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Tamoxifen (TAM), a widely used antiestrogen for breast cancer therapy and chemoprevention, increases the incidence of endometrial cancer in women. The formation of DNA adducts induced by tamoxifen may initiate endometrial cancer. To evaluate the genotoxic risk of TAM, the formation of DNA adducts in leukocytes was examined. Blood samples were collected from 47 breast cancer patients (61.7 +/- 12.5 years) taking TAM (20 mg/day; average duration until sampling, approximately 37 months) and 20 untreated patients (58.2 +/- 12.3 years), and their leukocyte DNA was analyzed by 32P-postlabeling/HPLC analysis. This assay resolves synthetic standards, trans- and cis-diastereoisomers of alpha-(N2-deoxyguanosinyl)tamoxifen 3'-monophosphate (dG3'P-N2-TAM), alpha-(N2-deoxyguanosinyl)-N-desmethyltamoxifen 3'-monophosphate (dG3'P-N2-N-dMeTAM), and alpha-(N2-deoxyguanosinyl)tamoxifen N-oxide 3'-monophosphate', and is capable of determining TAM adducts quantitatively. The detection limit of this assay is 0.6 adducts/10(9) nucleotides. trans-dG3'P-N2-TAM (fr-2; one of the two trans-isomers) was detected in six of 47 breast cancer patients treated with TAM. Among them, trans-dG(3'P-N2-N-dMeTAM (fr-2) was also detected in two patients. The total amounts of TAM-DNA adducts in the positive patients were 2.6 +/- 3.0 adducts/10(9) nucleotides. No adducts were detected in the controls. The presence of TAM-DNA adducts in the leukocyte DNA samples was confirmed using several 32P-postlabeling/HPLC systems. more...

Purpose: We compared the therapeutic usefulness of doxifluridine (5'-DFUR) alone and a combination of 5'-DFUR plus cyclophosphamide (CPM), both of which are considered effective against advanced and recurrent breast cancer, to determine which treatment is more beneficial as postoperative adjuvant chemotherapy., Patients and Methods: A total of 1,131 women with node-positive primary breast cancer were randomly assigned after primary surgery to receive 5'-DFUR alone or 5'-DFUR plus CPM. All patients initially received 5'-DFUR in an oral dose of 1,200 mg/d for 4 weeks, starting 4 weeks after surgery. Chemotherapy was then not given for 2 weeks. Patients in the 5'-DFUR group subsequently received five 4-week cycles of treatment consisting of oral 5'-DFUR (1,200 mg/d) for the first 2 weeks and no chemotherapy for the next 2 weeks. Those assigned to the 5'-DFUR plus CPM group also received oral CPM 100 mg/d for the first 2 weeks and no chemotherapy for the next 2 weeks. Women 50 years or older concurrently received 20 mg/d of tamoxifen for 2 years in both groups., Results: Of the 1,088 eligible women, 546 were assigned to receive 5'-DFUR alone and 542 were assigned to receive 5'-DFUR plus CPM. Overall disease-free survival was significantly better in women who received 5'-DFUR plus CPM than in those who received 5'-DFUR alone (log-rank test, P =.021). Toxic effects occurred in 20.0% of patients (109 of 546) in the 5'-DFUR group and 32.3% of patients (175 of 542) in the 5'-DFUR plus CPM group (chi(2) test, P <.001)., Conclusion: Combination therapy with 5'-DFUR plus CPM is more effective in preventing recurrence than 5'-DFUR alone. more...

A case of secretory carcinoma of the breast in a 61-year-old woman is described. She came to our hospital complaining of a bloody nipple discharge. The physical examination revealed a 2.8 x 2.1-cm, firm, irregular lump with bloody nipple discharge in her left breast. Mammography demonstrated an irregular mass and ultrasonography showed an irregular hypoechoic mass accompanied with a cyst. Ductgraphy was done. It showed a dilated mammary duct leading to the cyst which was partially occupied with carcinoma. A cytologic smear of the nipple discharge and fine-needle aspiration cytology revealed similar findings, and both findings were malignant. A modified radical mastectomy was performed. A pathological examination revealed secretory carcinoma of the breast which had spread inward and outward from the cyst. In addition, the nipple discharge flowed from the cyst through the dilated mammary duct. The patient is presently alive and well 2 years after the operation. Secretory carcinoma is an extremely rare tumor of the breast and 48 cases have been reported in Japan. The present case is the first known case of secretory carcinoma demonstrating a bloody nipple discharge to come from a cyst which has been invaded by carcinoma. more...

To assess the efficacy of 5'-DFUR, an intermediate of capecitabine, for adjuvant treatment of early breast cancer, we conducted an open-labeled multi-center randomized controlled trial to compare postoperative 5'-DFUR treatment with surgery alone. We enrolled 1217 primary breast cancer patients and randomly assigned them into two treatment groups; one received six-month postoperative 5'-DFUR treatment by consecutive or intermittent administration, and the other surgery alone. Follow-up surveys were conducted once a year for all subjects simultaneously and examined their outcome/presence or absence of the cancer recurrence. The central study committee reviewed all follow-up data and judged the recurrence data to be used for the analysis. Eight-year follow-up data showed no significant differences in relapse-free and overall survival between the two groups, and 5'-DFUR treatment regimen showed an extremely high tolerance. Possible explanations are discussed for the finding of no significant survival difference between adjuvant 6-month 5'-DFUR monotherapy and surgery alone in early breast cancer. more...

The purpose of this study was to evaluate the possibility of differential diagnosis of tumors, such as breast cancer, by measuring the mammary electrical bioimpedance via the skin surface noninvasively and by examining the relationship between the tissue structure of the breast and electrical bioimpedance. The mammary electrical bioimpedance was measured in 24 patients with breast cancer. Taking into account the measurement results and the distribution of the mammary glands and fatty tissue, a breast model with tumors was proposed. Based on this model, the distributions of the electric potential and electric field in the tissue were theoretically analyzed by the three-dimensional finite element method. In clinical cases, the Re values of the diseased breast were significantly larger than those of the contralateral healthy breast. In theoretical analysis based on the breast model, the Re value of mammary electrical bioimpedance varied due to the structure of the breast, that is, the ratio of fatty tissue to mammary gland and the presence of mammary tumors. The results of the measurement agreed with the theoretical analyses. These results suggest that differential diagnosis of breast tumors is possible by measuring the mammary electrical bioimpedance using noninvasive electrodes on the skin. more...

The effectiveness of combining mitomycin C (MMC), tamoxifen (TAM), and 1-(2-tetrahydrofuryl)-5-fluorouracil (tegafur) was evident in patients with estrogen receptor-positive (ER+) breast cancers. UFT, an oral preparation of tegafur and uracil at a molar ratio of 1:4, was reported to have higher antitumor effects than tegafur alone for patients with breast cancer. Therefore, the combined chemotherapy of MMC, TAM and UFT may possibly be effective for breast cancer. From 1988 to 1991. we studied the effects of postoperative adjuvant therapy for Japanese women with stage 11 breast cancer, all seen at 71 institutions in western areas of Japan. Five hundred and ninety four patients with stage II primary breast cancer who had undergone curative surgery, including total mastectomy and axillary lymph node dissection, were enrolled. On the day of surgery, each patient was given 13 mg/m2 of MMC intravenously. Patients with ER+ tumors were then assigned to group A or group B. Group A received 30 mg/day of TAM given orally from postoperative 2 weeks, for 2 years. Group B was additionally given an oral dose of 300 mg/day of UFT for 2 years, given concomitantly with 30 mg/day of TAM. Patients with ER- tumors were assigned to group C or group D. Group C were prescribed 300 mg/day of UFT, orally, from postoperative 2 weeks for 2 years, and group D were additionally given an oral dose of 30 mg/day of TAM together with 300 mg/day of UFT. There were no differences among the groups regarding prognostic factors or doses of MMC and TAM in ER+ patients and MMC and UFT in ER- patients. Toxicity rates for leukopenia, anorexia, and nausea/vomiting were higher in group B than in group A patients. There were no statistical differences in the overall survival and disease-free survival times between groups A and B, or groups C and D, for all eligible cases. In a retrospective subgroup analysis using Bonferroni's adjustments, the additional effect of UFT on the combined treatment of MMC and TAM lengthened the disease-free survival time for patients with premenopausal ER+ cancers (corrected P value by Bonferroni's adjustments <0.05). Multivariate analysis showed that effects of the combined treatment of MMC, TAM, and UFT was significantly related to the menopausal status (P<0.01). Our findings show that postoperative ingestion of MMC, TAM, and UFT was effective for patients with premenopausal ER+ stage II breast cancer. more...

We examined the effect of recombinant IFN-alpha and IFN-gamma on induction of LAK cells from peripheral blood mononuclear cells (PBMNCs) in 7 pre-operative breast cancer patients and 4 healthy volunteers. Significant LAK activity was developed from PBMNCs of pre-operative breast cancer patients and healthy volunteers after incubation for 4 days with IL-2 (presence of IL-2 vs. absence of IL-2). Incubation of PBMNCs of pre-operative breast cancer patients with 1000 U/ml of IFN-alpha for 4 days suppressed the LAK activity significantly (P < 0.05). By contrast, incubation of PBMNCs of pre-operative patients with 1000 U/ml of IFN-gamma for 4 days increased the LAK activity significantly (P < 0.05). Significant cytotoxicity against MCF-7 cells (estrogen receptor positive human breast cancer cell line) was developed from PBMNCs of pre-operative breast cancer patients at 20:1 and 40:1 E/T ratios after incubation for 4 days with IL-2 (absence of IL-2 vs. 20:1 or 40:1, P < 0.05, P < 0.05), whereas PBMNCs of healthy volunteers did not. Stimulation of LAK cells with IFN-gamma produced a significant augmentation of cytotoxic activity against MCF-7 (P < 0.05), while IFN-alpha suppressed the cytotoxicity significantly (P < 0.05). These findings suggested that combined stimulation by IFN-gamma and IL-2 might be a reasonable treatment for breast cancer patients. more...

Background: Multi-combination chemotherapy consisting of anthracyclines has been effective but has not invariably prolonged the survival period in advanced/recurrent breast cancer. The possibility has been discussed that chemoendocrine therapy combined with endocrine agents is more effective., Methods: In order to evaluate the toxicity and efficacy of a new endocrine therapy for advanced/recurrent breast cancer, we ran a pilot study during the period from July 1994 to July 1996., Results: Twenty-two patients with advanced/recurrent breast cancer were treated with chemoendocrine therapy consisting of cyclophosphamide (100 mg/body) p.o. daily for 14 days, with adriamycin (40 mg/m2) i.v. and 5-fluorouracil (500 mg/body) i.v. on day 1 (repeated every 3 weeks for 9 weeks) (CAF therapy), and high-dose toremifene (120 mg/body) p.o. daily. Of 20 evaluable patients, two showed complete response (10%), eight partial response (40%), six no change (30%) and four progressive disease (20%). The overall response rate was 50%, and the median duration of response was 69.5 days (28-133+ days). The major toxicities were drug-induced alopecia, gastrointestinal toxicity and hematological toxicity, but these were clinically well tolerated. No serious cardiac, liver or renal symptom was seen., Conclusions: Based on these results, we consider the addition of high-dose toremifene to the CAF therapy to be useful in the treatment of advanced and recurrent breast cancer. more...

Comparison of acquired mutations in the p53 tumor suppressor gene can illuminate factors contributing to carcinogenesis among cancer cohorts. Japan has an ethnically homogeneous population with a low incidence of breast cancer. Previously we reported an unusual frequency, allelic status, and clustering of mutations in breast cancers from the northern part of the main Japanese island. To extend these findings, exons 2-11 and adjacent intronic sequences were analysed in tumors of women from northern (Hokkaido) and southern (Tokushima) Japan. The frequency of breast cancers with p53 gene mutations in the Hokkaido group is the highest reported (81%) while that in Tokushima (28%) is similar to most other populations. Thirteen of the 19 mutations (68.4%) in the Hokkaido cohort were heterozygous, an unusually high frequency for p53 mutations in any tumor type. There were three missense mutations at codon 175, a known hotspot for alterations in the p53 gene, and three missense mutations at codon 179, a rare site for p53 changes. In addition, the patterns of p53 gene mutation differed between the two Japanese cohorts (P=0.04). The multiple differences in acquired p53 mutations suggest unsuspected biological differences among breast cancers in northern and southern Japan. In addition, the high frequency of p53 mutations in breast cancers from Hokkaido predicted a poorer prognosis for this population which was confirmed on examination of mortality data. more...

Between 1985 and 1988, the effect of using ftorafur (FT) or PSK (an immunotherapy agent) in combination with the conventional postoperative adjuvant therapy using mitomycin (MMC) plus tamoxifen (TAM) was assessed in stage II, oestrogen receptor-positive (ER+) breast cancer patients. Furthermore, in ER- breast cancer stage II patients, the effects of postoperative adjuvant therapy using MMC plus FT were compared with the effects of postoperative adjuvant therapy using MMC plus PSK. Patients had primary stage II breast cancer and had undergone total mastectomy plus axillary dissection or more radical surgery. On the day of surgery, MMC (13 mg/m2) was administered intravenously. Then, ER+ patients received one of three regimens of drug therapy, starting 2 weeks after surgery: regimen A (daily oral treatment with 30 mg of TAM), regimen B (daily oral treatment with 30 mg of TAM and 600 mg of FT) or regimen C (daily oral treatment with 30 mg of TAM and 3 g of PSK) [corrected]. ER- patients received either regimen D (daily oral treatment with 600 mg of FT) or regimen E (daily oral treatment with 3 g of PSK), starting 2 weeks after surgery. Of the 540 ER+ patients registered, 525 were evaluated. The 5-year overall survival rate for ER+ patients was higher for patients who received regimen B (94.2%) than for those who received regimen A (86.9%) or regimen C (89.9%) (P = 0.063). The 5-year relapse-free survival rate was higher for regimen B (88.9%) than for regimen A (78.6%) and regimen C (77.2%) (P = 0.010). Stratified analysis revealed better results with the FT-combined therapy in patients positive for lymph node metastasis and premenopausal patients. These results indicate the effectiveness of using FT in combination with TAM. Of the 376 ER- patients registered, 364 were evaluated. The 5-year overall and relapse-free survival rate for ER- patients did not differ significantly between patients who received regimen D and those who received regimen E. more...

Multiple sections of 40 consecutive cases with invasive ductal carcinoma of the breast, all of which bad wide intraductal cancerous extension, were examined by immunohistochemical analysis for evaluation of hormone dependency in several areas of breast cancer tissues. In this study, we examined the expression of pS2 protein in the central invasive area (CIV), central intraductal cancerous area (CDC) and forefront intraductal cancerous area (FDC). pS2 staining was positive in 52.5% (21/40) of CIV and a significant correlation was found between pS2 expression in CIV and the estrogen receptor status (ER). pS2 staining was positive in 77.5% of CDC and 85.0% of FDC, respectively. A majority (68.4%) of the cases that were negative pS2 in CIV were positive for pS2 in FDC. Moreover, the cases with noncomedo intraductal carcinoma in premenopausal status showed a higher positivity of pS2 expression in FDC than the cases with comedo-carcinoma, though the number of cases of comedo-carcinoma was limited. These findings suggest that endocrine therapy may be useful after breast conserving treatment regardless of the ER status of the primary tumor. more...

Thymidylate synthetase (TS) is a key enzyme as a methyl donor in the methylation reaction from dUMP to dTMP. TS activity was assessed in various tissue of mammary disorders. The descending order of TS activity was as follows: cancer-positive nodes, primary cancers, cancer-negative nodes, benign lesions, and normal parenchyma. Significant differences in TS activity were found between the positive nodes and each of the other tissues (p < 0.01). In node-positive cases, a significant correlation in TS activity was found between the primary cancers and positive nodes (r = 0.616, p = 0.033). There was no correlation between the nodal status and the TS activity in primary cancers. In 11 of 12 cases, the TS activity of positive nodes was higher than the 'calculated' TS activity of the primary cancer, which was defined as the TS activity per unit weight of cancer cells. A significant correlation was found between the calculated TS activity and the mitotic frequency in primary cancers (r = 0.697, p = 0.0001). On the other hand, a significant correlation could not be found between the TS activity and the mitotic frequency in positive nodes (r = 0.364, p = 0.244). more...

The patient was a 38-year-old woman who was diagnosed as having right breast cancer (T1aN1bM0, stage II) at the age of 36 when she underwent right mastectomy. Postoperative adjuvant therapy was performed using UFT and tamoxifen. After 2 years and 4 months, pulmonary metastasis was diagnosed from elevated tumor markers and chest X-P. After the relapse, treatment with goserelin acetate (Zoladex) and CPA was started. After 2 months of this treatment, the tumor in the lung had shrunk in size, and after 5 months partial remission (PR) was evaluated from improvements in chest X-P and normalization of tumor markers, This PR condition continues at present. A case report is presented of a patient with premenopausal recurrent breast cancer in whom good results were obtained by concomitant administration of Zoladex and CPA. more...

At age 35, the patient was diagnosed with left breast carcinoma (T4bN0M0, Stage IIIb) during her first pregnancy, and underwent mastectomy of the left breast and bilateral oophorectomy. Although CPA was administered as adjuvant chemotherapy after the operation, left pelvic pain developed about a year after the operation, and bone metastasis was detected from the imaging diagnosis. Then, the therapy was switched to UFT (600 mg/day) and tamoxifen (20 mg/day), which markedly relieved the pain along with bone scintiscan (NC) and simple X-P (NC). Five years have passed since the operation, and the progress is excellent. There is neither increase of pain nor adverse reactions to drugs. Furthermore, the patient received breast reconstruction operation at her strong insistence in the third year after operation, and has achieved a high quality of life (QOL). more...

Seventy tumors of invasive ductal carcinoma of the breast were examined for p53 alteration by the RT-PCR-SSCP method. Sixty-five samples (92.9%) were investigated in the regions of codons 101-200 and 201-300. In total, 16 samples (24.6%) showed p53 gene alteration. We found that p53 gene alteration showed a correlation with (1) a negative ER status, (2) a negative PgR status, and (3) a high histologic grade (especially numerous mitotic figures) of the tumor. However, we found no correlation between p53 gene alteration and the lymph node status or clinical stage. Thus, p53 gene alteration in breast cancer may occur in highly malignant breast cancer other than advanced clinical stage cancer or node-positive cancer. more...

A controlled cooperative study was carried out to assess the value of modified radical mastectomy for patients with stage II breast cancer. The data was analyzed from 11 institutions in the Shikoku District participating in a prospective clinical trial in which patients were randomly assigned either to a modified radical mastectomy group or an extended radical mastectomy group. These two groups of patients were similar to each other in terms of such background factors as age distribution, menopausal status, TNM classification, tumor size, location of the primary tumor, axillary nodal involvement, histological type, and estrogen receptor status. The median follow-up times in the modified and extended radical mastectomy groups were 4.7 and 4.5 years, respectively. The cumulative curves indicated no difference between the two groups in either disease-free survival or overall survival. The survival rates were classified according to the presence or absence of axillary nodal metastases. However, no significant difference was found between the two groups. These findings thus suggest that the routine removal of the grossly uninvolved major pectoral muscle and parasternal lymph nodes is not necessary in patients with stage II breast cancer. more...

Forty consecutive cases with invasive ductal carcinoma of the breast (samples of both the primary invasive area and the involved node were available for 19 cases, multiple sections of breast tissue including both the primary invasive area and forefront intraductal cancerous area were available for 15 cases; and multiple sections of breast cancerous tissue and the involved node were available for six cases) were examined by immunohistochemical analysis for evaluation of their proliferation rate. In this study, we selected the PCNA index as a marker of the proliferation rate of the tumor cells. We demonstrated that the PCNA index of the primary invasive area was significantly higher than that of the forefront intraductal area (P = 0.0017), and the PCNA index of the involved nodes was significantly higher than that of the primary invasive area (P = 0.0004). These preliminary findings suggest that the progression from the tumor cells of the intraductal cancerous area to the metastatic tumor cells must be accompanied by two phases of increase in the proliferation rate. more...

Sixty-five tumors of invasive ductal carcinoma of the breast were examined for p53 alteration by the reverse transcription-polymerase chain reaction-single strand conformation polymorphism (RT-PCR-SSCP) method and sequencing analysis. In total, 16 samples (24.6%) showed p53 gene alteration. Sixteen of these alterations were evaluated by sequencing analysis, and 15 showed missense point mutations while one showed a 9-base pair deletion. In the 15 point mutations, G:C to A:T transitions constituted the majority (53%), and five tumors (33%) had a transition at the CpG site, which are mutational patterns not commonly found in breast tumors from Europe and America. On the other hand, there were no G:C to T:A transversions in our cases, which were frequently observed transversions in Europe and America. These p53 mutation patterns in breast cancer in Japan are not similar to those in Europe and America reported by Hollstein et al. and Coles et al.. These findings suggest that there are some differences between mechanisms of breast cancer in Japan and in Europe and America. more...

Local tumor extension was studied using a continuous series of multiple blocks of mastectomy specimens to assess malignancy remaining after breast-conserving surgery for early-stage breast cancer. In this study, 183 cases were chosen, consisting of 6 noninvasive ductal carcinoma cases and 177 invasive ductal carcinoma cases. The histopathology in 59 (32%) of the 183 cases corresponded to that showing extensions of more than 2.6 cm from the tumor margin. These wide extensions were also seen in 17% of breast cancers with a tumor size of less than 2 cm. The incidence of wide extension was higher in younger patients with cases of noninvasive ductal carcinoma. Extension to the nipple-areola was seen in 14% of cases with a tumor size of less than 2 cm. Breast cancers with multicentric development accounted for 3% of those with a tumor size under 2 cm. These findings suggest that if lumpectomy is performed with a margin of 2 cm for tumors with a size of 2 cm or less, a cancerous residue would be found in the surgical margin of 15-20% of the cases. The actual incidence was 23% of cases after breast-conserving treatment in our study. On the basis of the data, breast-conserving treatment with only local resection of the primary lesion showed cancerous residue such as intraductal cancerous extension in about 20% of cases. Therefore, it was concluded that, as part of breast-conserving therapy of early-stage breast cancer, radiation therapy of the whole breast should be performed after surgery with clear margins to control local recurrence. more...

It is very unusual for a carcinoma of the breast to coexist with a phyllodes tumor, or for a carcinoma to arise within a fibroadenoma. We present herein an extremely rare case of lobular carcinoma in situ arising in a fibroadenoma, associated with a malignant phyllodes tumor in the opposite breast. A 49-year-old woman was admitted to our hospital with a large mass in the right breast and a small mass in the left breast. Microscopic examination of biopsy materials revealed a malignant phyllodes tumor in the right breast and a fibroadenoma in the left breast, for which a right standard radical mastectomy and left lumpectomy were performed. Microscopic findings of the material excised from the left breast showed the presence of multiple lobular carcinoma in situ within the tumor mass of the fibroadenoma. However, histological examination did not detect any metastasis to the bilateral axillary lymph nodes. To our knowledge this is the only such case ever to be reported in Japan. more...

A new system of impedance measurement over a frequency range of 0 to 200 kHz was developed by a three-electrode method. In this study, the electrical impedances of various tumors were measured in vivo in 54 patients with breast disease (31 breast cancers, 13 fibroadenomas, and 10 fibrocystic diseases) and 57 patients with pulmonary disease (44 lung cancers, 5 metastatic pulmonary tumors, 4 pulmonary tuberculoses, and 4 organized pneumonias). On the basis of those impedance measurements and the equivalent circuits in vivo, we calculated the extracellular resistance (Re), intracellular fluid resistance (Ri), and cell membrane capacitance (Cm) in tissues, all of which were compared among the various diseases. It was found that Re and Ri were significantly higher in breast cancers than in benign tumors and normal breast tissues and that Cm was significantly lower in breast cancers than in other tissues. On the other hand, Re and Ri were significantly higher, and Cm was significantly lower, in normal lung tissues than in pulmonary masses. Re and Ri were significantly higher, and Cm was significantly lower, in malignant tumors than in organized pneumonias. The results showed that these parameters (Re, Ri, and Cm) exhibit significant differences among various tissues and tumors, suggesting possible applications in tumor diagnosis. more...

Mass screening for breast cancer using physical examination alone has been carried out since 1983 in Zentsuji, Kagawa Prefecture, Japan. Over a 7-year period, breast cancer was detected in 11 of a total 8,271 examinees, the detection rate being high at 0.13%. The detected cases included a few early-staged breast cancers, suggesting that mass screenings are of slight efficacy. Seven cases of interval cancer were found by breast self-examination after the mass screenings, supporting the value of breast self-examination. A relatively large number of interval breast cancers was detected in 1985 and 1986, when the rates of required further examination remained under 1%. The sensitivity and specificity of this screening were 61.1% and 94.5%, respectively, indicating a low sensitivity. These results suggest that the qualitative diagnoses made from the first screening by physical examination alone were often revealed to be false negatives. Therefore, the existing diagnosis should be employed in the first screenings. It is recommended that mammography be introduced to detect breast tumors which are nonpalpable or undetectable by physical examination alone. more...

To investigate the characteristics of interval breast cancer in mass screening, comparisons were made of the following three groups: interval group (21 interval breast cancer cases), mass screening group (87 breast cancer cases detected by mass screening) and outpatient group (266 breast cancer cases diagnosed at outpatient clinics). There were no differences among the three groups in terms of the case distribution by age or obesity, but significant differences in the case distribution according to nodal involvement and tumor size. Histological grading of the malignancy of the primary tumors disclosed that the incidence of breast cancer showing frequent mitoses was high in the interval group compared to the mass screening and outpatient groups. The 7-year cumulative disease-free survival rate was 75.3% in the interval group, 90.0% in the mass screening group and 83.1% in the outpatient group. The mean tumor size of the interval cases at the time of mass screening, back-calculated on the basis of the estimated tumor doubling time, was 1.5 cm in diameter, smaller than that of the mass screening group. It is surmised that interval breast cancer is characterized by marked proliferation of the tumor cells and has a poorer prognosis than the other group cases. These findings might be due to the marked proliferation of interval breast cancer rather than because of cases having been overlooked at the time of the last screening. more...

Background: A randomized adjuvant trial was conducted from October 1982 to January 1985 to evaluate the addition of tamoxifen (TAM) to combination chemotherapy with perioperative mitomycin C (MMC) and ftorafur (FT) for patients with estrogen receptor (ER)-positive tumors and the addition of PSK, a biologic response modifier, to MMC+FT chemotherapy for patients with ER-negative tumors in operable Stage IIA, IIB, and IIIA cancer. The doses used were 20 mg of oral TAM daily, 600 mg of oral FT daily, and 3 g of oral PSK daily for 2 years. Intravenous MMC (13 mg/m2) was given on the day of operation., Methods: A total of 967 patients were entered and randomized by stratification based on ER status and staging (1978 International Union Against Cancer [UICC] criteria at the time of trial execution). Of 967 patients, 914 (94.5%) were evaluable. At 5-year follow-up, significant prolonged overall survival (OS) and relapse-free survival (RFS) times were seen with the addition of TAM in patients with ER-positive and Stage IIIA T3N0 cancer (1987 UICC-American Joint Committee on Cancer [AJCC] criteria); however, no significant survival benefit from TAM was seen in patients with ER-positive and Stage IIA T2N1 cancer. There was no significant difference between regimens, with or without PSK, in patients with ER-negative disease., Results: Results of subset analyses suggested a benefit from TAM in postmenopausal patients with ER-positive and Stage IIA T2N1 cancer and a benefit from PSK in patients with node-negative, ER-negative, and Stage IIA T2N1 cancer., Conclusions: The 5-year results of the current trial showed a survival advantage by the addition of TAM to chemotherapy in patients with ER-positive and Stage IIIA T3N0 cancer. more...

To investigate the characteristics and the prognosis of interval breast cancer, 21 interval cases were reviewed and compared with a total of 87 patients with breast cancer detected by mass screening and 266 found in outpatient clinics on the basis of the clinicopathological features. The postoperative cumulative 7-year disease-free rates were 61.1%, 81.4% and 69.0% in the interval cases, mass screening cases and outpatient clinic cases, respectively. The percentage of cases showing frequent mitoses in cancer cells was statistically higher for interval cancer than for the other breast cancers. The average tumor size of the interval cases calculated from the speculated tumor doubling times, was 1.51 cm. It is surmised that interval breast cancer is characterized by a marked proliferation of tumor cells and has a poorer prognosis than the other breast cancers. This might be due to the marked proliferation of interval breast cancer rather than under-counting because there were no malignant findings at the time of the last screening. more...

We report herein a case of a 31 year old housewife who underwent an excisional biopsy for a well-circumscribed lump in her breast. The lump contained 2 histological patterns, namely, fibroadenoma and tubular adenoma. These patterns had no transitional zone, were distinct and changed abruptly. This case was histologically diagnosed as "a fibroadenoma in tubular adenoma of the breast, benign", with no other such case ever having been reported in Japan. The histological findings of this case, convinced us that tubular adenoma is closely related to fibroadenoma. more...

Estrogen receptors (ER) and epidermal growth factor receptors (EGFR) in the tumor cells of breast cancer tissues (primary tumors) and metastatic lymph nodes (involved nodes) were analyzed by immunocytochemical study in 19 patients; 12 were ER positive, and seven were ER negative. Microscopic study was used to determine the percentage of positive cells and the staining index. The percentage of EGFR-positive cells and the EGFR staining index were higher in the ER-negative primary tumors than ER-positive primary tumors. In ER-positive cases, both the number of ER-positive cells and ER content per cell was less in the involved nodes than in the primary tumors, whereas the number of EGFR-positive cells and EGFR content per cell was greater in affected nodes. On the other hand, in the ER-negative cases the number of EGFR-positive cells and EGFR content per cell remain almost unchanged between the primary tumors and involved nodes. The authors supposed a probability, in this study, that estrogen may exert inhibitory action on EGFR production through binding to ER. more...

This report summarizes the clinicopathologic findings in 11 cases of low papillary carcinoma of the breast accompanied by the morphologic feature of mucus leakage into the mammary stroma. These cases were characterized by two morphologic findings. First, abundant mucus produced by the tumor cells filled the intraductal spaces where neoplastic epithelium formed very low papillary projections, ie, a feature of mucinous-producing low papillary carcinoma in situ. Second, there was expansive leakage of mucus into the mammary stroma occasionally accompanied by a few epithelial cells. All the cases showed a high level of mucus production and contained no elements of invasive ductal carcinoma or ordinary invasive mucinous carcinoma. These cases have no evidence of direct invasion of the mammary stroma by malignant cells. The average age of the 11 patients was 41 years. Foci of microcalcification were seen in some tumors (seven cases; 64%). There were no cases with lymph node metastases. All the patients underwent mastectomy with no adjuvant therapy, and they are currently alive and well. more...

Sixty-two breast carcinoma patients underwent mastectomy and were analyzed for correlations between estrogen receptor (ER) status of the tumor and the histological findings of tumor, age, nodal status, and tumor size. An immunocytochemical assay for the detection of ER in breast carcinomas was used to evaluate the staining intensity index (SII) of the ER level of the tumors, which was calculated from the staining intensity of cancer cells and the percentage of ER-positive cancer cells. The histological differentiation of carcinomas showed a strong correlation with the SII. A statistically significant (F = 10.580, P less than 0.0005) negative correlation was found between the grade of malignancy and the SII. Patients under 50 years of age tended to have a lower SII, whereas patients over 49 years of age tended to have a higher SII. The tumor size, and nodal status showed no correlations with the SII in any of the patients. The histological differentiation of the tumor cells showed a strong correlation with the heterogeneity of the distribution of ER-positive cells in breast cancers. more...

Serum level of sex hormone-binding globulin (SHBG) was measured by immunoradiometric assay in fifty two breast cancer patients and twenty nine healthy female volunteers. The results are as follows: 1) Although the serum SHBG concentration showed no significant difference between the breast cancer group and the healthy control group, the serum SHBG concentration in postmenopause was significantly higher in the breast cancer group (63.8 +/- 31.2nmol/ml/ml; mean +/- S.D.) than in the healthy control group (40.1 +/- 15.4nmol/ml). 2) Subsequently in the postmenopausal breast cancer group, the serum SHBG concentration was significantly higher in the estrogen receptor (ER)-negative cancer group (97.8 +/- 12.7nmol/ml) than in the ER-positive cancer group (55.8 +/- 32.1nol/ml). 3) No significant relationships were showed between the serum SHBG concentration and obesity or serum estradiol concentration in postmenopausal patients. 4) The serum SHBG concentration showed significant decrease 3 months after radical operation for breast cancer in postmenopausal patients. These results suggest the possibility of the SHBG synthesis in breast cancer tissue. more...

The purpose of this study was to investigate the biological behavior of male breast cancer. We evaluated 11 cases of male breast cancer with respect to tumor growth, extent of disease, hormone receptor status, and histological grade of the malignancy, in comparison with 241 cases of female breast cancer. The duration of symptoms was 8.6 +/- 9.1 months in males and 8.5 +/- 18.6 months in females. The incidences of stages I, II, and III were 46%, 27%, and 27%, respectively, in male breast cancer, and 38%, 49%, and 13% in female breast cancer. Metastasis to the lymph node was negative in 60% of the male patients and 54% of the female patients. All cases of male breast cancer were histologically grade I according to Bloom's classification; the histological grades were as follows for the female breast cancer cases: grade I in 99 patients, grade II in 87, and grade III in 55. The rates of hormone receptor positively were 89% for ER and 86% for PgR in male breast cancer, and 64% for ER and 44% for PgR in female breast cancer. Therefore, there was no significant difference in the growth of male breast cancer and female breast cancer, but in male breast cancer the rate of hormone receptor positivity was high, endocrine therapy was effective, and the histological grade was low. Accordingly, the result following appropriate treatment of male breast cancer should be at least comparable to the results with female breast cancer. more...

A new impedance analytical system was developed, and measurements were performed over a frequency range of 0-200 kHz by the three-electrode method. The three electrodes consist of a coaxial needle electrode inserted into the tumor and a large reference electrode on the upper abdominal wall. The electrical bio-impedance was measured in 54 patients with breast tumors. The biological tissue can be regarded electrically as an equivalent consisting of extracellular resistance (Re), intracellular resistance (Ri), and electrical capacitance of the cell membrane (Cm). These three parameters were calculated from the measured values of electrical bio-impedance by the curve-fitting technique using a computer program. It was found that Re and Ri of breast cancers were significantly higher than those of benign tumors (p less than 0.01), and that Cm of breast cancers was significantly lower than that of benign tumors (p less than 0.01). Measurement of the electrical bio-impedance of breast tumors may have value in the differential diagnosis of breast lesions. more...

In a review of 549 cases of breast cancer in the last 16 years, 7 cases with lobular carcinoma have been studied. All of the patients appeared well and were without recurrence. Two cases had been lobular carcinomas in situ, one of which had arisen in a small fibroadenoma associated with malignant phyllodes tumor in the opposite breast, and the other had shown multicentric foci of a lobular neoplasm. The remaining 5 cases had been invasive lobular carcinomas. The incidence of lobular carcinoma represented 1.3% (7/549) of all primary breast carcinomas, and had been increasing chronologically. Estrogen and progesterone receptors were positive in 5 eligible cases. more...

The effect of adriamycin (ADM) infused intraarterially as a preoperative procedure was analyzed retrospectively in 15 patients with primary advanced breast cancer. A high clinical response rate (CR+ PR) of 73% (11/15) was obtained by the treatment, and also remarkable degenerative changes of tumor cells were histologically noted in 10 out of 15 surgical specimens (67%). A correlation between the dose of ADM infused and the rate of tumor regression was observed. A significantly higher concentration of ADM was detected in metastatic lymph nodes and tumors obtained 3-4 weeks after intra-arterial infusion of ADM than that in normal mammary gland. As for side effects, alopecia, leukocytopenia, anorexia, nausea and vomiting occurred at high frequencies. The side effects due to this treatment were considered to be tolerable. Prognostically, a good survival rate was not observed using preoperative treatment with intra-arterial ADM infusion. more...

In Tokushima prefecture, mass screening for breast cancer has been conducted using physical examination alone since 1970. Breast cancer was detected in 116 of 111,571 screened women up until 1984. The detection rate was 0.08 per cent in total examinees, 0.13 per cent in initial examinees, and 0.04 per cent in subsequent examinees. The patients with breast cancer were divided into three groups, i.e., 62 cases detected at initial screening, 28 cases detected at subsequent screenings, and 26 interval cancer cases. 510 patients with breast cancer in the outpatient clinic were serving as controls. The stage classification and nodal involvement were significantly different between the mass screening group and the control group, but not significantly different among the three groups. The interval cases were detected at an early stage. The survival rates were not significantly different between the three groups and the control group. Efforts should be doubled to educate women about the proper method of breast self-examination in order to promote the early detection of breast cancer. more...

A case is reported of a patient who developed a histological unusual sarcoma in the chest wall 5.3 years after postoperative radiation therapy (5,000 rads) for breast cancer. This sarcoma showed microscopic features of malignant fibrous histiocytoma (MFH). A review of the literature disclosed 16 other cases in which MFH developed under similar circumstances. An analysis of these 16 cases and the case reported here showed that the mean radiation dose was 5,623 rads, that the time period between irradiation and the development of MFH ranged from 2 to 27 years and that wide resection offered better prognosis than chemotherapy. more...

The electrical bio-impedance of 17 breast tumors including 12 breast cancers and 5 fibroadenomas, were measured in vivo with three-electrode method in the frequency range of 0 to 200 KHZ. The three-electrode consists of a coaxial needle electrode inserted into the tumor and a large reference electrode on upper abdominal wall. The tissue can be regarded electrically as a equivalent consisted of extracellular resistance (R1), intracellular resistance (R2), and electric capacitance of the cell membrane (C). These three parameters were calculated from the measured values of electrical bioimpedance. It was found that R1, and R2 of breast cancers were significantly higher than those of fibroadenomas (p less than 0.001), and that C of breast cancers was significantly lower than that of fibroadenomas (p less than 0.001). The measurement of the electrical impedance of breast tumor in vivo may be useful for the differential diagnosis of breast lesions. more...

The aim of this study was to establish the role of estrogen receptor (ER) and progesterone receptor (PgR) as prognostic indicators for early recurrence and survival. In all, among breast cancer patients, 166 patients who had undergone radical or extended radical mastectomy were studied. These patients were treated with adjuvant chemotherapy alone for 2-3 years after surgery. No patients had adjuvant endocrine therapy. Local recurrence and/or distant metastases were treated by endocrine therapy and/or chemotherapy. The relapse-free interval was not different between the ER-positive and ER-negative patients. The postrelapse survival curve was significantly different between the two groups. There was no significant difference in the relapse-free interval and the postrelapse survival curve between the PgR-positive and PgR-negative patients. These results suggest that ER is a good predictor of the response to endocrine therapy given after relapse, but not of early recurrence. more...

The relationship of hormone receptor and postoperative prognosis was investigated in 166 patients with breast cancer who underwent curative operation and postoperative adjuvant chemotherapy. The endocrine therapy was performed only for the patients with recurrent disease. The content of estrogen receptor (ER) and progesterone receptor (PgR) were measured by binding assay using gel-filtration method. ER-positive cases accounted for 56% of 166 patients and PgR-positive ones for 36% of 124. The relapse free interval was not different between the ER-positive group and ER-negative one, but the survival curve after relapse was significantly different between the both groups. There was no significant difference in the relapse free interval and the survival curve after relapse between PgR-positive group and PgR-negative one. These results suggest that the ER is a good predictor as to the response to endocrine therapy given for recurrent disease, but not as to early recurrence. more...

5'-DFUR was administered orally to recurrent breast cancer patients at a daily dosage of 1,200 mg given 3 times a day for more than 8 weeks. Out of 16 evaluable cases, 1 CR, 5 PR, 5 NC and 5 PD were observed, and the overall response rate was 37.5%. There was no significant difference in the response rate between the patient with or without prior fluorinated pyrimidine therapy, or between sites of the lesion. Toxic effects consisted of gastrointestinal toxicity such as diarrhea (25%), anorexia (12.5%), abdominal pain (12.5%) and nausea and vomiting (6.3%). No other severe side effect was observed. These results suggest that 5'-DFUR can be useful for the treatment of breast cancer. more...

In 175 women with mucinous carcinoma (MC) of the breast, the morphologic features, the clinicopathological features (age, tumor size, and nodal status) and prognoses were investigated. They were divided into two types, those with "unmixed type" (n = 140) showing no component of invasive ductal carcinoma (IDC) and "mixed type" (n = 35) including an IDC component. The unmixed type showed less frequent (P less than 0.01) nodal involvement and a higher degree (P less than 0.005) of extracellular mucus production than the mixed type. The presence of nodal metastases showed no correlation with the degree of mucus production. The 10-year survival rate of the unmixed type (90.4%) was better (P less than 0.001) than in the mixed type (66.0%). In the unmixed type, a higher level of mucus production showed trends toward a better prognosis, younger age and smaller tumor size (P less than 0.01). In the mixed type, the degree of mucus production showed no significant correlation with either the age, tumor size, or prognosis. It is more important for the prognosis of patients with MC to have no IDC component than to show abundant mucus within the tumor. more...

In Tokushima prefecture, mass screening for breast cancer has been conducted using physical examination alone since 1970. Breast cancer was detected in 108 of 141,116 screened women up until 1986. The detection rate was 0.08% among total examinees, 0.12% among initial examinees, and 0.04% among subsequent examinees. Patients with breast cancer were divided into three groups. Group I consisted of 70 patients whose cancers were detected by initial screening examination. Group II consisted of 38 patients whose cancers were discovered by subsequent periodic screenings. Group III included "interval" patients, whose cancers were found in the interval within 2 years between a negative screening examination and the next screening; 19 patients were classified into this group. Serving as controls were 615 breast cancer patients who visited our outpatient clinic, independently of the screening program, during the same period as that of the mass screening. Of the 108 patients in Groups I and II, 51 patients (47%) had noticed a lump in the breast themselves by the time of the mass screening. The stage classification and nodal involvement showed significant differences between the mass screening group and the control group, but no significant differences among the three groups. The Group III cases (interval cases) were detected at an early stage, but some of these cases included patients with fast-growing tumors. When compared with cumulative survival curves according to age-matched case-control study, there was no significant difference between the patients whose tumors were detected in the mass screening and the controls. more...

A patient with stage IV advanced breast cancer with multiple metastasis (bones of the whole body, lungs) were treated by ovariectomy, administration of an non-steroidal antiestrogen (tamoxifen) and mild chemotherapeutic drugs, with favorable results. After four years, however, the patient had a relapse of the cancer. A steroidal antiestrogen (epitiostanol) was then administered with satisfactory results. When a breast cancer relapse occurs in patients once treated successfully with endocrinotherapy, a different form of endocrinotherapy should be tried. There is a possibility that the mechanism of action of Epitiostanol, which is regarded as a steroidal antiestrogen, is different from that of tamoxifen in which an estrogen receptor (ER) system is included. more...