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Background The potential of TAS-108 for the treatment of breast cancer has been shown by preclinical studies. We therefore investigated the safe dosage, tolerability, and effectiveness on hormone levels and bone metabolism markers and the pharmacokinetics of TAS-108 administered in postmenopausal Japanese women with metastatic breast cancer. Patients and methods The subjects had previously undergone standard endocrine therapeutic modalities. TAS-108 was given repeatedly to five patients each, at three dose levels (40, 80, and 120 mg p.o.) once a day after the first daily meal for a scheduled 8 weeks. Plasma concentrations of TAS-108 and its metabolites were measured at the scheduled time points. Results Fifteen patients received TAS-108 treatment. Orally administered TAS-108 was well tolerated at doses up to 120 mg and did not cause notable changes either in hormone levels or bone metabolism markers. Pharmacokinetic results indicated dose-dependent increases in plasma levels of TAS-108 and its metabolites. A steady state was achieved by 2 weeks at all dose levels, suggesting no marked accumulation. Clinical benefits were confirmed in 5 of 15 patients. Conclusions Repeated oral administration of TAS-108 at doses up to 120 mg was well tolerated, and the plasma level of this compound increased dose-dependently.

Fine needle aspiration (FNA) samples were obtained from 176 breast tumors suspected of malignancy, which were then subjected to conventional cytological and fluorescence in situ hybridization (FISH) analyses using the centromeric probes for chromosomes 1, 11, and 17. Histological examination revealed 157 breast cancers and 19 benign diseases (ten fibroadenomas, six intraductal papillomas, one intracystic papilloma, and two ADH). Sensitivity, specificity, and diagnostic accuracy were 85.4% 94.7%, and 86.4%, respectively, for cytology and 90.4%, 100%, and 91.5%, respectively, for FISH. These results demonstrate that FISH diagnosis of FNA samples has a diagnostic accuracy comparable to that of conventional cytology.

A 10-center cooperative clinical study with a new formulation of epirubicin hydrochloride injectable solution (Epirubicin-RTU) was conducted in patients with breast cancer. One course of treatment consisted of one intravenous administration of Epirubicin-RTU at the dose of 60 mg/m2 followed by a 3-week drug-free interval and concomitant daily administration of oral cyclophosphamide at 100 mg/day during the period between Days 1 through 14. At least, two courses of treatment were given. Among 20 registered cases, all 20 cases were eligible and 16 cases completed the whole course of the study. In 16 completers, PR was observed in 5 cases, indicating the efficacy rate of 31.3% (5/16).. No local irritation was observed at the injection sites. Adverse reactions frequently observed were leukopenia, neutropenia, anorexia, alopecia, and nausea/vomiting, which were all reversible and tolerable. From the above results, Adverse reactions both locally and systemically were tolerable. Intravenous administration of Epirubicin-RTU was considered to be useful for the treatment of breast cancer.

Urokinase-type plasminogen activator (u-PA) is a key protease in cancer invasion and metastasis. Recent studies demonstrated that u-PA, plasminogen activator inhibitor type-1 (PAI-1), and tissue-type plasminogen activator (t-PA) are prognostic factors in breast cancer. However, there have been no prospective studies of node-negative breast cancer on a multicenter basis. On the other hand, some patients, even those with node-negative breast cancer, developed recurrence, and only tumor size is available as a predicting factor in this group. Therefore, it is necessary to find other prognostic factors in node-negative breast cancer to determine suitable adjuvant therapies. Tissue samples in this prospective study were obtained from 130 patients with node-negative invasive breast cancer who underwent radical operation at four hospitals. The median follow-up was 52.6 months. u-PA, PAI-1, and t-PA antigen levels were assayed by ELISA kits using the cytosolic fractions of tumors. Patients with high u-PA, high PAI-1, or low t-PA had significantly higher relapse rates than did those with low u-PA, low PAI-1, or high t-PA, respectively, by the Kaplan-Meier method (P = 0.006, 0.032, and 0.028, respectively). Analyses of the combinations of both u-PA and PAI-1 or both u-PA and t-PA showed that the differences in relapse rate between the high- and low-risk groups were statistically very significant. In the univariate analysis, u-PA, PAI-1, t-PA, progesterone receptor, and tumor size (T3 versus T1) were significantly correlated with relapse. However, the multivariate analysis revealed that only u-PA (P = 0.023) was an independent prognostic factor. This study showed that u-PA was a new significant independent prognostic factor in node-negative breast cancer.

The main therapy for primary breast cancer is not surgery, but a systemic therapy involving administration of cytotoxic chemotherapy or the use of ablative or additive endocrine therapy to control disseminated micrometastasis. The results of randomized trials and meta-analysis show that CMF, the standard adjuvant chemotherapy, is effective regardless of axillar lymph node involvement or menopausal status. Effectiveness of adjuvant chemotherapy with an anthracyclin-based regimen remains controversial. The trial by CUBC and NSAS-BC comparing UFT, widely used in the management of patients with breast cancer in Japan, with CMF is on-going.

We measured pS2 protein in the serum of patients with adenocarcinoma and non-adenocarcinoma types of lung cancer, non-cancerous lung lesions, and the control sera. Although the serum pS2 protein level in patients with lung adenocarcinoma was significantly higher than that in patients with other diseases, as well in control samples, it had little clinical value as a screening tumor marker because the levels in control samples showed a wide range of variation. However, analysis according to the histological subtype of lung adenocarcinoma, ordinary and bronchioloalveolar, revealed a high serum level of pS2 protein in several patients with advanced stage disease in the former, and mucus-producing goblet cell subtypes in the latter, which showed strong pS2 protein expression in tissues, whose serum levels diminished to the control level after resection. Thus, the serum levels of pS2 protein may be a useful marker of tumor burden in selected patients with lung adenocarcinoma.

The histogeneses of fibroadenoma and phyllodes tumor of the breast appear to be closely related, but it is still unclear whether fibroadenoma can progress directly to phyllodes tumor.This issue was studied by conducting clonal analysis of fibroadenoma and phyllodes tumors that were obtained sequentially from the same patient. One patient developed local recurrence of phyllodes tumor twice, and the other two patients each developed a phyllodes tumor after excision of a primary fibroadenoma. The method for clonal analysis was based on trinucleotide repeat polymorphism of the X chromosome-linked androgen receptor (AR) gene and on random inactivation of the gene by methylation.Clonal analysis revealed that all the three primary fibroadenomas were monoclonal and all four recurrent phyllodes tumors were also monoclonal in origin. In addition, the same allele of the AR gene was inactivated in fibroadenoma and phyllodes tumor(s) in each patient. The probability that phyllodes tumors of different origin happen to inactivate the same allele of the AR gene as fibroadenomas in every case is quite low. Rather, it is more reasonable to assume that the phyllodes tumor has the same origin as fibroadenoma.These results identified monoclonal fibroadenomas that can progress to phyllodes tumors.

Recently, a variety of new prognostic factors for breast cancer have been advocated, although most of these studies are still preliminary. Until the results of definitive studies to evaluate the clinical usefulness of these new factors are obtained, it is practically relevant to plan a treatment schedule of breast cancer patients through classical prognostic factors such as tumor size, axillary lymph node status, histological grade, and estrogen/progesterone receptor status.

There is no established method for assessing the prognosis of patients with breast cancer and metastasis confined initially to bone. The medical records of 82 patients with breast cancer nad metastasis confined initially to bone were reviewed. The following variables were analyzed at the time when bone metastasis was first diagnosed, to determine their relationship to length of survival: distribution of metastatic bone lesions on bone scan, presence of radiographic osteosclerosis in metastatic bone lesions, menstrual status, and disease-free interval. Univariate and multivariate analyses revealed that the distribution of metastatic bone lesions and the presence of radiographic osteosclerosis in these lesions were significant predictors of survival. Premenopausal or late postmenopausal status, and longer disease-free intervals (or = 24 months) or no disease-free intervals (Stage IV breast cancer and metastasis confined to bone at the time of cancer diagnosis) showed a trend, although not statistically significant, toward longer survival. Distribution of metastatic bone lesions on bone scan and the presence of radiographic osteosclerosis in metastatic bone lesions should be considered prognostic variables for patients with breast cancer and metastasis confined initially to bone.

Background BOLERO-2, an international, phase III study in patients with locally advanced or metastatic breast cancer refractory to non-steroidal aromatase inhibitor therapy, previously reported that the addition of everolimus (EVE) to exemestane (EXE) significantly improved progression-free survival (PFS) (6.9 versus 2.8 months; HR = 0.43; P Methods Eligible patients were randomized (2:1) to EVE (10 mg/day) or matching placebo (PBO), with both arms receiving EXE (25 mg/day). Treatment was continued until disease progression, unacceptable toxicity, or withdrawal of consent. The primary end point was PFS by local assessment. Secondary end points included overall survival (OS), objective response rate (ORR), clinical benefit rate (CBR), and safety. Results Of the 724 patients from 24 countries enrolled in this study, 106 patients were Japanese, of whom 71 and 35 were assigned to EVE + EXE or PBO + EXE, respectively. Data from this Japanese subpopulation are presented. The addition of EVE to EXE prolonged median PFS (8.4 months versus 4.1 months; P = 0.025), increased ORR (16.9% versus 0%), and CBR (43.7% versus 25.7%) compared with EXE alone. In the EVE + EXE arm, most common grade 3/4 adverse events included stomatitis (9.9%), anemia (5.6%), and aspartate aminotransferase increased (4.2%). The incidence of non-infective lung-related adverse events was 31.0%, which was higher than in the overall population. The majority of these events were grade 1 or 2. Most patients showed recovery or relief after dose reduction or interruption, administration of corticosteroids, or oxygen therapy. Conclusion Japanese patients in the BOLERO-2 trial treated with EVE + EXE showed similar PFS benefits as the overall population and a manageable safety profile. Thus, EVE + EXE is a promising new therapeutic option for Japanese women with advanced breast cancer.

Inflammatory breast cancer (IBC) is one of the most aggressive subtypes of breast cancer. IBC represents 2%–4% of breast cancer, but it represents 10% of breast cancer-related mortality. Despite multimodality approaches, the prognosis for patients with this disease remains poor. Although we are making efforts to improve treatment for IBC, IBC research remains to be limited because this is a rare disease and there are few defined targets for IBC due to undefined IBC biology. To improve this situation, we require insights from clinical trials and epidemiologic studies investigating IBC biology. Molecular targets such as vasculolymphatic, proliferation, and metastatic process has been identified, but all of these unique targets require clinical validation by clinical trials. Molecular targets in cell proliferation processes have been investigated the most and have yielded promising clinical results leading to improved outcomes for patients with IBC. These cell proliferation targets include HER2 and EGFR. As was the case in non-IBC, the HER2 antibody trastuzumab dramatically changed the prognosis of patients with HER2-overexpressing IBC. Lapatinib, which inhibits both HER2 and EGFR, also showed benefit in patients with HER2-positive breast cancer, including IBC, in clinical trials. Additional cell proliferation targets—WISP3, RhoC GTPase, and p27kip1—have also been studied in IBC. Molecules involved in metastasis processes may have a unique role in IBC owing to the aggressiveness of this disease. E-cadherin has been observed to be overexpressed in IBC, and loss of E-cadherin is a hallmark of epithelial-mesenchymal transition (EMT). Although this E-cadherin overexpression might be a transient phenomenon, we may be able to target this unique feature. Other potential candidate is the EGFR pathway. We have been investigating the role of this pathway and the possibility of EGFR-targeted therapy for IBC. We are conducting a clinical trial with panitumumab, a human EGFR antibody, plus chemotherapy (nab-paclitaxel and carboplatin) as a preoperative regimen in patients with HER2-negative IBC. In summary, further extensive preclinical and clinical work based on molecular findings is needed to improve outcomes in patients with IBC.

Since ER positivity in breast cancer is highest in the early stage of its natural history, hormonal treatment should be given as the initial treatment after both surgery and recurrence. Tamoxifen and medroxyprogesterone acetate have been commonly used as the standard hormonal treatment with a response rate of 20-30% and a median duration of response of 6-10 months. New agents for hormone therapy include tamoxifen analogues, LH-RH analogues and aromatase inhibitors. They are now on or have just cleared phase studies. LH-RH analogue is a unique drug that is active for premenopausal patients and should be used as the first-line therapy for them. Aromatase inhibitors lower serum estrogen levels by inhibiting conversion from andreogens to estrogens, thus inducing regression of ER-positive tumors. They are used as the second-line treatment after tamoxifen failure for postmenopausal patients. An increasing body of information has been accumulated as to how the hormonal treatments affect breast cancer at subcellular levels. New approaches controlling growth factors such as anti-angiogenesis are under way.

Clonality of solitary intraductal papillomas of the breast was analyzed using a method based on restriction fragment length polymorphism of the X-chromosome-linked phosphoglycerokinase (PGK) gene and on random inactivation of the gene by methylation. The application of polymerase chain reaction to this method enabled clonal analysis of such a small intraductal lesion as papilloma. Clonal analysis of DNA samples obtained from the nine solitary intraductal papillomas and adjacent normal breast tissues showed that all of the papillomas were monoclonal and all the normal breast tissues were polyclonal in origin. When DNA samples were obtained from four widely separated sites in the papillomas, clonal analysis showed that all were monoclonal and, in addition, the same allele of PGK gene was inactivated in each case. These results demonstrate that solitary intraductal papilloma arises as a single monoclonal tumor and extends along the ducts rather than occurring as multicentric monoclonal tumors and merging together subsequently. Immunohistochemical staining of smooth muscle alpha-actin, a marker protein of myoepithelial cells, revealed that solitary intraductal papilloma was composed of approximately equal mixtures of luminal epithelial and myoepithelial cells. Since solitary intraductal papillomas were shown to be monoclonal in origin, it was suggested that this disease originates from a common precursor that could differentiate into both luminal epithelial and myoepithelial cells.

Clonal analysis has been done using the method based on restriction fragment length polymorphism of the X-chromosome-linked phosphoglycerokinase gene and on random inactivation of the gene by methylation. Introduction of polymerase chain reaction (PCR) of this method has enabled clonal analysis of minute lesions. Utilizing this PCR-based method, clonality of a variety of human breast tumors (breast carcinoma, fibroadenoma, phyllodes tumor, intraductal papilloma, and atypical ductal hyperplasia) was studied in the present investigation in order to obtain valuable information on the histogenesis of these tumors.

It is often difficult to draw a firm conclusion as to whether the second breast cancer is primary or secondary (metastasis from the initial breast cancer) in a patient with metachronous bilateral breast cancer. In this study we have applied clonal analysis of breast cancer to distinguish whether the second breast cancer is primary or secondary.A 54-year-old woman underwent modified radical mastectomy of the right breast as a result of breast cancer. Five years later she had tumors in the right chest wall and left breast. Fine-needle aspiration cytologic examination revealed that both tumors were adenocarcinoma. To elucidate the origin of these tumors, clonal analysis was done on DNA samples prepared from cryostat sections of the initial right breast cancer and from fine-needle aspirates of the tumors in the right chest wall and left breast. The method for clonal analysis was based on restriction fragment length polymorphism of X chromosome-linked phosphoglycerokinase gene and on differential methylation of the gene caused by random inactivation of one of two X chromosomes.Clonal analysis revealed that clonal origin of the right breast cancer was different from that of the left breast cancer and identical to that of the chest wall tumor. Therefore it was concluded that the left breast cancer was primary and the chest wall tumor was concluded that the left breast cancer was primary and the chest wall tumor was a recurrence of the initial breast cancer.Clonal analysis appears to be a useful method in discriminating a primary from a secondary cancer.

Purpose/Objective(s): Radiation-induced organizing pneumonia (RIOP), also called as radiation-induced bronchiolitis obliterans organizing pneumonia (BOOP) syndrome is rarely observed after radiation therapy for breast cancer as lung injury outside tangential fields. Corticosteroids are the mainstay for RIOP, which responds well. However, corticosteroid therapy requires reconsideration because of frequent exacerbation.

Clonality of fibroadenoma and phyllodes tumor of the breast was analyzed by means of the polymerase chain reaction using small DNA samples prepared from cryostat sections. The method of clonal analysis was based on restriction fragment length polymorphism of X-chromosome-linked phosphoglycerokinase gene and on differential methylation of the gene. Specimens from 10 fibroadenomas and 5 phyllodes tumors heterozygous for the BstXI polymorphism of PGK gene were subjected to clonal analysis. It was found that fibroadenoma was polyclonal, but phyllodes tumor was made up of both monoclonal and polyclonal cell components. Since these tumors contained both epithelial and stromal components, clonality of each component was analyzed separately. Analysis of clonality of each cell component showed that both the epithelial and stromal cells were polyclonal in fibroadenoma and that the epithelial cells were polyclonal, but the stromal cells were monoclonal in phyllodes tumor. When DNA samples were prepared from widely separated sites of phyllodes tumors, every sample was found to contain a monoclonal stromal cell component. These results demonstrate that fibroadenoma is a hyperplastic lesion rather than a neoplasm, and that phyllodes tumor is a neoplasm of the stromal cells.

The influence of tamoxifen treatment on transforming growth factor-alpha (TGF-alpha) levels in human breast cancer rarely has been studied in vivo.Postmenopausal patients with estrogen receptor (ER)-positive and progesterone receptor (PR)-positive primary breast cancer underwent two fine-needle aspiration biopsies (FNA) of the tumors. Between the two FNAs, 10 patients received no treatment (control group), and the other 10 patients received tamoxifen (20 mg/day) for 10 (8-12) days (TAM group). TGF-alpha levels in FNA samples were assayed by enzyme immunoassay.No significant difference was found in TGF-alpha levels between the first and second FNA samples in the control group. On the other hand, in the TAM group, TGF-alpha levels in the second FNA samples (2.5 +/- 0.5; mean +/- SEM ng/mg.DNA) were significantly (P0.01) lower than those in the first (4.5 +/- 0.8). Studies on the influence of tamoxifen treatment on TGF-alpha levels in ER-negative and PR-negative breast cancer showed that TGF-alpha levels were not affected by tamoxifen treatment. Positivity of epidermal growth factor receptor (EGFR) was 60% in ER-negative and PR-negative breast cancer and 30% in ER-positive and PR-positive breast cancer.Tamoxifen downregulates TGF-alpha levels in ER-positive and PR-positive breast cancers through ER. The significance of TGF-alpha as an autocrine growth factor appears to be more important in ER-negative and PR-negative breast cancer with high EGFR positivity than in ER-positive and PR-positive breast cancer with low EGFR positivity.

Clonality of human breast cancer was analyzed in small DNA samples prepared from cryostat sections, by means of the polymerase chain reaction (PCR). The method used for clonal analysis was based on restriction fragment length polymorphism of X-chromosome-linked phosphoglycerokinase (PGK) gene and on the differential methylation of the PGK gene due to random inactivation of one of two X-chromosomes by methylation in females. All the 20 breast cancer samples analyzed by the PCR-based method were monoclonal in origin and adjacent normal breast tissues were polyclonal. When DNA samples were prepared from widely separated sites of cancers, every sample was found to be monoclonal, always exhibiting inactivation of the same X-chromosome in each tumor. The study on sensitivity showed that the PCR-based method for clonal analysis can detect the presence of monoclonal cells against a polyclonal background when the monoclonal cell population is 50% or more. These results demonstrate that clonal analysis by means of PCR offers a good method for studying the clonality in small DNA samples prepared from cryostat sections of tumors. This method could be applied to distinguish between benign (polyclonal) and malignant (monoclonal) breast lesions.

Among the 93 surgical specimens of stage I breast cancer treated by breast preserving operation, surgical margins were less than 10mm in 23 (25%) cases because of intraductal spread. Such tumors with extensive intraductal component, however, were frequently positive for estrogen receptor (ER). Possible risk factors for local failure have been studied in an attempt to exclude high-risk patients not suitable for breast preserving operation. The results so far obtained suggest that biological markers such as c-erb B-2 or PS2 proteins may provide useful informations to select patients who are most likely to recur. In addition, adjuvant endocrine therapy may be recommended for the patients treated by breast preserving operation.

A phase II study of 5'-deoxy-5-fluorouridine (5'-DFUR) tablets for breast cancer was done at 31 institutions in Japan. Forty-five patients were registered and 44 of them were eligible for the study. Of the 40 patients whose results could be evaluated, 11 (28%) responded (four complete responses and seven partial responses). Side effects, such as diarrhea, anorexia, leukocytopenia, and liver dysfunction were observed in 24 of the 44 patients. The side effects were mild and transient. 5'-DFUR is a promising drug for breast cancer treatment, and its tablet form makes chemotherapy easier for the patient.

Six to 12 cycles of CMF is regarded as the standard regimen for adjuvant chemotherapy for breast cancer, producing 10-20% increase in survival for premenopausal and node-positive patients. Tamoxifen combined with CMF has induced an additional reduction in recurrence rate only in postmenopausal patients. Oral administration of 5-FU or its derivatives combined with tamoxifen for as long as 1-2 years is the regimen most widely used in Japan for considerable improvement in survival. But it needs further evaluation in comparison with CMF, and in ultimate duration of treatment and better combination with other drugs. Adjuvant chemotherapy for node-negative patients is advocated in the U.S., where the recurrence rate is as high as 30%. Only 10% of Japanese n0 patients undergo recurrence. Therefore, adjuvant therapy should be given only to high-risk patients.

Over the past 10 years, we have witnessed a variety of potential prognostic factors of breast cancer including proliferative rate, ploidy, growth factor receptors, oncogenes and cathepsin D production. Some of these variables seem to predict the prognosis of the patients but the available data are conflicting and call for carefully conducted quality-control studies to analyze intra- and interlaboratory variations. In this review, we provided a framework from which prognostic factor information can be used directly to make treatment decisions.

Abstract #2132 Background: A phase II study was conducted to identify the recommended dose of TAS-108, a novel steroidal antiestrogen with full ERα antagonist, mainly metabolized by CYP3A4, in post menopausal Japanese women with advanced or metastatic breast cancer. This study was prepared referring to the multi-center phase II trial that performed in four countries (USA, Russia, Mexico and Chile), and performed in Japan. Both studies are not the same designs. Patients and Methods: Patients with ER and/or PgR positive were eligible if they had one or two standard endocrine therapies, with or without one prior chemotherapy, for advanced disease. TAS-108 was administered orally at three different doses (40mg/80mg/120mg per day) for 24 weeks. The treatment was terminated if PD was observed. In this clinical study, clinical benefit (CB, CR+PR+SD for at least 24 weeks) rate as the primary end point was evaluated. The secondary endpoints were overall response rate and best overall response using RECIST; time to progression; adverse events (AEs) graded by CTC-AE (ver.3.0). Endometrial thickness (ET) and bone mineral density (BMD) as specific items of hormonal therapy were evaluated by transvaginal or transabdominal ultrasound, and dual-energy X-Ray absorptiometry method, respectively. Results: Ninety eight patients were enrolled and randomized. One ineligible patient in the 120mg dose group dropped out without administration; therefore a total of ninety seven patients were administered and assessed for efficacy and safety. Thirty three patients received 40mg, 32 received 80mg and 120mg. The three treatment groups were well balanced. CB was observed in 10 patients (30.3%) in the 40mg group, and 8 patients (25.0%) in both the 80mg and 120mg groups. Retrospective analysis showed TAS-108 had effectiveness to patients who had failed on prior tamoxifen (TAM) or aromatase inhibitors (AI) treatment, including relapse during the adjuvant therapy or within 6 months from its completion. CB rate at the three doses respectively were 25.0/33.3/25.0% in 14 (4/6/4) patients failed on TAM, and 30.8/31.6/20.0% in 70 (26/19/25) patients failed on AI. TAS-108 was well tolerated and most of the AEs were Grade1 or 2. The most frequent drug-related AEs were hot flush (22 patients, 22.7%, 7/8/7 patients in 40/80/120mg), perspiration (11 patients, 11.3%, 2/3/6), nausea (9 patients, 9.3%, 1/3/5), arthralgia (6 patients, 6.2%, 0/3/3). Neither remarkable change nor apparent dose-related trend among the three groups was observed in ET or BMD. Conclusion: According to the protocol, 40mg was chosen as the recommended dose of TAS-108 for breast cancer. It was suggested that TAS-108 has clinical benefit for patients with breast cancer who have failed on prior TAM or AI treatments. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2132.

Secondary prevention, detection and treatment at an early stage, may be the only means of controlling breast cancer. This is rational behind screening for breast cancer. We have previously reported that CEA measurement in nipple discharge is a useful adjunct in the diagnosis of nonpalpable breast cancer. As an extension, a dot-immunobinding assay was developed to screen a large number of patients with nipple discharge for nonpalpable breast cancer. This article is a review of the current status of CEA assay in nipple discharge for mass screening of breast cancer. False positive and negative cases will be also described.

As a second line therapy after failure to previous therapies, a combination therapy with MPA 1,200 mg po and 5'DFUR 1,200 mg po daily was given to 31 patients with recurrent breast cancer. At a median follow up period of 18 months, the overall response rate was 42%. The response rates for bone and visceral lesions were still good for the second line therapy. Patients previously exposed to tamoxifen (24 patients), 5-FU or its derivatives (21) and/or adriamycin (18) had response rates of 42%, 33%, 33%, respectively. The median duration of response in responders was 10 months. The overall median survival for the entire series was 9 months after start of the treatment. Thirteen (81%) of 16 patients with bone lesions were relieved from their bone pain. It is of special interest that the pain relief was also obtained in 7 out of 10 NC/PD patients with bone lesions, resulting in much improvement of their performance status. Side effects included obesity 52%, edema of the leg 35%, diarrhea 16% and so on. One patient developed venous thrombosis of her lower extremities and 4 were suspected to have the same condition. Fifty-five % of the patients underwent dose reduction of MPA at the 5th month of treatment in a median. This combination therapy is useful for recurrent disease even in late stages, so long as close observation is made for the occurrence of thrombosis.

A rare case of a non-invasive carcinoma of the breast is reported. A 39-year-old woman was admitted to our hospital complaining of large breast lump (11.5 X 8.0 cm) and an abnormal nipple discharge. Mammography revealed widely dispersed microcalcifications and an echographic diagnosis indicated a fibrocystic disease. A cytologic examination of the nipple discharge showed malignant cells with a CEA level that was very high. The patient was treated with a standard radical mastectomy. Specimen mammography showed microcalcification in almost all sections. The histological examination, using serial sections, was seen to be consistent with a non-invasive ductal carcinoma. No lymph node or remote distant metastasis was found.

Intra-arterial infusion chemotherapy was performed in 27 patients with locally advanced breast cancer. Through two catheters placed in the subclavian artery and the internal mammary artery, 30-50 mg of ADM was injected intermittently with/without continuous infusion of 5-FU. Higher response rate was noted in cases treated with ADM alone (80.0%, 16/20) in comparison with ADM-5-FU (57.1%, 4/7). Overall response rate was 74.1% (20/27). The correlation between the total dose of ADM infused and the rate of tumor regression was observed. Out of 18 cases who received 120 mg or more of ADM, 16 cases (88.9%) showed tumor regression greater than 50%, in contrast to 4 of 9 (44.4%) cases who received less than 120 mg of ADM. A significantly higher concentration of ADM was detected in tumor tissues obtained one hour after intra-arterial injection of ADM, compared with patients who received intravenous injection of ADM. The side effects due to this course of treatment were considered to be tolerated. Prognostically, although no definite correlation was observed between clinical or pathological effects and survival rate, a more favorable prognosis seems to be expected with this treatment compared with other forms of therapy.

A pancreas cancer-associated antigen (PCAA) and a pancreas-specific antigen (PaA) were simultaneously quantitated by enzyme-linked immunosorbent assays in serum specimens from 51 normal controls, 76 pancreatic cancers, 194 nonpancreatic cancers, and 22 benign pancreatic diseases. Primary immunological reagents used in the enzyme-linked immunosorbent assays were our polyclonal antibodies produced in rabbits against purified PCAA and PaA. Results revealed discordance of these two markers in pancreatic cancer, suggesting that the presence of these two biochemically and immunologically distinct pancreas proteins in patients' serum may reflect different biological aspects of cancer. The combination test resulted in a better sensitivity and specificity for pancreatic cancer, 90 and 85%, respectively, than either PCAA or PaA assay alone. This study demonstrated that the combination of serum PCAA and PaA tests yields an additive clinical value and may be a useful adjunctive aid for the immunodiagnosis of the pancreatic cancer.

In order to establish the optimal dose of Tamoxifen in the treatment of advanced breast cancer, a randomized trial comparing 40 mg/day to 20 mg/day was conducted. Thirty-four patients were entered in the study, and the results were as follows: 1) The response rates of 40 mg/day and 20 mg/day were 35.3% and 23.5%, respectively, without any significant difference between them. 2) The response rate in relation to metastatic sites were also similar at the two dose levels. 3) There was no significant difference in the median duration of response, either. 4) Among nine patients, one PR and three NC case were observed with subsequent increase of the dosage to 40 mg/day after 20 mg/day. The conclusion from this study was that 20 mg/day of Tamoxifen was suitable as an initial dosage for the treatment of advanced breast cancer. But, in certain cases who failed to respond, a dose-escalation to 40 mg/day appeared to be effective.

A retrospective analysis was undertaken on a series of 75 patients with locally advanced breast cancer treated with intraarterial infusion chemotherapy as an induction therapy. Several parameters were tested as to possible prognostic variables. Of these, only histological assessment of local response influenced survival; patients with good histological response had a better prognosis than those with poor response (77% versus 47% survival at 5 years). Thus, histological effect appeared to be an important prognostic factor in this treatment strategy.

The newly reported human prostate-specific antigen (PA) is a specific histiotypic product of human prostate. With the use of a sensitive enzyme immunoassay, the circulating PA in prostatic cancer patients has been evaluated clinically. In 96 patients with advanced stage of disease (D2) and receiving chemotherapies, the pretreatment serum PA levels were found to be of prognostic value with regard to the patient survival. Ten patients with metastatic prostate cancer were monitored for more than 32 weeks by 183 serial PA values and were found generally to respond to the treatment. Additionally, in another group of 32 patients who underwent curative therapies for localized prostate cancer, 161 serum samples were evaluated during periods of 12 to 114 weeks (average 56 weeks). Of these patients, five developed metastases during follow-up, and all were shown to exhibit increasingly elevated PA values, either corresponding to or preceding the clinical diagnosis of disease recurrence. These results suggest that PA is a new marker with potential value to merit further clinical study.

Serum prostate-specific antigen and prostatic acid phosphatase were simultaneously evaluated in 22 healthy males, 29 patients with benign prostatic hypertrophy, and 192 patients with prostate cancers at various stages as well as in 30 patients with cancers other than prostate cancer. Both markers were quantitated by specific sandwich-type, enzyme-linked, immunosorbent assays with the use of specific antiserum reagents. Serum assays revealed a discordance between these two markers; thus expressions of these two biochemically and immunologically distinct prostate-specific proteins may reflect different aspects in the biology of prostate cancer. A combination test with the use of 7.5 ng of prostate antigen and 15.5 ng of prostatic acid phosphatase/ml of serum, respectively, as cutoff values resulted in a positive detection rate of 58% for prostate cancers of stages A (7/12) and B (21/36) each, 68% for prostate cancer of stage C (19/28), 92% for prostate cancer of stage D (106/116), and only 10% for benign prostatic hypertrophy (3/29). None of 52 other cancers or healthy controls was registered as positive. This study demonstrates that a multiple marker test of tissue-specific antigens can be of an additive value in the immunodiagnosis of cancer and may be a logical and effective approach at this time, in light of the unavailability of human tumor-specific markers.

A case of a stromal sarcoma of the breast that developed after augmentation mammoplasty is presented. A 55-year-old woman, who had received mammoplasty twenty years earlier, was referred to our hospital due to a mass in her left breast. A diagnosis of myxoid sarcoma was determined by an incisional biopsy and a radical mastectomy was performed. A pathological specimen, however, revealed the mass to be a stromal sarcoma because of its metaplastic heterogeneous elements, such as bone, cartilage, and muscle. We also present previous cases, and discuss the matter of diagnosis and therapy.

We have previously reported carcinoembryonic antigen (CEA) measurement in nipple discharge to be a useful adjunct in the diagnosis of non-palpable breast cancer. As an extension, a dot-immunobinding assay was developed to screen a large number of patients with nipple discharge for non-palpable breast cancer. The principle is as follows. CEA bound to a solid phase monoclonal anti-CEA antibody is detected by a second monoclonal anti-CEA antibody conjugated with horseradish peroxidase. The use of tetramethylbenzidine as a chromogen results in a stable color reaction that can be semiquantitively analyzed by the naked eye. The CEA levels determined by this dot assay correlated well with CEA levels determined using the former Elmotec assay. To determine whether or not the method could also be feasible in the detection of non-palpable breast cancer, a collaborative study from 12 Japanese institutes was organized. The CEA levels in nipple discharges from 155 patients were assayed. Thirteen of 30 patients with palpable breast cancer and 22 of 30 patients with non-palpable breast cancer exhibited CEA values higher than 400 ng/ml, a cut-off value determined using 89 benign controls. The specificity (91%) and sensitivity (73%) of this test were higher than those of mammography or cytology. The incidence of elevated CEA levels in nipple discharge correlated significantly with the incidence of intratumoral antigen expression. Thus, the system could prove useful in screening for early breast cancer.