Phase II study of capecitabine and trastuzumab combination chemotherapy in patients with HER2 overexpressing metastatic breast cancers resistant to both anthracyclines and taxanes

To be eligible for the study, patients had to meet the following criteria: age greater than 20 years and less than 75 years; histologically proven breast cancer with HER2 overexpressing progressive metastatic disease; resistance to both anthracyclines and taxanes for metastatic and advanced disease as described in below, resistance definition section; at least one measurable tumor site (target lesion) with index lesions on physical examination, X-ray, ultrasound, or computed tomography scan; Eastern Cooperative Oncology Group (ECOG) performance status of 0–2; estimated life expectancy ≥3 months; reasonable bone marrow function (neutrophil count ≥ 1,500/μL, platelet count ≥ 100,000/μL, and hemoglobin levels ≥ 9 g/dL); adequate hepatic and renal function, including AST and ALT twice (in cases of liver metastasis, three times) the upper limit of normal, bilirubin 1.5 g/dL, alkaline phosphatase 2.5 times the upper limit of normal, serum creatine 1.2 mg/dL, and basal creatine clearance 50 mL/min; no evidence of cardiac dysfunction (LV ejection fraction > 50%). This capecitabine and trastuzumab combination regimen was eligible for patients in third line of therapy, resistant to both anthracyclines and taxanes. Hormonal therapy, in the neoadjuvant or adjuvant setting or for advanced disease, was permitted, but concomitant hormone therapy was not allowed. Moreover, prior trastuzumab was allowed. Brain or leptomeningeal involvement was not allowed. Written informed consent was obtained before registration. The HER2 status was assessed at study entry by immunohistochemistry (IHC) and/or fluorescence in situ hybridization (FISH). Patients with HER2-receptor overexpression at the 3+ level (Hercep Test; DakoCytomation, Capenteria, CA, USA) were immediately eligible for inclusion. A HER2 expression at the 2+ level required confirmation by the proof of a HER2 gene amplification by FISH. HER2 testing was performed on a sample of the primary tumor or a biopsy of a metastatic site. HER2 status was examined by the pathologists of each institution participated in this study. The FISH ratio was assessed as the number of genes proportional to the number of centromeres. The HER2 was considered amplified when the FISH signal ratio of HER2 was 2 and more. Exclusion criteria included pretreatment with capecitabine (Xeloda; Hoffman La, Rosche AG); hypersensitivity to trastuzumab (Herceptin; Hoffman-La Rosche AG, Basal, Switzerland), fluoropyrimidines, capecitabine, or any other substance of the drug preparation; known lack of dihydropyrimidine dehydrogenase; local resection or irradiation of the marker lesion after study entry; additional systemic antitumor therapy study; pregnancy or breastfeeding.

All data were managed and analyzed in a central data coordinating division located at the Foundation for Biological Research and Innovation, Translational Research Informatics Center, Kobe, Japan.

We used Ando’s definition [16] for reference to determine the primary resistance and secondary resistance to chemotherapeutic agents. All patients must not have received only anthracyclines, but also taxanes for metastatic disease. Primary resistance to anthracycline or taxane was defined as progressive disease during or within 6 months after completion of anthracycline or taxane, respectively. Patients without any documented tumor response to first-line chemotherapy that included anthracyclines or taxanes for metastatic disease also were classified as having primary resistance. Patients whose disease progressed more than 6 months after completion of anthracycline or taxane were treated as a first-line regimen for metastatic disease. Secondary resistance was defined as disease progression among 6–12 months after a documented clinical response to first-line chemotherapy with anthracyclines or taxanes for metastatic disease. Secondary resistance was further divided into three categories as follows: (a) absolute resistance: disease progression during treatment with regimens that contained anthracycline or taxane after a period after completion of the chemotherapy; (b) relative resistance: disease progression within 6 months after complete of the chemotherapy; and (c) sensitive regrowth: disease progression more than 12 months after completion of the chemotherapy.

Trastuzumab was administered at an initial dose of 4 mg/kg body weight and was administered subsequently at weekly doses of 2 mg/kg body weight during 90 min. Capecitabine was administered during 21 days with a subsequent pause of 7 days. The daily dose was 1,657 mg/m² administered in equal parts in the morning and in the evening. This cycle was repeated every 28 days for six cycles. Trastuzumab was discontinued while capecitabine was held. When capecitabine was withdrawn, a new treatment cycle was considered. Trastuzumab and capecitabine were administered until disease progression or unacceptable toxicity.

If capecitabine-associated toxicity occurred, dosage reduction and delayed were permitted.

A dose modification of trastuzumab was not allowed. Mild antiemetic drugs, such as metoclopramide and dexamethasone, and mild antidiarrheal drugs, such as loperamide hydrochloride were administered, if necessary. Trastuzumab was discontinued if patients developed congestive heart failure or the LVEF fell below 45%. The decision to discontinue trastuzumab at that point was discussed with the patient after the risks and potential benefits of trastuzumab therapy were assessed. Granulocyte colony-stimulating factor, to prevent febrile neutropenia was allowed, if grade ≥ 3 leukopenia occurred, and blood or platelet transfusion was allowed, if grade ≥ 3 anemia or thrombocytopenia occurred.

The pretreatment evaluation included medical history and physical examination, complete blood cell count, serum chemistries, liver function tests, ECG, echocardiography, tumor marker evaluation (CA15-3, CEA), hormone receptor status (ER, PgR, HER2), and staging studies appropriate to define the extent of metastatic disease, which included chest X-ray, abdominal ultrasound, brain, thoracic and/or abdominal computed tomography scan, and bone scan. Antitumor activity was evaluated every two cycles on all measurable lesions, and all patients were scheduled for at least a 2-week treatment to be eligible for assessment of tumor response. In patients with tumor response or stable disease, the treatment was planned to be continued for up to six cycles; thereafter, maintenance or no therapy was based on the clinician’s choice. After the completion of the treatment plan, the patients were monitored every two cycles. Clinical monitoring, complete blood cell count, serum chemistries, and liver function tests were performed every 2 weeks until six cycles, and thereafter every 12 weeks. Repeated multigated acquisition (MUGAs) or echocardiograms were performed after completion of cycle 2, 4, and 6, and thereafter every 12 weeks, if the medication is continued. Patients were evaluated for toxicity, graded according to the National Cancer Institute Common Toxicity Criteria version 2.0 [17].

Tumor response was evaluated according to the response evaluation criteria in solid tumors (RECIST) [18]. Progression-free survival was defined from the first day of treatment to the identification date of recurrence of cancer or death from any cause. Overall survival was dated from the first day of treatment until death or was censored on the date of the last follow-up appointment.

The primary endpoint of the study was the assessment of the overall survival. Secondary endpoints were the determination of the progression-free survival and response rate. In this trial, the targeted patients resistant to both anthracycline and taxane had highly dismal disease, whose 1 year survival was estimated <33% [16], thereby overall survival was chosen for the primary endpoint. The recent paper [19] reported that overall survival should be viewed as the endpoint of choice to assess the efficacy of new treatments in advanced breast cancer. The regimen would have been considered promising if the true 1-year survival were 50% or higher in conjunction with acceptable toxicity, and would be considered of no further interest if the true 1-year survival were 33% or lower. With 63 patients, the power of a two-sided 0.05-level test is 80%. However, the power was reduced to 62% because only 40 patients were enrolled in the study. Survival curves were estimated using the Kaplan–Meier method. To test the differences of the survival curves among subgroup of patients, the log-rank test was used. All statistical analyses were performed using the SAS version 9.1(SAS Institute, Inc, Cary, NC, USA). All tests were two-sided, and a P < 0.05 was considered statistically significant.