placebo-Controlled Trial.

BACKGROUND: Aromatase Inhibitor induced Arthralgia (AIA) can cause noncompliance leading to decreased breast-cancer survival. Effective interventions for AIA are limited. Tart cherry (TC) showed beneficial effect on musculoskeletal pain. 48 patients (Pts) randomized to TC versus placebo over 6 weeks, TC (23pts) had 34.7% mean pain decrease versus 1.4% in Placebo (25pts). TC can improve AIA in nonmetastatic breast-cancer patients. METHODS: Randomized, placebo-controlled, double-blind trial. Eligible patients with NMHPBC on AI for at least 4 weeks were randomized to TC concentrate [50 tart cherries] vs. placebo (P) [syrup] in 1:1 model. Patients instructed to consume 1 Oz of concentrate in 8 Oz water daily for 6 weeks, and document their pain intensity at baseline, weekly and at study completion in a diary using Visual Analog Scale (VAS), with 0 mm indicating no pain, and 100 mm indicating highest pain. RESULTS: Sixty patients were enrolled. Two patients did not complete the study due to diarrhea, and 10 patients were noncompliant. Forty-eight patients were included in the final analysis. TC group (23 pts) had 34.7% mean decrease in pain compared to 1.4% in P group (25 pts). This difference was statistically significant (Mann-Whitney U Test, P = .034). CONCLUSIONS: Tart cherry can significantly improve AIA in nonmetastatic breast cancer patient.

Pneumonitis and cellular immunodeficiency triggered by the CDK 4/6 inhibitor Abemaciclib.

Breast cancer is the second most common cancer amongst women in the United States following non-melanoma skin cancer. There were an estimated 276,480 new cases and 42,170 deaths in 2020. The lifetime risk for developing breast cancer in females is about 13%. In the United States this year approximately 284,200 people out of which 281,550 women and 2,650 men, will be diagnosed with invasive breast cancer. In recent years, treatment options with novel mechanisms have emerged. Cyclin dependent kinase (CDK) 4/6 inhibitors, namely palbociclib, ribociclib and abemaciclib, are relatively new targeted therapies for treating breast cancers express estrogen receptors (ER) and/or progesterone receptors (PR). CDKs are important regulatory enzymes in cell cycle transitions and cell division. Selective inhibition of CDK4/6 causes cell cycle to arrest in the G1 phase, resulting in reduced cell viability and tumor response. Abemaciclib is the only one approved as monotherapy. Palbociclib and ribociclib must be used as adjunctive therapy to endocrine therapy such as tamoxifen, aromatase inhibitors or fulvestrant. Common side effects include neutropenia, thrombocytopenia, fatigue, nausea, and vomiting. A black box warning for all CDK inhibitors is a rare but possibly fatal severe inflammation of the lungs, called pneumonitis. We present a fatal case of severe pneumonitis with superimposed fungal respiratory infection in the setting of hypogammaglobulinemia in a 65-year-old female with metastatic ER and PR positive, human epidermal growth factor receptor 2 (HER-2) negative breast cancer who received abemaciclib.

Hormone Receptor Positive/HER2 Negative Breast Cancer With Isolated Bladder Metastasis: A Rare Case.

Breast cancer is the most common cancer diagnosed in women in North America. Hormone receptor positive (HR+) and HER2 negative (HER2-) breast cancers account for at least 60% to 70% of all breast cancer cases. They usually metastasize to lymph nodes, bones, liver, lungs, and brain. Urinary bladder is a very unusual site for metastatic HR+/HER2- breast cancer and occurs in only 2% of all metastatic disease. In this article, we present a case of a 63-year-old female with locally advanced breast cancer who underwent mastectomy, adjuvant chemotherapy, radiation, and hormonal therapy. She was in remission for almost 17 years and subsequently presented with hematuria and lower abdominal pain. Cystoscopy was performed, which showed evidence of bladder wall thickening. Histopathology showed metastatic HR+/HER2- breast cancer consistent with her history of breast primary. Imaging studies did not show any other evidence of metastatic disease. She was started on cyclin D kinase 4/6 inhibitor, palbociclib, in combination with an aromatase inhibitor, letrozole. This is an exceedingly rare case of HR+ and HER2- breast cancer with metastasis to the urinary bladder. The late onset of recurrence with bladder metastasis makes this case very unique and to our knowledge only few similar cases have been reported in the literature.

Detecting early onset of anthracyclines-induced cardiotoxicity using a novel panel of biomarkers in West-Virginian population with breast cancer.

Cardiotoxic manifestation associated with breast cancer treatment by anthracycline regimen increases patients' susceptibility to myocardial injury, reduction in left ventricular ejection fraction and complications associated with heart failure. There is currently no standardized, minimally invasive, cost effective and clinically verified procedure to monitor cardiotoxicity post-anthracycline therapy initiation, and to detect early onset of irreversible cardiovascular complications. This study aims to create a panel of novel biomarkers and circulating miRNAs associated with cardiotoxicity, further assessing their correlation with cardiac injury specific markers, troponin I and T, and demonstrate the development of cardiac dysfunction in breast cancer patients. Blood obtained from West Virginian females clinically diagnosed with breast cancer and receiving anthracyclines showed upregulated level of biomarkers and circulating miRNAs after 3 and 6 months of chemotherapy initiation with increased levels of cardiac troponin I and T. These biomarkers and miRNAs significantly correlated with elevated troponins. Following 6 months of anthracycline-regimens, 23% of the patient population showed cardiotoxicity with reduced left ventricular ejection fraction. Our results support the clinical application of plasma biomarkers and circulating miRNAs to develop a panel for early diagnosis of chemotherapy related cardiac dysfunction which will enable early detection of disease progression and management of irreversible cardiac damage.

Ischemic Colitis Associated with Paclitaxel and Carboplatin Combination.

A 62-year-old white female with a history of early-stage triple-negative breast cancer on a combination of carboplatin and paclitaxel in the adjuvant setting presented with lower gastrointestinal bleeding. She tolerated 4 cycles of dose-dense adriamycin/cyclophosphamide with no major symptoms. After 6 cycles of weekly paclitaxel in combination with carboplatin every 3 weeks, she presented with diarrhea and lower gastrointestinal bleeding. Colonosopic examination showed erythema and inflammation in the splenic flexure, descending colon, and sigmoid colon consistent with ischemic colitis. Pathology favored the same diagnosis. She was treated conservatively with intravenous fluids and bowel rest. Chemotherapy was held for 2 weeks and resumed after recovery without carboplatin. She was able to tolerate the remaining 6 cycles of paclitaxel with no recurrence of her symptoms.

Prospect of the use of checkpoint inhibitors in hepatocellular cancer treatments.

Hepatocellular cancer (HCC) is a very fatal disease due to limited therapeutic options as well as due to its association with underlying chronic liver disease in the majority of cases. The immune evasion in HCC signifies a major barrier to the delivery of effective immunotherapy. Sorafenib is the only Food and Drug Administration-approved drug available with an overall response rate of 2%-3% and overall survival of 2.8 months. Chemotherapy has not been used routinely because of the relative refractoriness of advanced HCC. The introduction of immune checkpoint inhibitors (cytotoxic T-lymphocyte antigen 4, programmed death 1, and programmed death-ligand 1) has opened a new horizon for cancer immunotherapy. Future direction in immunotherapy for HCC is to rationally combine it with other treatment modalities, including surgery, radiofrequency ablation, and cytotoxic agents, to maximize its therapeutic efficacy.

Comparison of toxicity profile and tolerability between two standard of care paclitaxel-based adjuvant chemotherapy regimens in breast cancer.

In breast cancer, there are two widely used paclitaxel-based adjuvant chemotherapies, either dose dense paclitaxel (ddP) or weekly paclitaxel (wP). To our knowledge, the comparisons of toxicity and tolerability between the two regimens have never been reported in the literature. This is a retrospective single-institution charts review of breast cancer patients who were treated with paclitaxel-based chemotherapy either ddP or wP. In total, 76 and 45 patients with breast cancer received adjuvant standard ddP and wP, respectively. Patient characteristics in both groups were comparable. Our results showed no statistical significant difference in toxicity profile and tolerability between the two regimens. Particularly, chemotherapy-induced peripheral neuropathy (CIPN) was equally observed in both schedules. Furthermore, grade 3 and 4 CIPN was observed in 17 and 18 %, respectively (p = 0.93). In terms of tolerability, both regimens resulted in similar rates of hospitalization and treatment discontinuation. Our data analysis indicates no significant difference in toxicity profile between the two standard paclitaxel regimens in breast cancer. However, this is a small sample-sized retrospective study and further prospective trial with a larger sample size is warranted.

The Tri-State Experience. Outcome Analysis of Patients with Triple Negative Breast Cancer Treated at Marshall University.

Breast cancer is the most frequently diagnosed malignancy in women in the United States. It is the second most common malignancy to cause death, with approximately 39,000 women dying of breast cancer in the United States in 2013. Triple negative breast cancer is defined as the absence of estrogen, progesterone and human epidermal growth factor receptor 2 receptors. It has been associated with a higher incidence in African American women, a younger age and a more advanced stage at diagnosis, and an inferior overall survival. To recognize the differences of our West Virginia community population when compared to the national average, we conducted a retrospective review of all patients diagnosed with breast cancer from 2000-2012.

Prevention of breast cancer (Part II): risk reduction strategies.

Until recently, the best protection against breast cancer mortality was early diagnosis through mammographic screening. However, the possibility that breast cancer in some cases can be prevented has come to light over the past 30 years. Various risk reduction strategies of breast cancer have been explored including lifestyle modification, prophylactic surgeries, and the use of chemopreventive agents. This article is the second portion of a two-part series on breast cancer prevention, and will focus its discussion on the available risk reduction interventions that have been shown to prevent breast cancer in women considered high risk for the disease. (See Part I in Cancer Investigation, 28:743­750, 2010)

Prevention of breast cancer (part I): epidemiology, risk factors, and risk assessment tools.

Advances in breast cancer research have led to declining death rates from this disease because of early detection through mammographic screening and improved therapy for breast cancer. The concept that breast cancer, in some cases, can be prevented has been explored over the last three decades. This article, part I of a two-part series, will focus on the epidemiology, the risk factors associated with breast cancer, and the available risk assessment tools, which can help define who should be considered for risk reduction strategies. Part II will focus on discussing risk reduction strategies.

Building a statewide clinical trials network for cancer care in West Virginia.

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.

Triple-negative breast cancer in West Virginia.

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.

Hematopoietic stem cell transplantation in the elderly.

Hematopoietic stem cell (HSC) transplantation may improve outcomes of patients with hematologic malignancies not curable with conventional therapies. In some clinical settings, transplantation represents the only curative option. The feasibility and efficacy of this approach in older patients are undefined, since this population has been excluded from nearly all clinical trials. Advances in supportive care, HSC harvesting, and safer conditioning regimens have made this therapy available to patients well into their 6th and 7th decades of life. Recent evidence suggests that elderly patients with good performance status and no comorbidities could, in fact, not only survive the transplant with reasonable risk, but also benefit in the same measure as younger patients.

Nicotine patch therapy based on smoking rate followed by bupropion for prevention of relapse to smoking.

PURPOSE: To determine whether (1) tailored nicotine patch therapy that is based on smoking rate can be carried out in a multisite oncology investigative group practice setting, (2) long-term use of bupropion reduces the rate of relapse to smoking in smokers who stop smoking with nicotine patch therapy, and (3) bupropion can initiate smoking abstinence among smokers who have failed to stop smoking after nicotine patch therapy. PARTICIPANTS AND METHODS: Fourteen North Central Cancer Treatment Group sites recruited generally healthy adult smokers from the general population for nicotine patch therapy and based the patch dosage on smoking rates. At completion of nicotine patch therapy, nonsmoking participants were eligible to be assigned to bupropion or placebo for 6 months (for relapse prevention). and smoking participants were eligible to be assigned to bupropion or placebo for 8 weeks of treatment. RESULTS: Of 578 subjects, 31% were abstinent from smoking at the end of nicotine patch therapy. Of those subjects not smoking at the end of nicotine patch therapy who entered the relapse prevention phase, 28% and 25% were not smoking at 6 months (the end of the medication phase) for bupropion and placebo, respectively (P =.73). For those still smoking at the end of nicotine patch therapy, 3.1% and 0.0% stopped smoking with bupropion or placebo, respectively (P =.12). CONCLUSION: Tailored nicotine patch therapy for the general population of smokers can be provided in a multisite oncology investigative group setting. Bupropion did not reduce relapse to smoking in smokers who stopped smoking with nicotine patch therapy. Bupropion did not initiate abstinence among smokers who failed to stop smoking with nicotine patch therapy.

Randomized, placebo-controlled, phase III surgical adjuvant clinical trial of megestrol acetate (Megace) in selected patients with malignant melanoma.

A randomized, double-blind, placebo-controlled phase III clinical trial was performed to assess megestrol acetate (Megace) as a postsurgical adjuvant therapy for patients with locally advanced malignant melanoma. Patients whose tumors were greater than 1.7 mm thick and had no regional lymph node involvement and patients with regional lymph node involvement were randomized to receive either 160 mg twice per day oral suspension of megestrol acetate or placebo. Treatment was administered for a maximum of 2 years or until disease progression. The study accrued 262 eligible patients. All but two patients were followed until death or a minimum of 4.5 years. Disease progression was documented in 156 patients. Neither progression-free survival (PFS) nor overall survival (OS) was found to differ between the treatments. The median PFS was 2.4 years in the megestrol acetate arm and 2.3 years in the placebo arm. Multivariate analysis revealed a significantly decreased PFS for patients with four or more positive regional lymph nodes and metachronous nodal disease. Median OS was 5.3 years in the megestrol acetate arm and 3.9 years in the placebo arm. Multivariate analysis revealed that OS was significantly decreased for patients 70 years of age or older with four or more positive lymph nodes. Adjuvant therapy with megestrol acetate oral suspension administered at a dose of 160 mg twice a day for 2 years was not found to be effective in prolonging PFS or OS in patients with surgically resected, locally advanced melanoma.

Efficacy and quality-of-life data are related in a phase II trial of oral chemotherapy in previously untreated patients with metastatic colorectal carcinoma.

PURPOSE: To evaluate quality of life (QOL) and tumor response after administration of an oral chemotherapy regimen in patients with previously untreated metastatic colorectal cancer. PATIENTS AND METHODS: Seventy-eight patients received a mean number of 5.8 cycles of therapy. QOL data were analyzed at baseline, after every two cycles of therapy, and at the time of treatment discontinuation. The Uniscale and the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire C30 were both utilized. RESULTS: The confirmed response rate was 26% (95% confidence interval [CI], 17% to 37%). Median survival was 11.3 months (95% CI, 9.6 to 15.1 months). Global QOL scores were unchanged over the course of therapy by either tool. Only the physical function subscale score had worsened at the end of therapy. In an analysis of responding patients, significant and durable improvements in both global QOL measures as well as select subscale scores were observed. Diarrhea and physical function QOL scores had declined at the time of treatment discontinuation. Patients who did not respond to therapy had preserved QOL scores when they were evaluated after two cycles of therapy. CONCLUSION: This oral treatment strategy preserved QOL in treated patients. Global QOL measures as well as several QOL subscale scores significantly improved in patients with a documented response to therapy. The profile of improved QOL components indicated that patient well-being was related to tumor response in specific and perceivable ways. Nonresponding patients reported preserved QOL during the first two cycles of therapy. QOL analysis was feasible and informative in this moderately sized multicenter phase II trial.

Phase III evaluation of nortriptyline for alleviation of symptoms of cis-platinum-induced peripheral neuropathy.

Tricyclic antidepressants have been reported to relieve the paresthesiae associated with peripheral neuropathies of many etiologies. We designed a randomized, double-blind, placebo-controlled, crossover trial to establish the efficacy of nortriptyline in the treatment of cis-diamminedichloroplatinum (CDDP)-induced paresthesiae. The study included 51 evaluable patients with CDDP-induced peripheral neuropathy and painful paresthesiae. The study consisted of two 4 week phases, separated by a 1 week 'wash-out' period, in which patients received escalating dosages of either placebo or nortriptyline. The target maximum dose of nortriptyline was 100 mg/day. Each patient filled out pre-randomization and then weekly questionnaires assessing paresthesiae severity, hours of sleep, quality of life, and adverse effects over the 9 week study. No significant differences in paresthesia were observed in the first treatment period between nortriptyline and placebo (means of 49 and 55 respectively on a 0-100 point scale, P=0.78). Although some evidence of a modest effect in favor of nortriptyline was observed during the second treatment period (about one patient in five got a 10-point reduction in pain from drug above placebo effect), this occurred in the presence of a strong carryover effect. Linear models analysis and Bayes methods confirmed that the effect of nortriptyline on paresthesia was modest at best. Hours of sleep increased in the nortriptyline phase (P=0.02). There was no significant difference in measures of quality of life and the effect of paresthesiae on patients' daily activities between nortriptyline and placebo. There was no major toxicity associated with nortriptyline, but dry mouth, dizziness, and constipation were more common with nortriptyline. In summary, nortriptyline failed to demonstrate strong evidence of any effect on paresthesia or pain. The presence of a potential effect which appeared in the second period of the crossover design is questionable due to the observed carryover effect. Cross-validation sensitivity analysis of results support the conclusion that nortriptyline provides modest improvement at best over placebo in terms of chemotherapy-related neuropathy.