Phase I Study of Combination Therapy With Weekly Nanoparticle Albumin-bound Paclitaxel and Cyclophosphamide in Metastatic Breast Cancer Patients.

BACKGROUND/AIM: The objective of this phase I study was to determine the maximum-tolerated dose (MTD) and recommended dose (RD) of combination therapy with weekly nanoparticle albumin-bound paclitaxel (nab-paclitaxel) and cyclophosphamide (CPA) in metastatic breast cancer (MBC) patients. PATIENTS AND METHODS: Five patients who had human epidermal growth factor receptor 2 (HER2) negative MBC were recruited in this study. They received nab-paclitaxel at dose levels of 100-150 mg once a week for three weeks, repeated every 4 weeks, and CPA (600 mg/m2) administered on day 1. RESULTS: No patient had grade 4 toxicity, however, two patients discontinued protocol treatment due to adverse events at level 2. Thus, the Data and Safety Monitoring Committee recommended the MTD of nab-paclitaxel and CPA to be determined at level 2. CONCLUSION: The combination therapy with weekly nab-paclitaxel and CPA was tolerable, and the RD for these drugs for MBC were 100 and 600 mg/m2, respectively.

A case of adenomyoepithelioma with myoepithelial carcinoma of the breast.

Adenomyoepithelioma with myoepithelial carcinoma of the breast is rare and diagnosed with histology and immunohistochemistry. We present a case of malignant transformation over 10 years, with ultrasonographic findings, highlighting the importance of an early excisional biopsy. Conservative surgery and radiation therapy were performed. There was no recurrence for 2 years.

Identification of complications in mastectomy with immediate reconstruction using tissue expanders and permanent implants for breast cancer patients.

BACKGROUND: Since complications of postmastectomy breast reconstruction may reduce patient satisfaction, we investigated complications of reconstruction with tissue expanders (TEs), particularly surgical site infections requiring TE/permanent implant (PI) removal. PATIENTS AND METHODS: A retrospective review was performed of 234 primary breast cancer patients undergoing 239 postmastectomy breast reconstructions with TEs/PIs from 1997 to 2009. Clinicopathological findings and postoperative complications, particularly infections, were analyzed. Data were analyzed by the Chi-square test and a multivariate logistic regression model. TE infection risk factors considered for model inclusion were excisional biopsy, (neo) adjuvant chemotherapy, lymph node resection, body mass index (BMI), simultaneous bilateral reconstructions, and seroma aspiration. RESULTS: Removal of TEs/PIs was observed in 15.5% (37/239) of reconstructions, and 18/37 underwent re-reconstructions. Of the 19/37 reconstructions that were not achieved completely, the most frequent reason was TE infection (11 reconstructions). The completion rate was 92% (220/239 reconstructions) and it was significantly higher in reconstructions without TE infection than with infection (96 vs. 54%, p < 0.0001). Patients with BMI ≥ 25 kg/m² and seroma aspiration were more likely to develop TE infections (p = 0.0019, p < 0.001, respectively). By multivariate logistic regression analysis, seroma aspiration was a significant independent risk factor for TE infection (odds ratio 28.75, 95% confidence interval 5.71-40.03, p < 0.0001). CONCLUSION: To improve completion rates of breast reconstruction, prevention of TE infection plays a key role. We should reduce unnecessary seroma aspirations and delay elevation/exercise of the ipsilateral arm.

A case of femoral diaphyseal fracture after long-term treatment with zoledronic acid.

We report here a case of femoral diaphyseal fracture thought to be caused by oversuppression of bone remodeling due to long-term bisphosphonate treatment. The patient was a 63-year-old postmenopausal woman. She had undergone left lumpectomy and sentinel node biopsy for left breast cancer at age 57. The case was diagnosed as pT2N0M0, stage IIA breast cancer. The biopsy sample was positive for hormone receptors and negative for HER2 protein. Postoperatively, exemestane was administered as adjuvant therapy. Right axillary lymph node metastasis was found at age 59, and right axillary lymph node dissection was performed. Postoperatively, epirubicin/cyclophosphamide and paclitaxel were administered. Subsequently, letrozole was administered. However, bone metastases to the first thoracic vertebra and right ilium were found at age 60, and zoledronic acid administration (4 mg/month) for bone metastasis was initiated. The patient developed a transverse fracture in the proximal left femoral diaphysis when she walked on a flat surface after zoledronic acid was administered for 2 years, 10 months. She was treated with an intramedullary nail for left femoral diaphyseal fracture. Cancellous bone of the medullary cavity was histopathologically examined, but there were no metastatic lesions from the breast cancer and no osteoblasts or osteoclasts were observed. Zoledronic acid was immediately discontinued in this patient. In recent years, cases of atypical femoral diaphyseal fractures caused by minor trauma in patients undergoing long-term bisphosphonate treatment have been reported. Thus, careful observation is required for patients who are anticipating bisphosphonate treatment.

Clinical outcome of reconstruction with tissue expanders for patients with breast cancer and mastectomy.

BACKGROUND: Because the number of patients with breast cancer who have reconstruction after mastectomy is increasing, we analyzed the outcomes of reconstruction with tissue expanders (TEs). PATIENTS AND METHODS: From 2004 to 2009, 133 patients with unilateral primary breast cancer who required mastectomy concurrent with reconstruction using TEs (TE group) and 308 patients with breast cancer who underwent mastectomy without reconstruction (MT group) were examined. RESULTS: The median follow-up period was 47 months versus 44 months (TE group vs. MT group, respectively). The median age was 46 years in the TE group and 58 years in the MT group (P < .0001). The rate of hormone receptor positivity in the TE group was significantly higher than in the MT group (P = .0123). The incidence of local recurrence, time to detection of local recurrence, and size of tumor in local recurrence in the TE group and the MT group were 3.8% versus 1.6% (P = .1560), 17.2 months versus 12.4 months (P = .9166), and 1.9 cm versus 2.4 cm (P = .6742), respectively. In the TE versus the MT groups, relapse-free survival (RFS) and overall survival (OS) at 45 months were 89.0% versus 87.9% (P = .8706) and 93.9% versus 94.2% (P = .9947), respectively. The incidence of infection was significantly higher in the TE group than in the MT group-14.3 % versus 2.9%, respectively (P < .0001). CONCLUSION: Compared with mastectomy alone, immediate reconstruction with TEs did not impair prognosis or contribute to a delay in detection of local recurrence, although the incidence of surgical site infection in the TE group was significantly higher than in the MT group.

Plastin3 is a novel marker for circulating tumor cells undergoing the epithelial-mesenchymal transition and is associated with colorectal cancer prognosis.

Circulating tumor cells (CTC) in blood have attracted attention both as potential seeds for metastasis and as biomarkers. However, most CTC detection systems might miss epithelial-mesenchymal transition (EMT)-induced metastatic cells because detection is based on epithelial markers. First, to discover novel markers capable of detecting CTCs in which EMT has not been repressed, microarray analysis of 132 colorectal cancers (CRC) from Japanese patients was conducted, and 2,969 genes were detected that were overexpressed relative to normal colon mucosa. From the detected genes, we selected those that were overexpressed CRC with distant metastasis. Then, we analyzed the CRC metastasis-specific genes (n = 22) to determine whether they were expressed in normal circulation. As a result, PLS3 was discovered as a CTC marker that was expressed in metastatic CRC cells but not in normal circulation. Using fluorescent immunocytochemistry, we validated that PLS3 was expressed in EMT-induced CTC in peripheral blood from patients with CRC with distant metastasis. PLS3-expressing cells were detected in the peripheral blood of approximately one-third of an independent set of 711 Japanese patients with CRC. Multivariate analysis showed that PLS3-positive CTC was independently associated with prognosis in the training set (n = 381) and the validation set [n = 330; HR = 2.17; 95% confidence interval (CI) = 1.38-3.40 and HR = 3.92; 95% CI = 2.27-6.85]. The association between PLS3-positive CTC and prognosis was particularly strong in patients with Dukes B (HR = 4.07; 95% CI = 1.50-11.57) and Dukes C (HR = 2.57; 95% CI = 1.42-4.63). PLS3 is a novel marker for metastatic CRC cells, and it possesses significant prognostic value.

Identification of recurrence-related microRNAs in the bone marrow of breast cancer patients.

Recently, bone marrow has been considered as playing a critical role in the generation of both metastasis and recurrent disease. The accumulation of a single microRNA in the bone marrow has the potential to regulate the translation of multiple genes in cancer metastasis and may therefore serve as a prognostic marker for cancer recurrence. MicroRNA microarray analysis was performed to compare microRNA levels in bone marrow from 4 breast cancer patients with recurrent disease and 4 patients without recurrence. Accumulation of two of these microRNAs, miR-21 and miR-181a, in the recurrent breast cancer cases was validated by RT-PCR in bone marrow from 291 additional breast cancer cases. Expression of a common target gene, PDCD4, was also determined in bone marrow from 291 breast cancer cases. Increased miR-21 and miR-181a levels were significantly associated with shortened disease-free survival (DFS; p=0.0003, 0.0007) and overall survival (OS; p=0.0351, 0.0443), respectively. While low PDCD4 expression was also significantly associated with poorer DFS (p=0.036). Multivariate analysis identified bone marrow miR-21 and mR-181a levels as valuable independent prognostic factors, with correlation coefficients that were significantly higher than that of the transcript of their common target gene. Accumulation of miR-21 and miR-181a in bone marrow appears to be associated with prognosis in breast cancer patients. The much higher significant correlation with microRNA levels and prognosis suggests epistatic effects on multiple target genes in the bone marrow of breast cancer patients.

A case of mucinous carcinoma of the breast in which needle tract seeding was diagnosed by preoperative diagnostic imaging.

Herein we report a 62-year-old woman with an excisable breast tumor in whom needle tract seeding was suspected during preoperative ultrasound and magnetic resonance imaging (MRI). A tumor of the right breast was observed during initial examination, and she was referred to our hospital after fine-needle aspiration cytology led to diagnosis of breast cancer, even though core needle biopsy results were negative. Mammography showed a high-density mass with a portion of the margin exhibiting very fine serrations. Ultrasonography revealed a circular mass with a border that was indistinct in some regions, and a hypoechoic band that extended from the tumor toward the skin. A mass was observed on MRI, with a linear enhancement extending on the skin side, and needle tract seeding was suspected. Fine-needle aspiration cytology revealed malignancy, and the histological appearance was consistent with mucinous carcinoma. T1cN0M0 stage I breast cancer was diagnosed, and wide excision and sentinel lymph node biopsy were performed. The skin directly above the tumor was concurrently excised to remove the biopsy puncture site. Histopathological diagnosis confirmed mucinous carcinoma, with the tumor observed to extend linearly into the subcutaneous adipose tissue in a pattern corresponding to the biopsy puncture site. The stump of the excised breast was negative for cancer cells. The possibility of tumor seeding must be considered during fine-needle aspiration cytology and biopsy. As demonstrated in this case, diagnosis of such seeding through preoperative imaging may enable extraction of the entire lesion, including the needle tract.

A case of invasive micropapillary carcinoma of the breast.

BACKGROUND: Invasive micropapillary carcinoma (IMP) of the breast is uncommon and has only recently been characterized. Knowing the cytological appearance of IMP is important to enable early diagnosis by fine needle aspiration cytology (FNAC). We describe a case of IMP diagnosed by preoperative FNAC. CASE: A 48-year-old menopausal woman presented in 2003 with a mass in her left breast. Mammogram and ultrasound findings indicated that the tumor was malignant. Cytological examination showed papillary clusters of hyperchromatic cells with irregular and crowded nuclei, but lacking papillary cores. No myoepithelial cells were seen. Based on the cytological findings, invasive micropapillary carcinoma was diagnosed. Microscopic findings showed cancer cells with moderate atypia in abundant micropapillary cancer nests without a fibrovascular core. These cancer nests were morula-like, surrounded by empty, clear spaces lined with delicate strands of fibrocollagenous stroma. The polarity of each cancer nest was reversed, with the secretion border facing fibrocollagenous stroma. These pathological features occupied the invasive part of the primary tumor. CONCLUSION: The cytologic features of IMP are distinctive and correlate with histology. FNAC of IMP is important role to confirm the diagnosis.

Prognostic predictors in breast cancer patients with postoperative 5-fluorouracil-based chemotherapy.

Thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) are enzymes involved in the metabolism of 5-fluorouracil (FU). To investigate the relationship of these activities with clinicopathological factors and survival, we measured TS (88 patients) and DPD (122 patients) activities in resected specimens of breast cancer by enzyme assay. Significant difference was found only in TS activity between tumors > or = 20 mm in diameter and those < 20 mm (p = 0.015). There were no significant differences in TS or DPD activity among any other factors. When patients were grouped based on the cut-off levels of TS and DPD activities, 5-year recurrence-free survival rate was 68.8% in the low TS group and 39.7% in the high TS group (p = 0.0081), and 50.8% in the low DPD group and 66.5% in the high DPD group (p = 0.1627). The Cox proportional hazard model demonstrated that in patients in whom we measured TS activity, significant prognostic factors were nodal status and estrogen receptor (ER) status by univariate analysis, and ER status was also significant by multivariate analysis. In patients in whom DPD activity was measured, the significant prognostic factor was ER status by univariate analysis, and ER and Progesterone receptor (PgR) status by multivariate analysis. These results suggested that TS activity, nodal status and hormone receptors may be possible predictors of clinical outcome in breast cancer, but further investigation on prognostic predictors in 5-FU-based chemotherapy is required.

Evaluation of sensitivity to 5-FU on the basis of thymidylate synthase (TS)/dihydropyrimidine dehydrogenase (DPD) activity and chromosomal analysis in micro tissue specimens of breast cancer.

BACKGROUND: Preoperative assessment of the anticancer drug sensitivity of tumors plays an important role in the selection of therapy. If evaluation of the 5-FU sensitivity of microtissue specimens obtained by techniques such as core needle biopsy could be performed, the addition of fluorouracil to adriamycin and cyclophosphamide may further enhance response rates. In order to evaluate a simple sensitivity test for the anti-tumor agent 5-fluorouracil (5-FU), we examined whether an assay of a small sample could measure mRNA to predict the activities of thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD). In addition, gene abnormalities on chromosomes 1 and 18 corresponding to DPD, TS and the relationships between the gene abnormalities and the amount of mRNA and activity were examined. METHOD: TS and DPD activity were measured using the fluorodeoxyuridine monophosphate ligand binding assay and radio enzymatic assay, respectively, while mRNA levels were assayed by real-time polymerase chain reaction. Chromosome 1 and 18 aberrations were investigated by fluorescence in situ hybridization (FISH) with centromere probes. RESULTS: TS mRNA and TS activity showed a positive correlation (r=0.518, p=0.0017). TS activity and TS mRNA were significantly higher in the nuclear grade 3 group than in the other groups (p=0.04, p=0.0072, respectively). TS activity and mRNA in tumor tissue tended to decrease in the progesterone receptor positive groups (p=0.059, p=0.066, respectively). There was no correlation between DPD mRNA and DPD activity in tumor tissue (r=0.139, p=0.4423). DPD mRNA was measured as 282.88+/-170.68 copies/cell in tumor tissue and 635.88+/-310.04 copies/cell in normal tissue, and was thus significantly higher in normal tissue (p<0.001). CONCLUSIONS: TS mRNA showed a positive correlation with TS activity, suggesting that this method of using small amounts of tissue can replace anti-cancer drug sensitivity tests.

[A case of aged advanced breast cancer with multiple lung and pleural metastases responding to exemestane monotherapy].

A 76-year-old woman was diagnosed with advanced breast cancer with bilateral multiple lung and pleural metastases in March 2003. Her CEA and CA15-3 level were 7.6 ng/ml and 98.3 U/l, respectively. However, she refused intensive chemotherapy and chose a hormonal monotherapy with exemestane instead. The patient then did not return to our department for about one year, during which time she continued to take the same medications. When she visited again, CEA and CA15-3 level were reduced to within the normal range, and her multiple lung and pleural metastases were found to have almost completely disappeared upon computed tomography. Exemestane is expected to be an effective agent for the treatment of hormonal receptor-positive postmenopausal woman with life-threatening advanced breast cancer.

[A case of breast cancer with multiple bone metastases that responded remarkably to doxifluridine (5'-DFUR), cyclophosphamide (CPA), medroxyprogesterone acetate (MPA) and pamidronate disodium therapy].

A 49-year-old female underwent bilateral breast preserving surgery for heterochronic breast cancers. She later developed a sternal metastasis and was recommended for intravenous chemotherapy. However, she refused such an intensive therapy and opted for immunotherapy. Afterward, she came to our hospital because of spinal metastases with back pain. She was treated with oral administration of 5'-DFUR and MPA 1,200 mg/day for 3 weeks, respectively, CPA 100 mg/day for 2 weeks, and pamidronate disodium 30 mg intravenously every 4 weeks. This combined chemotherapy relieved her pain after one course. After 5 courses, tumor markers were reduced to the normal range. After 14 courses, bone X-P revealed that the osteolytic bone showed sclerotic changes and bone scintigraphy showed a complete remission (CR). The adverse effects were not remarkable. This regimen is possible on an outpatient basis, and it may play an important role from the standpoint of treatment effectiveness and the quality of life of the patient.