warfarin and Breast-Neoplasms

Breast fat necrosis (BFN) is usually a benign inflammatory response to breast trauma. However, an extremely rare cause of fat necrosis is calciphylaxis, a calcification of small- and medium-sized arteries causing thrombosis and ischemia. It is classified into (A) uremic (B) nonuremic-induced calciphylaxis. Calciphylaxis has been reported to be encountered in different parts of the body. However, to the best of our knowledge there is only one case in the English literature of BFN 2ry to warfarin-induced calciphylaxis. We report a 65-year-old female, known case of atrial fibrillation on warfarin, presented with a left breast mass of 4-month duration. The mass was painful and progressively enlarging. Examination of the left breast showed 7 × 4 cm mass, spanning from 10-2 o'clock, free from surrounding structures, with preserved overlying skin. However, the mass was not visualized on mammogram. Ultrasound showed a left breast lobulated hypoechoic mass containing a hyperechoic component. Biopsy showed fat necrosis. After 1 month, she presented with ulceration of the overlying skin. After wide local excision, histopathology demonstrated a calciphylaxis-induced fat necrosis. Considering the patient's background, the diagnosis was BFN secondary to warfarin-induced calciphylaxis. Hence, the warfarin was shifted to Rivaroxaban, 6 months follow-up showed no evidence of recurrence. In conclusion, the rarity of nonuremic calciphylaxis is reflected on the delay of diagnosis in some of the reported cases and the lack of grading system used to guide the management of such difficult wounds. However, keeping a high index of suspicion is important whenever such wounds are encountered with presence of risk factors other than end-stage kidney disease.

Topics: Aged; Breast Neoplasms; Calciphylaxis; Fat Necrosis; Female; Humans; Necrosis; Neoplasm Recurrence, Local; Warfarin

The cytochome P450 enzyme system is responsible for the metabolism of xenobiotics, including > 75% of commonly prescribed medications. Many of the cytochrome enzymes exhibit polymorphic genotypes, partly accounting for the variations observed in individual drug responses. Recent advances in the understanding of functional alleles of cytochrome P450 enzymes have changed the use of medications. Improvements in drug efficacy and the prevention of toxicity, as well as improvements in clinical drug dosing, have enhanced pharmacotherapy decisions in medical practice. In addition to personalizing medicine, the identification and quantification of genotypic differences in cytochrome P450 metabolism has the potential to facilitate population-based personalized medicine in countries without the resources to perform genotypic tests at the point of care. This review provides an update on the utility of genotype-guided therapy when treating breast cancer, malaria and coagulation disorders. Also discussed are advancements made in diagnostic tests for cytochrome genotypes and the need for future research in the area of diagnostic tests.

Topics: Amodiaquine; Anticoagulants; Antimalarials; Breast Neoplasms; Cytochrome P-450 Enzyme System; Estrogen Antagonists; Female; Genotype; Humans; Isoenzymes; Malaria; Molecular Structure; Pharmaceutical Preparations; Precision Medicine; Tamoxifen; Warfarin; Xenobiotics

To determine the potential impact of genetic testing and pharmacogenomics on healthcare delivery and costs.. Literature review.. We examined 3 examples: (1) BRCA1/2 testing for breast cancer risk, (2) HER2/neu overexpression testing to guide drug treatment in women with breast cancer, and (3) CYP2C9 testing before the use of the anticoagulant warfarin. We discussed each genetic testing example from the perspective of the patient, provider, insurer, industry, government, and society.. The expanded use of genetic information offers many potential clinical benefits, but also many economic challenges. One of those challenges will be managing the impact of genetic testing on healthcare delivery and costs.. Systematic, evidence-based technology assessments and economic evaluations will have to be used to guide the incorporation of genomics into clinical practice. More research also will be needed to assess patient preferences and willingness to pay for genomic technologies; how providers can assess and use genomic technologies; and how the industry, insurers, and government can best balance the relevant costs and benefits.

Topics: Breast Neoplasms; Delivery of Health Care; Female; Genetic Testing; Health Services Research; Humans; Managed Care Programs; Pharmacogenetics; United States; Warfarin

Breast and nipple skin is commonly affected by various inflammatory and neoplastic processes. Despite this fact, many physicians are unaware of the spectrum of diseases that can involve this area. Because breast and nipple skin represents a cosmetically, sexually, and functionally important entity to most patients, awareness of these disease entities is invaluable. This article reviews the normal anatomy of the breast, cutaneous manifestations of neoplastic processes that can present in these areas, and common inflammatory diseases of the breast and nipple skin.

Topics: Anticoagulants; Breast Diseases; Breast Neoplasms; Dermatitis; Female; Hidradenitis Suppurativa; Humans; Mastitis; Necrosis; Nipples; Panniculitis, Lupus Erythematosus; Scleroderma, Localized; Warfarin

Adjuvant chemotherapy for breast cancer, although generally safe and of proven benefit, can have severe complications. Central venous catheter (CVC) complications are relatively common forms of treatment-related morbidity in this setting. We report a rare type of CVC-related complication, that of chemotherapy-induced mediastinitis from central venous extravasation of the drug vinblastine, in a women undergoing adjuvant chemotherapy. The patient presented with signs and symptoms consistent with mediastinitis, but the diagnosis was delayed because the initial findings were nonspecific and there was little suspicion for a CVC-related problem. A radionuclide venous flow study was misleading, but a computed tomographic study of the chest and contrast venography confirmed the diagnosis. Conservative treatment with CVC removal, systemic anticoagulation, antibiotics, and pain controlled to gradual improvement in the patient's clinical status. More aggressive strategies, such as thrombolytic therapy and surgical intervention, were considered, but these approaches have not been used in this particular setting. The complication reported here is the first described in the literature in an adult patient. Two similar cases have been reported in pediatric patients. It is likely that this clinical problem is underreported. Patients with CVCs actively undergoing chemotherapy with vesicant agents should be watched carefully for early signs of CVC disruption and subsequent extravasation, as it is likely that early intervention will be of benefit.

Topics: Amoxicillin; Amoxicillin-Potassium Clavulanate Combination; Analgesics, Opioid; Anticoagulants; Antineoplastic Agents, Phytogenic; Breast Neoplasms; Catheterization, Central Venous; Chemotherapy, Adjuvant; Clavulanic Acids; Contrast Media; Dextropropoxyphene; Drug Therapy, Combination; Extravasation of Diagnostic and Therapeutic Materials; Female; Humans; Mediastinitis; Middle Aged; Radionuclide Imaging; Subclavian Vein; Thrombosis; Tomography, X-Ray Computed; Vinblastine; Warfarin

Topics: Adjuvants, Immunologic; Animals; B-Lymphocytes; BCG Vaccine; Breast Neoplasms; Female; Humans; Immunization, Passive; Immunoglobulins; Immunotherapy; Levamisole; Lymphatic Metastasis; Plasmapheresis; Propionibacterium acnes; T-Lymphocytes; Warfarin

Malignancy is a risk factor for thromboembolism and anti-cancer chemotherapy can increase this risk. Prophylaxis of thrombosis with very-low-dose warfarin given concurrently with chemotherapy has a significantly reduced rate of thromboembolism in a randomized trial in women with stage IV breast cancer. In a group of 32 patients randomized in one center (16 subjects on warfarin and 16 on placebo), we have prospectively studied the plasma levels of: 1. Markers of 'in vivo' clotting activation (thrombin-antithrombin complex [TAT], prothrombin fragment 1+2 [F1+2] and D-dimer), 2. Factor VII (FVII), and 3. Natural anticoagulants (protein C [PC] and antithrombin [AT]). The aims of this study were: 1. to examine whether laboratory tests predicted those patients who developed thrombosis, and 2. to evaluate the effect of very-low-dose warfarin on hemostatic variables. The patients' hemostatic parameters were evaluated before entry into the study and after starting chemotherapy +/- prophylaxis, before each course for nine courses. Before-treatment results were compared to those of a sex and age-matched non-cancer control group. There was a significant elevation of plasma levels of TAT (p <0.001), F1+2 (p <0.001), D-dimer (p <0.0001) and FVIIa (p <0.05), as well as an increase of FVII proteolysis (p <0.05), whereas plasma PC and AT concentrations were not different from controls. After starting chemotherapy, markers of clotting activation were progressively lower in the group receiving warfarin prophylaxis compared to the group on placebo. Differences between the groups became statistically significant (p <0.01) after the 4th course of chemotherapy. Deep vein thrombosis occurred in two patients in the placebo arm. The results of this study indicate that before therapy, an hypercoagulable state is present in stage IV breast cancer, and after starting chemotherapy, abnormalities of hypercoagulation markers persist, however they are reduced by very-low-dose-warfarin. None of the laboratory variables could predict thrombosis in the single patient.

Topics: Adult; Aged; Anticoagulants; Biomarkers, Tumor; Blood Coagulation Disorders; Breast Neoplasms; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Middle Aged; Neoplasm Metastasis; Prospective Studies; Risk Factors; Thromboembolism; Warfarin

A recent double-blind, randomized trial demonstrated that very low-dose warfarin (VLDW) reduced the incidence of venous thromboembolism (VTE) without increasing the rate of bleeding in women with metastatic breast cancer receiving chemotherapy. We have evaluated the economic impact on the health care system of using VLDW in such patients.. The records of patients entered onto the trial and a simultaneous, fully allocated, costing model for a tertiary care hospital in Hamilton, Canada were used to determine the difference in costs associated with the care of patients with and without VLDW.. The cost of providing VLDW was $ 21,854 (Canadian dollars) per 100 patients. This therapy led to a reduction in costs of $ 24,297 per 100 patients, thus saving the health care system $ 2,443 per 100 patients. In the sensitivity analysis, VLDW prophylaxis still did not increase health care costs unless the cost of VLDW was greatly increased, the cost of treating thromboembolic episodes was markedly reduced, or the incidence of either VTE or bleeding with VLDW was increased above the rates observed in the trial.. We conclude that for women receiving chemotherapy for metastatic breast cancer, the benefits of VLDW can be realized without increased health care costs.

Topics: Breast Neoplasms; Canada; Female; Health Care Costs; Humans; Thromboembolism; Warfarin

Patients receiving chemotherapy for metastatic breast cancer are at high risk of thromboembolic disease. Long-term oral anticoagulant therapy is needed but increases the risk of haemorrhagic complications. We have assessed the safety and efficacy of warfarin in very low doses as prophylaxis. Women receiving chemotherapy for metastatic breast cancer were randomly assigned either very-low-dose warfarin (152 patients) or placebo (159). The warfarin dose was 1 mg daily for 6 weeks and was then adjusted to maintain the prothrombin time at an international normalised ratio (INR) of 1.3 to 1.9. Study treatment continued until 1 week after the end of chemotherapy. The average daily dose from initiation of titration was 2.6 (SD 1.2) mg for the warfarin group and the mean INR was 1.52. The mean time at risk of thrombosis was 199 (126) days for warfarin-treated patients and 188 (137) days for placebo recipients (p = 0.45). There were 7 thromboembolic events (6 deep-vein thrombosis, 1 pulmonary embolism) in the placebo group and 1 (pulmonary embolism) in the warfarin group, a relative risk reduction of about 85% (p = 0.031). Major bleeding occurred in 2 placebo recipients and 1 warfarin-treated patient. There was no detectable difference in survival between the treatment groups. Very-low-dose warfarin is a safe and effective method for prevention of thromboembolism in patients with metastatic breast cancer who are receiving chemotherapy.

Topics: Antineoplastic Agents; Breast Neoplasms; Double-Blind Method; Female; Humans; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Thromboembolism; Thrombophlebitis; Treatment Outcome; Warfarin

Topics: Breast Neoplasms; Carcinoma, Small Cell; Double-Blind Method; Female; Humans; Lung Neoplasms; Prospective Studies; Thromboembolism; Warfarin

Topics: Adjuvants, Pharmaceutic; Administration, Oral; Adult; BCG Vaccine; Breast Neoplasms; Drug Therapy, Combination; Female; Humans; Injections, Intravenous; Levamisole; Middle Aged; Warfarin

The value of the oral anticoagulant warfarin sodium and fibrinolytic agents is discussed in relation to cancer surgery. A controlled trial of 128 patients showed that in a variety of recurrent cases the addition of warfarin to chemotherapy doubled the 2-year survival rate. The best results were obtained in postmenopausal patients with breast cancer. Warfarin depresses cellular immune responses which might militate against its use for cases undergoing "curative" surgery. Instead, induction of fibrinolysis by streptokinase or Brinase is suggested, because it increases the activity of the cellular immune mechanism. The results to date of an ongoing controlled randomized trial of streptokinase with surgery of tumors of the large bowel are presented, showing that the trends are in favor of streptokinase therapy; however, insufficient time has elapsed to make it, as yet, statistically significant. The action of streptokinase-induced plasmin and Brinase on lymphocytes is described.

Topics: Adenocarcinoma; Administration, Oral; Antineoplastic Agents; Aspergillus; Breast Neoplasms; Colonic Neoplasms; Drug Evaluation; Female; Fibrinolysis; Fibrinolytic Agents; Humans; Immunity, Cellular; Lymphoma, Non-Hodgkin; Male; Neoplasms; Ovarian Neoplasms; Peptide Hydrolases; Rectal Neoplasms; Streptokinase; Warfarin

Topics: Administration, Oral; Anticoagulants; Antineoplastic Agents; Breast Neoplasms; Busulfan; Chlorambucil; Clinical Trials as Topic; Cyclophosphamide; Female; Hodgkin Disease; Humans; Leukemia, Myeloid; Lung Neoplasms; Male; Neoplasm Metastasis; Neoplasm Recurrence, Local; Neoplasms; Prognosis; Warfarin

Antiestrogen agents have been reported to enhance the anticoagulant activity of warfarin. The use of tamoxifen with warfarin has been contraindicated. However, warfarin in combination with toremifene has not been reported. We report a case in which warfarin was combined with toremifene and applied warfarin dose prediction models to predict the dose of warfarin.. We report the case of a 50-year-old woman with a history of breast cancer, who underwent long-term toremifene therapy after mastectomy. The patient was treated with warfarin after prosthetic valve replacement and had a fluctuating international normalized ratio (INR) following the concomitant administration of toremifene. We applied the warfarin dose prediction model to adjust the warfarin dose during treatment. Finally, her INR stabilized with a lower dose of warfarin, and there was no serious bleeding during the 1-year follow-up.. Warfarin does not have a serious interaction with toremifene in this case, but it needed about 37.5% dose reduction which was comparable to the interaction of some common antibiotics with warfarin.

Topics: Anticoagulants; Breast Neoplasms; Female; Humans; International Normalized Ratio; Mastectomy; Middle Aged; Toremifene; Warfarin

Various components of the coagulation cascade have been linked to breast cancer progression.. All anticoagulants used from 1995 to 2015 in women (. At a median of 5.8 years after breast cancer diagnosis, 10,900 (15%) women had died from breast cancer. In total, 25,622 (35%) women had used anticoagulants during the study period. Postdiagnostic anticoagulant use increased the risk of breast cancer death (HR = 1.41; 95% confidence interval, 1.33-1.49). The risk was especially high for low-molecular weight heparin, although the effect disappeared in long-term users.. Anticoagulant use provides no clinical benefit for breast cancer survival; however, the association between thrombosis and cancer might mask potential survival benefits.. Future pharmacoepidemiologic studies should adjust for anticoagulant use. Research should focus on the use of new oral anticoagulants because these are rarely studied and might be associated with improved breast cancer survival.

Topics: Aged; Anticoagulants; Breast Neoplasms; Drug Prescriptions; Female; Finland; Follow-Up Studies; Heparin, Low-Molecular-Weight; Humans; Middle Aged; Registries; Retrospective Studies; Risk Factors; Survival Analysis; Venous Thromboembolism; Warfarin

We aimed to investigate whether the concomitant use of tamoxifen with warfarin is associated with higher risk for bleeding among patients with early estrogen-receptor (ER)-positive breast in a population-based nested case-control study. We identified 1787 patients taking warfarin and 92 cases hospitalized for bleeding and found an adjusted odds ratio (OR) of 1.42 (95% confidence interval (CI): 0.84-2.40) for the risk of bleeding in patients treated with warfarin that initiated tamoxifen within the previous 30 days. As a result, we could not definitively rule out a potential association between tamoxifen use during warfarin and bleeding risk in patients with breast cancer.

Topics: Antineoplastic Agents, Hormonal; Breast Neoplasms; Case-Control Studies; Female; Humans; Tamoxifen; Warfarin

Topics: Adenocarcinoma; Albumins; Anticoagulants; Breast Neoplasms; Deoxycytidine; Female; Gemcitabine; Heart Ventricles; Humans; Magnetic Resonance Imaging; Middle Aged; Paclitaxel; Pancreatic Neoplasms; Thrombosis; Warfarin

Central venous catheter-associated bacteraemia caused by Nocardia species is very rare; the diagnosis of nocardiosis in patients with cancer is challenging because its clinical presentation is varied, sometimes mimicking metastases, and the high index of clinical suspicion is required for prompt institution of therapy. Herein, we report a case of nocardial sepsis with native aortic valve endocarditis in a patient with breast cancer in whom multidisciplinary team involvement and prompt initiation of therapy have led to successful outcome.

Topics: Amikacin; Anti-Bacterial Agents; Anticoagulants; Aortic Valve; Breast Neoplasms; Central Venous Catheters; Clopidogrel; Cough; Endocarditis, Bacterial; Fatigue; Female; Headache; Heart Valve Prosthesis Implantation; Humans; Meropenem; Middle Aged; Nocardia; Nocardia Infections; Platelet Aggregation Inhibitors; Radiography, Thoracic; Sepsis; Treatment Outcome; Warfarin

Asparagine endopeptidase (AEP), also called legumain, is highly expressed in various solid tumors, promoting cancer cell invasion, migration, and metastasis. It has been proposed to be a prognostic marker and therapeutic target for cancer treatment. However, an effective nonpeptide, small-molecule inhibitor against this protease has not yet been identified. Here we show that a family of xanthine derivatives selectively inhibit AEP and suppress matrix metalloproteinase (MMP) cleavage, leading to the inhibition of cancer metastasis. Through structure-activity relationship (SAR) analysis, we obtained an optimized lead compound (38u) that represses breast cancer invasion and migration. Chronic treatment of nude mice, which had been inoculated with MDA-MB-231 cells, with inhibitor 38u via oral administration robustly inhibits breast cancer lung metastasis in a dose-dependent manner, associated with blockade of MMP-2 by AEP. Therefore, our study supports that 38u might act as a potent and specific AEP inhibitor useful for cancer treatment.

Topics: Animals; Antineoplastic Agents; Breast; Breast Neoplasms; Cell Line, Tumor; Cysteine Endopeptidases; Cysteine Proteinase Inhibitors; Female; Humans; Lung; Lung Neoplasms; Mice; Mice, Nude; Neoplasm Invasiveness; Structure-Activity Relationship; Xanthine

Topics: Aged, 80 and over; Anticoagulants; Antifibrinolytic Agents; Atrial Fibrillation; Blood Component Transfusion; Breast Neoplasms; Female; Heart Failure; Humans; International Normalized Ratio; Plasma; Pleural Effusion, Malignant; Preoperative Care; Stroke; Thoracentesis; Transfusion Reaction; Vitamin K; Warfarin

Novel pyrazolopyrimidines displaying high potency and selectivity toward SRC family kinases have been developed by combining ligand-based design and phenotypic screening in an iterative manner. Compounds were derived from the promiscuous kinase inhibitor PP1 to search for analogs that could potentially target a broad spectrum of kinases involved in cancer. Phenotypic screening against MCF7 mammary adenocarcinoma cells generated target-agnostic structure-activity relationships that biased subsequent designs toward breast cancer treatment rather than to a particular target. This strategy led to the discovery of two potent antiproliferative leads with phenotypically distinct anticancer mode of actions. Kinase profiling and further optimization resulted in eCF506, the first small molecule with subnanomolar IC50 for SRC that requires 3 orders of magnitude greater concentration to inhibit ABL. eCF506 exhibits excellent water solubility, an optimal DMPK profile and oral bioavailability, halts SRC-associated neuromast migration in zebrafish embryos without inducing life-threatening heart defects, and inhibits SRC phosphorylation in tumor xenografts in mice.

Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Drug Discovery; Drug Screening Assays, Antitumor; Female; HCT116 Cells; Humans; Lateral Line System; MCF-7 Cells; Mice; Molecular Structure; Neoplasms, Experimental; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Rats; src-Family Kinases; Structure-Activity Relationship; Zebrafish

Tamoxifen is a selective estrogen- receptor modulator commonly associated with an increased risk of thrombotic events, including cere- bral venous thrombosis. Ihe superior sagittal sinus appears to be the most affected site of cerebral venous thrombosis in patients with a history of malignancy. However, the underlying mechanism of tamoxifen- induced hypercoagulability and location of cerebral venous thrombosis are notwellunderstood. Here, we present a case of a 47-year-old female with a history of breast cancer, on tamoxifen for 10 months, found to have superior sagittal sinus thrombosis with additional thrombosis of the draining cortical veins. Furthermore, we review similar cases published in literature. We recommend that physicians should be aware ofthe potential of developing superior sagittal sinus thrombosis in patients who take tamoxifen and warn patients of this adverse event when prescribing the medication.

Topics: Anticoagulants; Anticonvulsants; Antineoplastic Agents, Hormonal; Blood Coagulation; Blood Coagulation Tests; Breast Neoplasms; Female; Humans; Levetiracetam; Magnetic Resonance Angiography; Middle Aged; Phlebography; Piracetam; Sagittal Sinus Thrombosis; Superior Sagittal Sinus; Tamoxifen; Treatment Outcome; Warfarin

A thromboembolic complication such as pulmonary embolism in patients who had cancer and mobile thrombi in the heart is a rare but fatal complication. Surgical thromboembolectomy is considered as the classical treatment of choice. In case of inoperable patient, catheter-directed therapy may be an alternative treatment. We report an interesting case of metastatic breast cancer with a large and mobile right atrial thrombus complicated by a massive and subsequently recurring pulmonary embolism, followed by thrombocytopenia developed after heparin and warfarin treatment.

Topics: Adult; Bone Neoplasms; Breast Neoplasms; Fatal Outcome; Female; Fibrinolytic Agents; Heart Atria; Heparin; Humans; Pulmonary Embolism; Recurrence; Thrombocytopenia; Thrombolytic Therapy; Thrombosis; Ultrasonography; Warfarin

Topics: Alkaptonuria; Arsenites; Blood Grouping and Crossmatching; Blood Transfusion; Breast Neoplasms; Classification; Cytochrome P-450 Enzyme System; Female; Genetic Testing; Genetic Therapy; Genetics; Genome, Human; Genotype; Greece; History, 18th Century; History, 19th Century; History, 20th Century; History, 21st Century; History, Ancient; Human Genome Project; Humans; Medical History Taking; Medicine, Ayurvedic; Pharmacogenetics; Phenylthiourea; Potassium Compounds; Precision Medicine; Sequence Analysis, DNA; Taste; Warfarin

Pre-clinical studies suggest that oral anticoagulant agents, such as warfarin, may inhibit metastases and potentially prolong survival in cancer patients. However, few population-based studies have examined the association between warfarin use and cancer-specific mortality.. Using prescribing, cause of death, and cancer registration data from the UK Clinical Practice Research Datalink, four population-based cohorts were constructed, comprising breast, colorectal, lung, and prostate cancer patients diagnosed between 1 January 1998, and the 31 December 2010. Comparing pre-diagnostic warfarin users to non-users, multivariable Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95 % confidence intervals (CIs) for cancer-specific mortality.. Overall, 16,525 breast, 12,902 colorectal, 12,296 lung, and 12,772 prostate cancers were included. Pre-diagnostic warfarin use ranged from 2.4 to 4.7 %. There was little evidence of any strong association between warfarin use pre-diagnosis and cancer-specific mortality in prostate (adjusted HR 1.03, 95 % CI 0.84-1.26), lung (adjusted HR 1.06, 95 % CI 0.96-1.16), breast (adjusted HR 0.81, 95 % CI 0.62-1.07), or colorectal (adjusted HR 0.88, 95 % CI 0.77-1.01) cancer patients. Dose-response analyses did not reveal consistent evidence of reductions in users of warfarin defined by the number of prescriptions used and daily defined doses.. There was little evidence of associations between pre-diagnostic use of warfarin and cancer-specific mortality in lung, prostate, breast, or colorectal cancer patients.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Anticoagulants; Breast Neoplasms; Cohort Studies; Colorectal Neoplasms; Databases, Factual; Female; Humans; Incidence; Lung Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Proportional Hazards Models; Prostatic Neoplasms; Warfarin

We used the prothrombin time international normalized ratio(PT-INR)to investigate the change in degree and term of warfarin following co-administration and after discontinuation of capecitabine. In this study, approximately 3 years of medical records of 7 patients receiving co-administration therapy of warfarin and capecitabine were obtained from 4 hospitals. We observed daily increases in PT-INR values up to peak PT-INR levels following co-administration of warfarin and capecitabine. Interestingly, the peak PT-INR values of 4 of the patients remained remarkably high despite discontinuation of capecitabine. The peak PT-INR values for concomitant warfarin and capecitabine were attained after an average of 31.3 days of usage. When compared with the average PT-INR values attained before co-administration, the PT-INR values following co-administration significantly increased by 3 times (p<0.05). After discontinuation of capecitabine for an average of 15.1 days, i. e., for approximately 14 days, the PT-INR values returned to the PT-INR values attained prior to co-administration. These results suggest that capecitabine has influence on the anticoagulant effect of warfarin during not only the co-administered term but also the discontinuation term, and that this influence occasionally continues after discontinuation of capecitabine. These findings also suggest that a period of approximately 14 days after discontinuation is necessary for the interaction of capecitabine to dissipate and the PT-INR values to return the levels attained before receiving concomitant warfarin and capecitabine.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Capecitabine; Colorectal Neoplasms; Deoxycytidine; Female; Fluorouracil; Humans; Male; Retrospective Studies; Treatment Outcome; Warfarin

The association between breast cancer and warfarin is inconclusive as most previous studies examined their association using patients with thromboembolism, whereas thromboembolism itself is a risk factor for cancer. We explored this issue using patients received mechanical heart valves replacement as a proxy for warfarin exposure as these patients need a lifelong warfarin treatment, and compared them with patients received bioprosthesis valves replacement (short-term warfarin treatment) in Sweden between 1987 and 2010. Patients who were operated on for valve replacement were identified from the Swedish Hospital Discharge Registry and linked to the Swedish Cancer Registry to examine the hazard ratios of subsequent breast cancer. A total of 12,242 women were operated on for valve replacement (5481 with mechanical valve and 6401 with bioprosthetic valve). For the entire cohort, the HR of breast cancer was 1.49 (95 % CI 1.09-2.02) among patients with mechanical valve replacement compared to those with bioprosthetic valve replacement. After controlling for a number of confounding factors using propensity score weighting, the HR was 1.69 (95 % CI 1.15-2.47). Our study found that patients with mechanical valve replacement have an increased risk of breast cancer compared to those with bioprosthetic valve replacement. If confirmed, this increased risk should be considered when recommending breast cancer screening for women with mechanical valve replacement. Long-term use of warfarin may explain the observed increase. If so, patients who have used warfarin long-term for other reasons should be studied for a possible increased risk of breast cancer.

Topics: Aged; Aged, 80 and over; Bioprosthesis; Breast Neoplasms; Female; Follow-Up Studies; Heart Valve Prosthesis; Humans; Middle Aged; Population Surveillance; Registries; Risk; Sweden; Warfarin

Metronidazole (MTZ) ointment has been used widely as a hospital preparation against cancerous malodor. Although cancerous tissue with ulcer-like symptoms is likely to have a higher capacity to absorb drugs than normal skin, the extent to which MTZ is absorbed when a topical preparation is applied to cancerous tissue remains unclear. Furthermore, few studies have investigated the drug interactions involving MTZ despite its long use in clinical practice. In the present study, plasma concentration of MTZ was measured in a breast cancer patient using MTZ ointment for cancerous malodor and basic research was also conducted with the objective of investigating the safety of topical MTZ from a pharmacokinetic perspective. 4.75 µg/mL (27.8 µM) of MTZ was detected in the patient's plasma, which was close to the plasma concentration after oral dosage of MTZ. In a metabolic inhibition study using human liver microsomes, cytochrome P450 (CYP) 2C9-mediated hydroxylation of S-warfarin was almost unaffected by MTZ at the corresponding concentrations. In addition, 3-d repeated oral administration of MTZ (200 mg/kg/d) to rats did not show any significant effects on the hepatic mRNA levels of various CYP isozymes and CYP2C protein levels. These results suggest that the reported interaction of oral MTZ and S-warfarin was not due to CYP2C9 inhibition and that drug interactions via inhibition of CYP2C9 is unlikely to occur when MTZ ointment is applied to ulcerous skin. This information should be valuable for assessing the safety of MTZ ointment used for mitigating cancerous malodor.

Topics: Administration, Topical; Animals; Anti-Infective Agents; Anticoagulants; Breast Neoplasms; Carcinoma, Ductal, Breast; Cytochrome P-450 Enzyme System; Drug Interactions; Female; Humans; Liver; Male; Metronidazole; Microsomes, Liver; Middle Aged; Odorants; Ointments; Rats; Rats, Sprague-Dawley; RNA, Messenger; Warfarin

Report descriptive outcome measures related to the quality of pharmacist-managed anticoagulation care with warfarin in patients with breast cancer since the formation of the anticoagulation management service (AMS).. Retrospective review of 145 patients with breast cancer (median age 54 years) receiving warfarin therapy for venous thromboembolism (VTE) managed by the pharmacist-run AMS between 1998 and 2005.. The median time followed by the AMS was 151 days. Fifty three percent (n = 1651) of total lab draws (n = 3129) were within the target therapeutic INR range 2-3. Recurrent thrombosis occurred in 4.1% of patients. Minor bleeding occurred in 18.6% of patients and major bleeding occurred in three patients (2.1%, gastrointestinal, intra-abdominal, and subdural hematoma).. To date, this is the largest known published database of cancer patients receiving anticoagulation in a pharmacist-managed anticoagulation service. Recurrent VTE rates, major and minor bleeding rates, and percentage of time spent within the therapeutic range are slightly different in our patient population compared to an oncology population receiving warfarin and a non-oncology population with warfarin managed by AMS. Oral anticoagulation with warfarin is an effective, albeit complicated, treatment for venous thromboembolism in the oncology population. Although low-molecular weight heparin (LMWH) therapy is now the preferred treatment for thrombosis in malignancy, warfarin is still relevant in patients who are unable to receive treatment with LMWH. This report provides valuable information supporting coordinated anticoagulation therapy with a pharmacist-managed service in a breast cancer-specific population, and contributes to the growing data supporting the challenging nature of maintaining warfarin anticoagulation in patients with cancer.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Anticoagulants; Breast Neoplasms; Databases, Factual; Female; Hemorrhage; Humans; Middle Aged; Pharmacists; Pharmacy Service, Hospital; Professional Role; Recurrence; Retrospective Studies; Treatment Outcome; Venous Thromboembolism; Warfarin

Topics: Breast Neoplasms; Delivery of Health Care; Female; Genomics; Humans; Life Style; Patient-Centered Care; Pharmacogenetics; Physician-Patient Relations; Precision Medicine; Warfarin

The Institute for Pharmacogenomics and Individualized Therapy (IPIT) at the University of North Carolina at Chapel Hill (NC, USA) is a collaborative, multidisciplinary unit that brings together faculty from different disciplines and crosses the traditional departmental/school structure to perform pharmacogenomics research. IPIT investigators work together towards the goal of developing therapies to enable the delivery of individualized medical care. The NIH-supported Comprehensive Research on Expressed Alleles in Therapeutic Evaluation (CREATE) group leads the field in the evaluation of pathways regulating drug activity, and also provides a foundation for future IPIT research. IPIT members perform bench research, clinical cohort analysis and prospective clinical intervention studies, research on the integration of pharmacogenomic therapy into practice and research to foster global health pharmacogenomics application through the Pharmacogenetics for Every Nation Initiative. IPIT Investigators are actively incorporating a pharmacogenomics curriculum into existing teaching programs at all levels.

Topics: Academies and Institutes; Biomedical Research; Breast Neoplasms; Female; Genotype; Humans; Molecular Biology; North Carolina; Pharmacogenetics; Precision Medicine; Randomized Controlled Trials as Topic; RNA, Small Interfering; Tamoxifen; Warfarin

To report on possible adverse interaction between capecitabine and warfarin in a patient with cancer, who developed subconjunctival and nose bleeding during treatment with these drugs and review of the previously reported five cases in the literature.. In the second week of capecitabine treatment the patient was hospitalized owing to subconjunctival hemorrhage and nose bleeding. Her international normalized ratio (INR) level was found to have increased, and both drugs were discontinued. Fresh frozen plasma replacement was administered. Warfarin and capecitabine treatment were restarted again but the warfarin dose was decreased. The patients INR was kept between 2.5-3 with the reduced dose of warfarin.. Capecitabine is an orally active prodrug of fluorouracil (FU) and is extensively used as an antineoplastic agent. It is converted to 5-FU in the liver and tumor tissues. Warfarin is an antithrombolytic agent and is metabolized by liver cytochorom P450 (CYP) isoenzymes in liver. Preclinical in vitro studies using human liver microsomes report no inhibitory effects between capecitabine and substrates of CYP. However, the concomitant administration of capecitabine and warfarin resulted in gastrointestinal, retroperitoneal bleeding and hemorrhagic blisters in the five cases previously reported. The exact mechanism of this interaction is unknown; however, a significant pharmacokinetic interaction between capecitabine and S-warfarin resulting in exaggerated anticoagulant activity has recently been demonstrated. Here, we describe another case and use of the Naranjo adverse drug reaction (ADR) probability scale, which indicated a probable relationship between subconjunctival bleeding and epistaxis in this patient after concomitant warfarin and capecitabine use.. Capecitabine is extensively used in outpatient clinics, and physicians should be aware of ADRs arising from combined used of capecitabine and warfarin. In the light of the current data, INR levels should be closely monitored in patients using this medication regimen.

Topics: Aged; Anticoagulants; Antimetabolites, Antineoplastic; Breast Neoplasms; Capecitabine; Deoxycytidine; Dose-Response Relationship, Drug; Drug Interactions; Female; Fluorouracil; Hemorrhage; Humans; International Normalized Ratio; Neoplasm Recurrence, Local; Plasma; Warfarin

Capecitabine can interact with warfarin, resulting in altered coagulation parameters and bleeding. Four cases have been reported. We describe a fifth case with life-threatening interaction between these two drugs. A 67-year-old female with metastatic breast cancer developed hemorrhagic blisters, purpura and ecchymoses. She had been well controlled on long-term warfarin (5 mg/day). Capecitabine was initiated 4.5 weeks prior to the bleeding episode. Laboratory work-up revealed an international normalized ratio of 8.56, partial prothrombin time of 61 seconds and prothrombin time of 5.2%. The coagulation parameters gradually normalized within 4 days following vitamin K administration and discontinuation of capecitabine and warfarin. Careful monitoring of coagulation parameters and proper adjustment of the warfarin dose are required in patients taking warfarin and capecitabine concomitantly.

Topics: Aged; Anticoagulants; Antimetabolites, Antineoplastic; Breast Neoplasms; Capecitabine; Deoxycytidine; Drug Interactions; Female; Fluorouracil; Hemorrhage; Humans; Warfarin

One of the standard treatments for cancer-associated thrombosis has been initial therapy with unfractionated heparin (UFH) followed by long-term therapy with an oral anticoagulant (i.e., warfarin). However, characteristics associated with these two agents may make them suboptimal for many cancer patients. This article will explore some of the considerations and limitations when using UFH and warfarin in the cancer population and will also utilize case studies to emphasize the importance of individualized care.. UFH is an effective anticoagulant when doses are adjusted to maintain the activated partial thromboplastin time (aPTT) within a specified therapeutic range. However, due to the complex pharmacokinetics of this agent, patients must undergo frequent monitoring to maintain a therapeutic aPTT. In addition, UFH can be associated with serious adverse events including osteoporosis, heparin-induced thrombocytopenia, and bleeding. Similar to UFH, warfarin requires frequent monitoring and dose adjustments to maintain the International Normalized Ratio (INR) within the therapeutic range of 2.0 to 3.0. Warfarin also has numerous drug-herbal, drug-food, and drug-drug interactions, including interactions with many commonly used anti-tumor therapies. Complications related to UFH and warfarin in the treatment of cancer-associated thrombosis have gradually been minimized with the increased use of low molecular weight heparins (LMWHs), which are associated with reduced incidence of bleeding, heparin-induced thrombocytopenia, and drug interactions. In addition, LMWHs allow for convenient daily dosing without requiring routine monitoring and the option of home therapy.. When deciding on the optimal anticoagulant strategy, pharmacists must take into account the unique characteristics and needs of each individual patient as well as the specifics of the various anticoagulant therapies. Future strategies for the initial and long-term treatment of cancer-associated thrombosis may increasingly incorporate LMWHs because of factors related to safety and convenience.

Topics: Anticoagulants; Bone Neoplasms; Breast Neoplasms; Carcinoma, Non-Small-Cell Lung; Fatigue; Female; Heparin; Heparin, Low-Molecular-Weight; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasms; Thrombosis; Warfarin

Topics: Aged; Anticoagulants; Antineoplastic Agents; Aromatase Inhibitors; Breast Neoplasms; Contraindications; Enzyme Inhibitors; Female; Humans; Letrozole; Nitriles; Pulmonary Embolism; Risk; Tamoxifen; Triazoles; Venous Thrombosis; Warfarin

Topics: Anticoagulants; Breast Neoplasms; Heart Valve Prosthesis; Humans; Prosthesis Failure; Radiodermatitis; Stroke; Warfarin

In a pilot study of continuous infusion 5-fluorouracil and intermittent bolus doxorubicin and cyclophosphamide in women with breast cancer, four of 24 patients developed symptomatic superior vena cava or innominate vein thrombosis associated with the Hickman line, despite prophylactic treatment with very low dose warfarin (1-3 mg/day). In all four patients, local thrombolysis with streptokinase was successful and chemotherapy was continued through the Hickman line under anticoagulant cover, maintaining an international normalized ratio of 2.0-3.0. No patient developed recurrent thrombosis. Prophylactic anticoagulation should be considered in patients receiving continuous infusion chemotherapy through Hickman lines, as they are at risk of proximal vein thrombosis. A randomized study is needed to address the question of the optimum anticoagulant regimen to prevent such thromboses.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cyclophosphamide; Doxorubicin; Female; Fluorouracil; Humans; Infusions, Intravenous; Middle Aged; Pilot Projects; Thrombosis; Vena Cava, Superior; Warfarin

Aminoglutethimide is an aromatase inhibitor that is successfully used for endocrine treatment of advanced breast cancer. This drug also stimulates the activity of hepatic mixed-function oxidases, increasing the metabolism of several drugs, including warfarin, digitoxin, antipyrine and theophylline. It also increases the plasma clearance rate of oestrone sulphate. As this oestrogen may be an important substrate for tumour cells, stimulation of oestrone sulphate metabolism may be a component of the mechanism of action of aminoglutethimide.

Topics: Aminoglutethimide; Antipyrine; Aromatase Inhibitors; Breast Neoplasms; Digitoxin; Drug Interactions; Estrogens; Humans; Theophylline; Warfarin

Topics: Breast Neoplasms; Echocardiography; Female; Heart Atria; Heart Diseases; Humans; Middle Aged; Thrombosis; Warfarin

The influence of two progestins, medroxyprogesterone acetate (MPA) and megestrol acetate (MA), given orally in high doses, on the pharmacokinetics of antipyrine, digitoxin, and warfarin were studied in patients with advanced breast cancer. Antipyrine and warfarin were given as a single test dose before and after 5 weeks of progestin treatment. The pharmacokinetics of digitoxin was investigated at steady state in patients receiving this drug therapeutically before and during treatment with progestins. Small changes in clearance rates for antipyrine, warfarin, and digitoxin were found. A minor decrease observed in warfarin clearance however may be of clinical importance. Half-lives decreased by 13% for antipyrine and increased by 71% for warfarin. High-dose progestins given orally do not seem to have a major influence on drug metabolism, probably reflecting a minor effect on drug and steroid-metabolizing microsomal mono-oxygenases in the liver.

Topics: Administration, Oral; Aged; Aged, 80 and over; Antipyrine; Breast Neoplasms; Digitoxin; Female; Humans; Kinetics; Male; Medroxyprogesterone; Medroxyprogesterone Acetate; Megestrol; Megestrol Acetate; Middle Aged; Progesterone Congeners; Warfarin

The pharmacokinetics of the optical enantiomers of warfarin (R-warfarin and S-warfarin) were investigated in patients treated for breast cancer with aminoglutethimide (AG). The patients received 125 mg AG b.i.d. (i.e., low-dosage regimen); 250 mg AG q.i.d. together with cortisone acetate (i.e. high-dosage regimen); or an escalating dose schedule was followed (i.e. low-dosage regimen followed by high-dosage regimen). The pharmacokinetics for R-warfarin and S-warfarin were determined before initiation of AG treatment and again after 2, 4, or 8 weeks of continuous AG treatment. The plasma clearance for both enantiomers showed a moderate increase (mean 41.2%) in patients receiving the low AG dose, whereas in patients treated according to the high-dosage regimen a marked increase (mean 90.8%) was observed. There was a corresponding reduction in warfarin half-life, and no alteration in distribution volume. These effects on the warfarin pharmacokinetics appeared after 14 days of AG treatment, and after this time point there was no further increase in warfarin clearance. Notably, the effect of AG on warfarin kinetics was the same for both enantiomeric forms of warfarin. These data show that there is a dose-response relationship between AG dose and induction of warfarin metabolism.

Topics: Administration, Oral; Aminoglutethimide; Breast Neoplasms; Dose-Response Relationship, Drug; Female; Humans; Metabolic Clearance Rate; Stereoisomerism; Tissue Distribution; Warfarin

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Female; Femoral Vein; Humans; Male; Middle Aged; Prothrombin Time; Thrombosis; Warfarin

A case of ovarian carcinoma with bilateral metastases to the breasts is presented. This is the first report of simultaneous involvement of both breasts presenting as an inflammatory tumor. Axillary lymph node enlargement preceded breast involvement. The related literature is reviewed briefly, and the unpredictable invasiveness of malignant neoplasms is emphasized.

Topics: Adenocarcinoma, Papillary; Breast Diseases; Breast Neoplasms; Diagnosis, Differential; Female; Humans; Middle Aged; Necrosis; Ovarian Neoplasms; Warfarin

Analysis of 182 patients with chronic disseminated intravascular coagulopathy and malignancy shows common features. Migratory thrombophlebitis occurred in 96 patients while at least a single episode of thrombophlebitis was noted in 113. Seventy-five of the patients bled and 45 had arterial emboli in various organs. Twelve patients had the triad of thrombophlebitis, hemorrhage, and arterial emboli, often sequentially. Hematologic data showed derangements associated with intravascular coagulation, the most prominent of which were hypofibrinogenemia and thrombocytopenia. Other abnormalities included prolonged prothrombin time, increased fibrinogen-fibrin degradation products, decreased levels of factors V and VIII, cryofibrinogenemia, and microangiopathic hemolytic anemia. Forty-one patients had lesions of non-bacterial thrombotic endocarditis at autopsy; 31 of these had arterial emboli during life. None of the lesions were infected. Mitral and aortic valves were most frequently involved. No single mechanism that causes the disseminated intravascular coagulopathy has been identified. However, cell products--secretions and enzymes--and the cells themselves have been proposed as the procoagulant(s) responsible for the syndrome. In addition to treatment of the underlying neoplasm, symptomatic disseminated intravascular coagulopathy should be controlled. Heparin is the drug of choice for treatment of this problem, very little benefit having been observed with warfarin therapy. Long-term use of anticoagulants is potentially feasible for control of chronic disseminated intravascular coagulopathy, but without effective control of the underlying tumor ultimately will be unsuccessful.

Topics: Adult; Aged; Blood Cell Count; Blood Coagulation Factors; Blood Platelets; Brain Neoplasms; Breast Neoplasms; Chronic Disease; Disseminated Intravascular Coagulation; Female; Heparin; Humans; Kidney Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Neoplasms; Prostatic Neoplasms; Prothrombin Time; Pulmonary Embolism; Solitary Pulmonary Nodule; Thrombophlebitis; Warfarin