Kan Yonemori

64Cu-DOTA-Trastuzumab PET Imaging in Patients with HER2-Positive Breast Cancer

The purpose of this study was to determine the safety, distribution, internal dosimetry, and initial human epidermal growth factor receptor 2 (HER2)–positive tumor images of 64Cu-DOTA-trastuzumab in humans. Methods: PET was performed on 6 patients with primary or metastatic HER2-positive breast cancer at 1, 24, and 48 h after injection of approximately 130 MBq of the probe 64Cu-DOTA-trastuzumab. Radioactivity data were collected from the blood, urine, and normal-tissue samples of these 6 patients, and the multiorgan biodistribution and internal dosimetry of the probe were evaluated. Safety data were collected for all the patients after the administration of 64Cu-DOTA-trastuzumab and during the 1-wk follow-up period. Results: According to our results, the best timing for the assessment of 64Cu-DOTA-trastuzumab uptake by the tumor was 48 h after injection. Radiation exposure during 64Cu-DOTA-trastuzumab PET was equivalent to that during conventional 18F-FDG PET. The radioactivity in the blood was high, but uptake of 64Cu-DOTA-trastuzumab in normal tissues was low. In 2 patients, 64Cu-DOTA-trastuzumab PET showed brain metastases, indicative of blood–brain barrier disruptions. In 3 patients, 64Cu-DOTA-trastuzumab PET imaging also revealed primary breast tumors at the lesion sites initially identified by CT. Conclusion: The findings of this study indicated that 64Cu-DOTA-trastuzumab PET is feasible for the identification of HER2-positive lesions in patients with primary and metastatic breast cancer. The dosimetry and pharmacologic safety results were acceptable at the dose required for adequate PET imaging.

FcγR2A and 3A polymorphisms predict clinical outcome of trastuzumab in both neoadjuvant and metastatic settings in patients with HER2-positive breast cancer

BACKGROUND Antibody-dependent-mediated cytotoxicity (ADCC) is one of the modes of action for trastuzumab. Recent data have suggested that fragment C γ receptor (FcγR) polymorphisms have an effect on ADCC. This prospective phase II trial aimed to evaluate whether these polymorphisms are associated with clinical efficacies in patients who received trastuzumab. PATIENTS AND METHODS Patients in a neoadjuvant (N) setting received Adriamycin and cyclophosphamide followed by weekly paclitaxel/trastuzumab. Patients in a metastatic (M) setting received single trastuzumab until progression. In total, 384 distinct single nucleotide polymorphisms of different FcγR, HER2, and fucosyltransferase loci were assessed. RESULTS Fifteen operable and 35 metastatic HER2-positive breast cancer patients were enrolled in each of the N and M settings, respectively. The FcγR2A-131 H/H genotype was significantly correlated with the pathologically documented response (pathological response) (P = 0.015) and the objective response (P = 0.043). The FcγR3A-158 V/V genotype was not correlated with the pathological response, but exhibited a tendency to be correlated with the objective response. Patients with the FcγR2A-131 H/H genotype had significantly longer progression-free survival in the M setting (P = 0.034). CONCLUSION The FcγR2A-131 H/H polymorphism predicted the pathological response to trastuzumab-based neoadjuvant chemotherapy in early-stage breast cancer, and the objective response to trastuzumab in metastatic breast cancer.

Severe drug toxicity associated with a single-nucleotide polymorphism of the cytidine deaminase gene in a Japanese cancer patient treated with gemcitabine plus cisplatin.

Purpose: We investigated single-nucleotide polymorphisms of the cytidine deaminase gene (CDA), which encodes an enzyme that metabolizes gemcitabine, to clarify the relationship between the single-nucleotide polymorphism 208G>A and the pharmacokinetics and toxicity of gemcitabine in cancer patients treated with gemcitabine plus cisplatin. Experimental Design: Six Japanese cancer patients treated with gemcitabine plus cisplatin were examined. Plasma gemcitabine and its metabolite 2′,2′-difluorodeoxyuridine were measured using an high-performance liquid chromatography method, and the CDA genotypes were determined with DNA sequencing. Results: One patient, a 45-year-old man with pancreatic carcinoma, showed severe hematologic and nonhematologic toxicities during the first course of chemotherapy with gemcitabine and cisplatin. The area under the concentration-time curve value of gemcitabine in this patient (54.54 μg hour/mL) was five times higher than the average value for five other patients (10.88 μg hour/mL) treated with gemcitabine plus cisplatin. The area under the concentration-time curve of 2′,2′-difluorodeoxyuridine in this patient (41.58 μg hour/mL) was less than the half of the average value of the five patients (106.13 μg hour/mL). This patient was found to be homozygous for 208A (Thr70) in the CDA gene, whereas the other patients were homozygous for 208G (Ala70). Conclusion: Homozygous 208G>A alteration in CDA might have caused the severe drug toxicity experienced by a Japanese cancer patient treated with gemcitabine plus cisplatin.

Efficacy of everolimus, a novel mTOR inhibitor, against basal-like triple-negative breast cancer cells.

Patients with triple‐negative breast cancers (TNBCs) typically have a poor prognosis because such cancers have no effective therapeutic targets, such as estrogen receptors for endocrine therapy or human epidermal growth factor receptor 2 (HER2) receptors for anti‐HER2 therapy. As the phosphatidylinositol 3′ kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) cascade is activated in TNBCs, mTOR is a potential molecular target for anticancer therapy. In this study, we investigated the antitumor activities of everolimus, an oral mTOR inhibitor, in nine TNBC cell lines. Everolimus effectively inhibited cell growth at concentrations under 100 nM (IC50) in five cell lines and even in the 1‐nM range in three of the five cell lines. To identify specific characteristics that could be used as predictive markers of efficacy, we evaluated the expressions of proteins in the mTOR cascade, basal markers, and cancer stem cell markers using western blotting, fluorescent in situ hybridization (FISH), or immunohistochemistry. All five of the sensitive cell lines were categorized as a basal‐like subtype positive for either epidermal growth factor receptor (EGFR) or CK5/6, although resistant cell lines were not of this subtype and tended to exhibit the characteristics of cancer stem cells, with decreased E‐cadherin and the increased expression of Snail or Twist. In vivo assays demonstrated antitumor activity in a mouse xenograft model of basal‐like breast cancer, rather than non‐basal breast cancer. These results suggest that everolimus has favorable activity against basal‐like subtypes of TNBCs. Epidermal growth factor receptor and CK5/6 are positive predictive markers of the TNBC response to everolimus, while cancer stem cell markers are negative predictive markers.

Disruption of the blood brain barrier by brain metastases of triple‐negative and basal‐type breast cancer but not HER2/neu‐positive breast cancer

Generally, the blood‐brain barrier (BBB) of brain metastasis was thought to be disrupted.

Feasibility and usefulness of the ‘Distress Screening Program in Ambulatory Care’ in clinical oncology practice†

Objective: Although the implementation of routine screening for distress is desirable, doing so is difficult in todays busy clinical oncology practice. We developed the ‘Distress Screening Program in Ambulatory Care’ (DISPAC program) as a practical means of screening for and facilitating the treatment of major depression and adjustment disorders in cancer patients. This study assessed the feasibility and usefulness of the DISPAC program in actual clinical situations.

Phase 1 trial of denosumab safety, pharmacokinetics, and pharmacodynamics in Japanese women with breast cancer-related bone metastases

Denosumab, a fully human monoclonal antibody to receptor activator of nuclear factor–kappa B ligand (RANKL), suppresses bone resorption. This open‐label, multicenter, phase 1 study evaluated the safety, pharmacodynamics, and pharmacokinetics of denosumab in Japanese women with breast cancer–related bone metastases. Patients (n = 18; median age, 57 years) received a single subcutaneous injection of denosumab 60 mg or 180 mg or three doses of denosumab 180 mg on days 1, 29, and 57 (every 4 weeks) and were followed for ≥ 141 days. No major safety concerns related to denosumab were noted in any cohort. All patients experienced at least 1 adverse event (AE); most were mild (grade ≤ 2). One patient reported grade 4 myositis and grade 3 anemia, malaise, and dysphagia that the investigator deemed treatment‐related; other treatment‐related AE were grade ≤ 2. No antidenosumab antibodies or clinically significant changes in laboratory findings, vital signs, or electrocardiograms were observed. Pharmacokinetics were approximately dose‐linear. Denosumab caused rapid, substantial, and sustained suppression of urinary N‐telopeptide corrected for creatinine (uNTx/Cr) across all doses; at day 85, the median change from baseline uNTx/Cr ranged from –61.9% to –90.8%. No dose‐limiting toxicity was observed at any dosage. Coupled with pharmacokinetic and pharmacodynamic data, these results were consistent with those observed in non‐Japanese populations. (Cancer Sci 2008; 99: 1237–1242)

Brain metastases in patients who receive trastuzumab-containing chemotherapy for HER2-overexpressing metastatic breast cancer

BackgroundRecently, a high rate of brain metastases has been reported among patients with human epidermal growth factor receptor (HER2)-overexpressing metastatic breast cancer who were treated with trastuzumab. The present study examined risk factors for the development of brain metastasis in patients with HER2-overexpressing breast cancer who were treated with trastuzumab.MethodsWe retrospectively reviewed 204 patients with HER-2-overexpressing breast cancer who were treated with a trastuzumab-containing regimen between 1999 and 2006. Patients with clinical symptoms were diagnosed as having brain metastases when brain magnetic resonance imaging (MRI) or a computed tomography (CT) scan revealed positive findings for brain metastases. The median follow-up time of this cohort was 53.6 months.ResultsAmong the patients who received a trastuzumabcontaining regimen, 74 patients (36.3%) developed brain metastases. The median survival from the diagnosis of brain metastases was 13.5 months (95% confidence interval [CI], 12.2–14.7 months). The median time interval between the beginning of trastuzumab treatment and the diagnosis of brain metastases was 13.6 months (range, 0.0–45.8 months). Among patients with brain metastases, the median overall survival period was 39 months. A multivariate logistic regression analysis showed that age (≤50 years), recurrent breast cancer, and liver metastases were significant risk factors for the development of brain metastases.ConclusionPatients with HER2-overexpressing breast cancer treated with trastuzumab had a high incidence of brain metastases (36.3%). Routine screening for brain metastases 1 year after the start of trastuzumab treatment, may be warranted in younger patients (≤50 years) who had recurrent breast cancer with liver metastases.

Development and validation of diagnostic prediction model for solitary pulmonary nodules

Background and objective:  The aim of this study was to develop a simple prediction model for the underlying diagnosis of solitary pulmonary nodules (SPN) based on clinical characteristics and thin‐section CT findings.

Efficacy of weekly paclitaxel in patients with docetaxel-resistant metastatic breast cancer.

SummaryBackground. Partial cross-resistance to paclitaxel and docetaxel has been demonstrated in pre-clinical studies. Patients and methods. We retrospectively evaluated the efficacy of weekly paclitaxel 80 mg/m2 in 82 patients with docetaxel-resisitant metastatic breast cancer. Docetaxel resistance was classified into primary resistance, defined as progressive disease while receiving docetaxel, and secondary resistance, defined as progression after achievement of a documented clinical response to docetaxel. Secondary resistance was subclassified according to the interval between the final infusion of docetaxel and the start of weekly paclitaxel into: (1) short interval, ≦120 days, and (2) long interval, >120 days. Results. The response rate of the 82 patients was 19.5% (95% confidence interval, 10.8–27.9%). The response rate according to the docetaxel resistance category was: primary resistance (n=24), 8.3%; secondary resistance (n=58), 24.1% (short interval [n=39], 17.9%, and long interval, [n=19], 36.8%). The differences in response rates among the three categories were statistically significant (p=0.0247, Cochran–Mantel–Haenszel test). The interval between from the final docetaxel infusion and disease progression were predictors for response of weekly paclitaxel. Conclusion. Weekly paclitaxel is modestly effective and safe in docetaxel-resistant metastatic breast cancer patients. However, weekly paclitaxel should not be recommended for primary resistance patients with docetaxel.