Molecular morphological approach to the pathological study of development and advancement of human breast cancer.

Since the concept of gene profile-based intrinsic subtypes was proposed, various studies on pathological characteristics have been performed. Particularly, triplenegative (TN) breast cancer, which is negative for all hormone receptors [estrogen receptor (ER) and/or progesterone receptor (PgR) and human epidermal growth factor 2 (HER2)], has been attracting attention because effects of endocrine and targeting therapies cannot be anticipated and thus selecting a treatment method is difficult. TN cancer accounts for about 10%-15% of all invasive breast cancer cases in Japanese, which is significantly lower than the incidence reported in the United States. Cytokeratin (CK) 5/6 or epidermal growth factor receptor (EGFR) is positive in 80%, being classified as basal-like carcinoma, but it should be understood that TN breast cancer and basal-like carcinoma are not necessarily the same. Criteria for positivity judgment of ER, PgR, and HER2 were established to select treatment in cases positive for each marker, and greater importance is attached to strict accuracy control. Inversely, the level of negative findings to judge TN varies among the judgment criteria. In any case, the prognosis of TN breast cancer is poor. Pathologically, TN breast cancer shows certain morphological characteristics, such as high grade and a pushing margin, and abnormalities of BRCA1 and p53 are frequently noted. At present, as no effective therapeutic strategy has been established for TN breast cancer, further clarification of the molecular biological characteristics of such cancers is needed. In addition, the incidence of TN-type ductal carcinoma in situ (DCIS) is low, suggesting that TN does not remain preinvasive DCIS for a prolonged period and that it transforms to invasive cancer in an early stage. Because mammary gland basal cells have characters of progenitor or stem cells that differentiate into both luminal epithelium and myoepithelial cells, these cells may be utilized for the differential diagnosis of the benignity or malignancy of intraductal lesions in routine pathological practice. As proliferation markers, such as Ki-67, and multiple gene arrays for gene signature are also utilized to select adjuvant therapy, analysis may progress further in the future.

Dose-escalation phase I study in metastatic breast cancer patients with combination of paclitaxel and tegafur·uracil.

The study present the results of the dose-setting study of concomitant weekly administration of paclitaxel and tegafur·uracil (UFT) for metastatic breast cancer. Eligible patients who entered the study underwent two or more courses of weekly paclitaxel + UFT therapy as the protocol therapy. The initial dose (level 1) was paclitaxel, 80 mg/m(2) and UFT, 400 mg/day. At level 2, paclitaxel remained the same, but UFT was increased to 600 mg/day. At level 3, only paclitaxel was increased to 90 mg/m(2). Twelve patients were enrolled in this study between September 2000 and September 2002. Three patients were assigned to level 1. Grade 3 liver dysfunction (increased aspartate aminotransferase and alanine aminotransferase) was noted in one patient and grade 4 neutropenia was noted in one patient, showing that dose-limiting toxicity was detected in 2/3 patients. In accordance with the protocol, UFT was fixed at 400 mg/day and paclitaxel was decreased to 60 mg/m(2) at level -1, and then increased to 70 mg/m(2) at level 0. The overall effective rate after completion of two courses was 33% (3/9) including one case of complete response and two cases of partial responses. The remaining patients presented with stable diseases and no patient had progressive disease. In this study, weekly paclitaxel with concomitant UFT was administered. The recommended doses of paclitaxel and UFT were determined to be 70 mg/m(2) and 400 mg/day, respectively. As the toxicity profile shows, the highest toxicity level of this regimen was neutropenia and liver dysfunction, and dose-limiting toxicity was neutropenia.