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Background Epirubicin is metabolized by uridine glucuronosyltransferase 2B7 (UGT2B7). Patients homozygous for the minor allele (CC) in the UGT2B7 -161 promoter polymorphism have lower clearance and significantly higher rates of leukopenia compared to wild-type homozygote (TT) or heterozygote (CT) patients. This study was designed to determine if TT and CT genotype patients could tolerate a higher epirubicin dose compared to CC genotype patients. Patients and Methods We studied women with histologically confirmed non-metastatic, invasive breast cancer who were scheduled to receive at least three cycles of FE100C in the (neo)adjuvant setting. Patients received standard-dose FE100C during the first 21-day cycle. Based on genotype, the epirubicin dose was escalated in the second and third cycles to 115 and 130 mg/m2 or to 120 and 140 mg/m2 for CT and TT genotype patients, respectively. The main outcome measurements were myelosuppression and dose-limiting toxicity. These were analyzed for relationships with the three genotypes. Results Forty-five patients were enrolled (10 CC, 21 CT, and 14 TT genotypes) and received 100 mg/m2 of epirubicin in the first cycle. Twelve and 10 TT patients were dose escalated at the second and third cycles, respectively; 16 CT patients were dose escalated at the second and third cycles. Leukopenia, but not febrile neutropenia, was genotype and dose dependent and increased in patients with CT and TT genotypes as their dose was increased. However, the third-cycle leukopenia rates were comparable to patients with the CC genotype receiving standard-dose epirubicin. Conclusion Pharmacogenetically guided epirubicin dosing is well tolerated and allowed dose escalation without increased toxicity.

Background Current clinical guidelines recommend mammography as the only imaging method for surveillance in asymptomatic survivors of early breast cancer (EBC). However, non-recommended tests are commonly used. We estimated the imaging radiation-induced malignancies (IRIM) risks in survivors of EBC undergoing different imaging surveillance models. Materials and Methods We built 5 theoretical models of imaging surveillance, from annual mammography only (model 1) to increasingly imaging-intensive approaches, including computed tomography (CT) scan, positron emission tomography-CT, bone scan, and multigated acquisition scan (models 2 through 5). Using the National Cancer Institute’s Radiation Risk Assessment Tool, we compared the excess lifetime attributable cancer risk (LAR) for hypothetical survivors of EBC starting surveillance at the ages of 30, 60, or 75 years and ending at 81 years. Results For all age groups analyzed, there is a statistically significant increase in LAR when comparing model 1 with more intensive models. As an example, in a patient beginning surveillance at the age of 60 years, there is a 28.5-fold increase in the IRIM risk when comparing mammography only versus a schedule with mammography plus CT scan of chest-abdomen and bone scan. We found no differences when comparing models 2 through 5. LAR is higher when surveillance starts at a younger age, although the age effect was only statistically significant in model 1. Conclusion Non-recommended imaging during EBC surveillance can be associated with a significant increase in LAR. In addition to the lack of survival benefit, additional tests may have significant IRIM risks and should be avoided.

Background Epirubicin is metabolized by uridine glucuronosyltransferase 2B7 (UGT2B7), an enzyme rich in single nucleotide polymorphisms (SNPs). We studied whether the −161 C > T germline SNP in UGT2B7 was related to epirubicin metabolism and whether differences exist in the toxicity and efficacy of epirubicin-based chemotherapy among patients who were TT homozygotes, CT heterozygotes, and CC homozygotes. Patients and Methods A total of 132 women with non–metastatic breast cancer receiving FEC (5-fluorouracil 500 mg/m 2 , epirubicin 100 mg/m 2 , cyclophosphamide 500 mg/m 2 ) were prospectively enrolled. Toxicity was assessed in cycle 1 using the National Cancer Institute Common Toxicity Criteria, version 2.0. Results The sequence at −161 was studied in 132 subjects; 37 were TT homozygotes, 63 were CT heterozygotes, 26 were CC homozygotes, and 6 could not be genotyped. The CC genotype patients had decreased epirubicin clearance (median, 103.3 L/hr) compared with the CT/TT genotype patients (median, 134.0 L/hr; P = .002). The CC homozygous patients had an increased risk of grade 3 to 4 leukopenia compared with the TT homozygotes or heterozygotes ( P = .038 and P = .032, respectively). TT homozygotes or heterozygotes had an increased risk of early recurrence ( P = .039; χ 2 test). Conclusion The results of the present prospective pharmacogenetic study suggest that the UGT2B7 −161 C > T SNP correlate with drug metabolism, toxicity, and efficacy in patients receiving epirubicin chemotherapy. Further studies of this UGT2B7 SNP as a predictor of epirubicin toxicity and efficacy are warranted.

In this multinational, placebo-controlled, randomized phase III trial, Translational Research In Oncology (TRIO) will define the efficacy and safety of adding a novel antiangiogenic agent, IMC-1121B (ramucirumab), to standard first-line docetaxel chemotherapy for women with HER2-negative metastatic breast cancer. We will evaluate whether the addition of IMC-1121B prolongs progression-free survival and whether its use improves overall survival. Accrual is under way.

A 40-year-old woman, 6 years after mastectomy, lymph node dissection, and locoregional radiation, presented with hepatic metastases, pruritis, and jaundice. Physical examination revealed uniformly jaundiced skin and no arm lymphedema. Ultrasonography confirmed progressive hepatic metastases with no evidence of intrahepatic or extrahepatic biliary dilatation. Eight weeks after starting chemotherapy, her pruritis and jaundice were markedly improved, but the jaundice on the skin of her left arm was substantially slower to clear than the other skin areas. With further therapy, serum bilirubin normalized and her left arm jaundice completely resolved. We hypothesize that the delayed resolution of jaundice on her left arm resulted from impaired lymphatic drainage after left axillary lymph node dissection and irradiation, and conclude that lymphatic drainage might play a key role in the transport and clearance of bilirubin and related pigments from peripheral tissues.

The addition of capecitabine to docetaxel on a 3-week schedule resulted in superior response rate, increased time to progression (TTP), and improved overall survival in patients with anthracycline-pretreated metastatic breast cancer (MBC). Because the toxicity profile of weekly docetaxel differs from the standard 21-day docetaxel schedule, we performed a phase I/II trial to test the efficacy and safety of weekly docetaxel in combination with capecitabine given for 14 days every 21 days. The phase I study identified the doses of docetaxel (30 mg/m2 weekly) and capecitabine (900 mg/m2 twice daily on days 1-14 every 21 days) used in phase II. Twenty female patients with measurable or assessable MBC were enrolled. Eighteen patients had previously received anthracyclines; 2 had contraindications to anthracyclines. Patients remained on study for a maximum of eight 3-week cycles or until tumor progression or unacceptable toxicity occurred; response assessments were scheduled after cycle 2, 5, and 8. Seventeen patients were assessed after cycle 2; 3 subjects (18%) had a partial response (PR), 9 had stable disease (53%; SD), and 5 patients (29%) had progressive disease (PD). Ten patients were assessable after cycle 5. Two patients (20%) had a PR, 5 patients (50%) had SD, and 3 patients (30%) had PD. The most common grade 3 toxicities were nail loss (45%), asthenia (30%), and hand-foot syndrome (30%), and toxicities led to study discontinuation in 10 patients. The median time to treatment failure was 10 weeks and median TTP was 26 weeks. The median duration of response was 9 weeks and the median duration of SD was 16 weeks. The median overall survival was 82 weeks. This schedule of weekly docetaxel in combination with day 1-14 capecitabine has activity; however, toxicity discourages the use of this schedule in lieu of the standard docetaxel/capecitabine regimen.

HER2 overexpression is associated with poor breast cancer prognosis and is the target for the humanized monoclonal antibody trastuzumab. This novel agent, when administered until disease progression in combination with chemotherapy, extends the survival of women with HER2-positive metastatic breast cancer (MBC). However, the optimal duration of trastuzumab therapy remains to be confirmed. We conducted a retrospective case review study of women with HER2-positive MBC who continued to receive trastuzumab beyond disease progression. Objectives were to assess whether treatment beyond disease progression shows any evidence of efficacy and to evaluate the feasibility of this approach. One hundred five patients (median age, 47 years; range, 24–77 years) were identified in 13 centers. Women had received ≤ 6 chemotherapy regimens (median, 1) before trastuzumab therapy. Median survival from first trastuzumab dose was 29 months. The overall response rate to trastuzumab alone or with a taxane as the first regimen was 39%; a further 30% of patients had stable disease as the best response. These rates were 36% and 38% after a second regimen of trastuzumab alone or with paclitaxel or vinorelbine was administered. Some patients responded to both the first and second regimens; others responded to the second regimen after the first had failed. Twenty-two patients experienced cardiac events, of whom 18 received ≥ 1 more trastuzumab regimen. Trastuzumab treatment beyond progression appears to be of value, producing responses and clinical benefit, and is well tolerated without significant cardiac toxicity. The feasibility of this approach warrants examination in prospective trials.

This randomized, double-blind, phase III trial compared granulocyte colony-stimulating factor (G-CSF; filgrastim) and leridistim (formerly myelopoietin), a chimeric dual agonist that binds both G-CSF and interleukin-3 receptors, for the prevention of neutropenic complications in patients with breast cancer receiving TAC (docetaxel/doxorubicin/cyclophosphamide) chemotherapy. Patients with metastatic (44%) or localized breast cancer (56%) were randomized to G-CSF 5 microg/kg subcutaneously (s.c.) daily (n = 135), leridistim 5 microg/kg s.c. daily (n = 139), or leridistim 10 microg/kg s.c. every other day alternating with placebo (n = 139). Following administration of TAC (docetaxel 75 mg/m2, doxorubicin 50 mg/m2, cyclophosphamide 500 mg/m2) on day 1, patients received growth factor beginning on day 2 until the postnadir absolute neutrophil count exceeded 1500 cells/ microL. Chemotherapy cycles were repeated every 21 days. The incidence of febrile neutropenia was 7% in the G-CSF arm, 19% in the daily leridistim arm (P = 0.003 for comparison with G-CSF) and 22% in the alternate-day leridistim arm (P < 0.001 for comparison with G-CSF). There was no significant difference between treatment arms in the cumulative percentage of patients experiencing grade 4 neutropenia at some point during therapy (85%-88%). However, grade 4 neutropenia occurred in 53% of cycles in the G-CSF cohort, 61% of cycles in the daily leridistim group (P = 0.063 for comparison with G-CSF), and 63% of cycles in the alternate-day leridistim group (P = 0.015 for comparison with G-CSF). We conclude that G-CSF is superior to leridistim in the prevention of febrile neutropenia in patients with advanced breast cancer receiving TAC chemotherapy. The up-front prophylactic use of G-CSF is a reasonable supportive therapy for patients treated with docetaxel/anthracycline-based combination chemotherapy.

An increasing number of breast cancer patients are accessing the Internet for medical information. A survey was administered to breast cancer patients and their families attending follow-up outpatient clinics in a comprehensive cancer care center to explore their frequency of Internet use, their motivation for online activity, the type of information they sought, and the perceived impact of the information they found on the Internet on their medical care. The survey was conducted over a 4-month period. A total of 107 surveys were returned. Seventy-nine of these (74%) were from patients while 28 (26%) were from family members and friends. Thirty-four of the patient responses (43%) indicated that the patient had used the Internet to look for cancer-related information. Patients who had used the Internet to access cancer-related information were significantly younger (P = 0.007), better educated (P = 0.027), and less satisfied with the amount of treatment-related information given by caregivers than those patients who had not used the Internet to access cancer-related information (P = 0.032). The majority of patient Internet users desired more information on their cancer and its treatment (91%), looked up information that was presented to them by their clinicians (66%), researched other treatment options (63%), and obtained more information on "alternative treatments" (63%). Patient Internet users generally found the cancer-related information on the Internet to be useful, and the majority discussed Internet-derived information with their health care providers and perceived that clinicians listened to such information. However, 53% were undecided about the trustworthiness of the medical information obtained via the Internet. Internet nonusers commonly lacked Internet access (53%) or were unfamiliar with the Internet (33%), but few (13%) distrusted Internet-derived information. This exploratory study underscores the need for more research in this area, specifically with the aims of identifying and verifying factors that lead patients to use the Internet and the impact of their online activities on their medical care.