Response of meningeal carcinomatosis from breast cancer to capecitabine monotherapy: a case report.

A 62-year-old woman with breast cancer received neoadjuvant chemotherapy followed by breast-conserving surgery and sentinel node biopsy. During adjuvant endocrine therapy with aromatase inhibitor, she developed multiple bone metastases. Thereafter, she received tamoxifen and zoledronate therapy. In May 2011, she developed a tongue deviation and was diagnosed as having meningeal carcinomatosis. The tongue deviation disappeared 3 weeks after taking capecitabine (2,400 mg/day). Magnetic resonance imaging of the brain showed regression of meningeal carcinomatosis. Levels of tumor markers CEA and CA15-3 changed from 96.0 IU/ml and 3.5 ng/ml to 47.0 IU/ml and 1.5 ng/ml, respectively. Progression-free survival with capecitabine monotherapy was 5 months.

[The importance of p53 and ras mutation as predictive markers for adjuvant chemotherapy in non-small-cell lung cancer].

OBJECTIVE: A previous large, randomized, control trial(JBR.10)revealed that adjuvant chemotherapy with cisplatin(CDDP) and vinorelbine(VNR)was effective for non-small-cell lung cancer(NSCLC). It was also reported that adjuvant chemotherapy was not effective for p53-negative or K-ras mutation-positive patients. To clarify whether p53 and ras statuses are true predictive markers for chemotherapy with cisplatin, chemosensitivity was examined using an in vitro drug sensitivity assay. MATERIALS AND METHODS: Surgically resected fresh tumor specimens obtained from 27 patients at our institute with NSCLC were used for this study. Histoculture Drug Response Assay(HDRA)was applied to evaluate the chemosensitivity of CDDP and VNR in these specimens. p53 expression was evaluated by immunohistochemistry, and K-ras mutation by direct sequencing. RESULT: Four of the 27 patients were positive for K-ras mutation. The inhibition rate of CDDP was 54±5% for K-ras mutation positive-patients, and 50±13% for negative-patients. There was no significant difference between these two groups. p53 overexpression was observed in 14 patients, but not in 13 patients. The inhibition rate of CDDP was 50±12% for p53- overexpressed patients, and 50±12% for patients not overexpressed. The inhibition rate of VNR was 36±17% for p53- overexpressed patients, and 33±14%for patients not overexpressed. As for 8 adenocarcinoma patients, the inhibition rate of CDDP of p53-overexpressed patients(59±8%)was significantly(p=0. 018)higher than that of patients not overexpressed (45±9%). p53 overexpression may be a predictive marker for chemotherapy using CDDP in lung adenocarcinoma. CONCLUSION: p53 overexpression may be a possible predictive marker for adjuvant chemotherapy using CDDP in NSCLC.

A case of pseudo-meigs' syndrome associated with ovarian metastases from breast cancer.

A 54-year-old woman with long-lasting pleural effusion developed abdominal distention due to ascites from bilateral ovarian tumors. The patient had undergone breast-conserving surgery and axillary lymph node dissection for left breast cancer in October 2000, and had developed left pleural effusion in July 2006. Cytological examination of the pleural effusion found no malignant cells. Thoracic drainage with intrathoracic administration of OK-432 (Picibanil) had failed to control the pleural effusion. Positron emission tomography taken at the abdominal distention showed bilateral ovarian tumors. After failure to control the ascites with systemic and intra-abdominal chemotherapy, bilateral oophorectomy resulted in normalization of elevated serum tumor-marker levels and the disappearance of both the ascites and pleural effusions (i.e., pseudo-Meigs' syndrome). Pathological examination showed the tumors to be estrogen receptor-positive metastatic ovarian tumors from her breast cancer. The patient remained well with no further recurrence for 40 months under aromatase inhibitor therapy.

Epidermal growth factor receptor mutations are associated with docetaxel sensitivity in lung cancer.

INTRODUCTION: A recent large randomized controlled trial revealed that patients with lung cancer with epidermal growth factor receptor (EGFR) mutations had better prognoses when treated with the EGFR-tyrosine kinase inhibitor, gefitinib, than with cytotoxic chemotherapeutic agents. Lung cancer with EGFR mutations is highly sensitive to EGFR-tyrosine kinase inhibitors. The previous trial implied that EGFR mutations might be predictive of the response to cytotoxic chemotherapy. METHODS: Forty-six tumor tissue specimens (32 adenocarcinomas and 14 nonadenocarcinomas) were obtained from patients with lung cancer who underwent surgical resection. EGFR mutations were detected using polymerase chain reaction-invader assay. A histoculture drug response assay was used as an in vitro drug sensitivity test. The inhibition rates of cisplatin, docetaxel (DOC), vinorelbine, and gemcitabine were measured. RESULTS: Sensitizing EGFR mutations were detected in samples from 14 patients, all with adenocarcinomas. The inhibition rate of cisplatin in tumors with EGFR mutations (group M) was 34.8 ± 15.5%, which was significantly lower (p = 0.0153) than in wild-type tumors (group W; 46.6 ± 14.0%). The inhibition rate of DOC in group M (18.8 ± 13.4%) was also significantly lower (p = 0.0051) than in group W (35.4 ± 19.1%). There were no significant differences in inhibition rates of gemcitabine and vinorelbine between groups M and W. Inhibition rates of DOC were significantly lower in group M (p = 0.0256) than in group W (32.6 ± 18.4) in samples from patients with adenocarcinoma. CONCLUSION: The histoculture drug response assay indicated that lung cancers with EGFR mutations were less sensitive to DOC than EGFR wild-type tumors.

Is class III beta-tubulin a true predictive marker of sensitivity to vinorelbine in non-small cell lung cancer? Chemosensitivity data evidence.

AIM: To clarify whether class III ß-tubulin (TUBB3) is a true predictive marker for chemotherapy with vinorelbine, chemosensitivity was examined using an in vitro drug sensitivity assay. PATIENTS AND METHODS: Initially, 9 specimens were obtained to analyze the dose-response curve and to measure the median effective dose 50 (ED(50)) in the histoculture drug response assay (HDRA). Subsequently, 68 surgically resected non-small cell lung cancer (NSCLC) specimens were applied to the HDRA and H-scores were calculated by immunohistochemical staining. RESULTS: The mean (±SD) slope factor, ED(50) and maximal response was 8.7±5.4, 39.0±17.9 µg/ml and 85.5±5.1% respectively. The mean inhibition rate was 26.4±16.2% and the mean H-score was 1.09±1.07. The inhibition rate was significantly correlated with TUBB3 expression (r=0.27, p=0.03), and was significantly higher in TUBB3-positive specimens than in TUBB3-negative specimens (p=0.003). CONCLUSION: Tumors with high TUBB3 levels exhibited greater chemosensitivity to vinorelbine than tumors with low TUBB3 levels. This finding provides support for the results of the JBR.10 trial.

[Feasibility of adjuvant docetaxel plus cyclophosphamide therapy for breast cancer].

PURPOSE: To evaluate the feasibility of adjuvant docetaxel plus cyclophosphamide(TC)therapy for breast cancer. PATIENTS AND METHODS: A total of 16 patients with intermediate risk-breast cancer were enrolled. TC therapy consisted of four courses of docetaxel 75 mg/m² plus cyclophosphamide 600 mg/m² intravenous administration over three weeks. Every infusion was premedicated with intravenous administration of granisetron 3 mg plus dexamethasone 16 mg, followed by dexamethasone 8 mg p. o. on days 2 and 3. RESULTS: Due to the allergic reaction, one patient discontinued TC therapy. Fifteen (94%) of the 16 patients completed the scheduled TC therapy. Feasibility was 93.7%. Grade 3/4 toxicity was limited to leucopenia, neutropenia, and febrile neutropenia. No non-hematological serious adverse events were observed. CONCLUSION: Adjuvant TC therapy is a feasible option for breast cancer.

[Histoculture drug response assay guided adjuvant chemotherapy in patients with ERCC1-positive non-small cell lung cancer].

PURPOSE: A previous large randomized control study(IALT)revealed that cisplatin(CDDP)-based adjuvant chemotherapy was not effective for patients with ERCC1-positive non-small cell lung cancer(NSCLC). We evaluated the chemosensitivity of surgically resected specimens of NSCLC using in vitro chemosensitivity test and searched for promising adjuvant chemotherapy protocols in the ERCC1-positive subgroup of NSCLC. PATIENTS AND METHODS: Chemosensitivities of 10 anticancer agents including cisplatin were evaluated by histoculture drug response assay(HDRA) using 28 surgically resected NSCLC specimens. ERCC 1 status was evaluated by immunohistochemistry. RESULTS: ERCC1 was positive in 22 and negative in 6 specimens. All ERCC1-negative specimens were sensitive for CDDP in HDRA, and all CDDP-resistant specimens in HDRA showed positive ERCC1 staining. ERCC1 status was significantly correlated with CDDP sensitivity(p=0.01). HDRA showed average 3(0-6)sensitive anticancer agents except for CDDP even in ERCC1-positive specimens. CONCLUSION: HDRA may provide effective non-platinum adjuvant chemotherapy protocols for patients with ERCC1-positive, i.e. CDDP resistant, NSCLC.

Histoculture drug response assay for gefitinib in non-small-cell lung cancer.

OBJECTIVE: There are many predictive factors for gefitinib sensitivity, including epidermal growth factor receptor (EGFR) gene mutation, EGFR copy number, and k-ras mutation. To investigate all of them is too expensive. We evaluated the chemosensitivity for gefitinib in non-small-cell lung cancer (NSCLC) using a histoculture drug response assay (HDRA). METHODS: Surgically resected fresh tumor specimens from 22 patients with NSCLC were used. There were 13 male and 9 female patients, ranging in age from 49 to 84 (average 70) years old. Sixteen patients (73%) were smokers. Sixteen adenocarcinomas, four squamous cell carcinomas, and two other histological types were included. Small pieces of viable cancer tissue were placed on the collagen gel and then cultured for 7 days in the presence of gefitinib. RESULTS: The HDRA was successful in all specimens. A dose-response relation was observed between inhibition rates and gefitinib concentration (p = 0.016). The inhibition rate at 20 microg/ml (IR(20)) in adenocarcinoma without smoking (39.2% +/- 35.1%, n = 6) was higher than that with smoking (2.2% +/- 5.0%, n = 10, P = 0.001) and that of nonadenocarcinoma (16.9% +/- 23.6%, n = 6, P = 0.09). Gene mutation analysis was performed in two of three adenocarcinomas without smoking, which showed especially high IR(20) values, and sensitizing mutations were observed in these specimens. A cutoff inhibition rate of approximately 40%-50% appeared to be suitable for a concentration of 20 microg/ml. CONCLUSION: HDRA appears to be applicable for evaluating sensitivity to gefitinib in NSCLC. It provides a convenient method for predicting the response to gefitinib in patients with NSCLC whose fresh tumor specimens are available.

[Safety and efficacy of weekly paclitaxel followed by FEC100 as primary systemic therapy for breast cancer].

The efficacy and safety of primary systemic therapy with weekly paclitaxel (wPTX; 80 mg/m2) followed by FEC100 (cyclophosphamide 500 mg/m2, epirubicin 100 mg/m2, 5-fluorouracil 500 mg/m2)were investigated in 52 patients with stage I-III A locally advanced breast cancer. Clinical response was complete in 30 patients (58%) and partial in 19 patients (37%). Pathological complete response was found in 23 primary lesions and 17 sentinel and/or sampling lymph nodes. No patients developed progressive disease and major adverse events except for febrile neutropenia in ten patients. These results showed that primary systemic therapy with wPTX followed by FEC100 is a feasible therapeutic option for breast cancer.

In vitro evaluation of dose-response curve for paclitaxel in breast cancer.

BACKGROUND: The dose-response curve for anticancer agents cannot be evaluated by studying patients directly. To investigate individual differences in the dose-response curve for paclitaxel in breast cancer, we utilized the histoculture drug response assay (HDRA) technique. MATERIALS AND METHODS: Twenty specimens obtained from breast cancer patients who underwent surgical resection were used in this study. The inhibition rates of paclitaxel at several concentrations were measured and fitted to a sigmoid dose-response curve, using non-linear least squares analysis with the fitting equation y=A(1-1/(1+exp(B(x-log(C))))), where A denotes maximal response; B, slope factor; and C, ED50. RESULTS: A dose-response curve was obtained in all tumors. The mean value (+/-SD) of maximum response, slope factor, and ED50 were 90.2+/-5.5%, 9.4+/-4.3, and 36.8+/-17.2 microg/ml, respectively. The slope factor was higher in nuclear grade 3 tumors compared with nuclear grade 1 and 2 tumors. CONCLUSION: An individual dose-response curve for paclitaxel in breast cancer can be obtained using the HDRA technique. Nuclear grade 3 tumors appeared to have more uniform chemosensitivity to paclitaxel compared with nuclear grade 1 and 2 tumors.