Relationship between existence of lymphatic invasion in peritumoral breast tissue and presence of axillary lymph node metastasis in invasive ductal carcinoma of the breast.

Specimens obtained from 92 patients with invasive ductal carcinoma of the breast by quadrantectomy and axillary lymph node dissection were examined to evaluate the relationship between existence of lymphatic invasion in peritumoral breast tissue and presence of axillary lymph node metastasis. The number of lymphatic invasions was classified into 4 groups (ly0-3) by counting the number of peritumoral lymphatic invasions. In addition, immunohistochemistry for cytokeratin was performed to locate micrometastasis in the dissected lymph nodes. Thirty-seven (40.2%) of 92 cases had foci of lymphatic invasion and 29 (31.5%) cases revealed lymph node metastasis on initial routine examination. The rate of diagnosis of lymph node metastasis assessed by the existence of lymphatic invasion had an accuracy of 84.8%, a sensitivity of 89.7% and a specificity of 82.5%. On the other hand, all 3 cases (4.8%) with micrometastasis detected by immunohistochemistry for cytokeratin, showed lymphatic invasion. The rate of diagnosis after detection of micrometastasis increased and exhibited 88.0% accuracy. In addition, the rate of prediction of lymph node metastasis in cases with tumor larger than 15 mm was also high, and its accuracy was 88.2%. These results suggest that the assessment of peritumoral lymphatic invasion is very useful for predicting the presence of axillary lymph node metastasis including micrometastasis. They also suggest that excision specimens should be examined for lymphatic invasion, and that the results of the examination might be necessary to pick up false-negative cases and those at high risk for lymph node metastasis among patients who have not undergone lymph node dissection based on the result of sentinel lymph node biopsy.

[A case of lung and pleural metastases from breast cancer responding to toremifene].

A patient with lung and pleural metastases from breast cancer treated effectively with toremifene is reported. A 62-year-old woman underwent mastectomy for breast cancer, and had high levels of estrogen and progesterone receptor. After 2-years of adjuvant UFT therapy, lung and pleural metastases were seen on a chest x-ray. The patient received a high-dose of toremifene (120 mg/day). After five months with toremifene, a chest x-ray and CT scan showed the disappearance of lung and pleural metastases. No recurrence or metastases have been detected for twenty months to date. No serious side effects were noticed. High-dose toremifene might be an effective therapy for cases of postmenopausal metastatic breast cancer, with high levels of estrogen and progesterone receptor.

Enhancement of immunohistochemical reactivity for thymidine phosphorylase in breast carcinoma cells after administration of docetaxel as a neoadjuvant chemotherapy in advanced breast cancer patients.

For the purpose of demonstrating possible effects of docetaxel on thymidine phosphorylase (TP) activity in human breast carcinoma, we examined breast carcinoma tissues pre- and post-administration of docetaxel, by an immunohistochemical method using an anti-TP monoclonal antibody. Eight patients with advanced breast carcinoma were initially treated with 3 cycles of 60 mg/m2 of docetaxel once every 3 weeks after incisional biopsy of tumors, and following 3 cycles of docetaxel, they underwent mastectomy with axillary dissection. Grades of immunohistochemical reactivity for TP of carcinoma cells in pre- and post-treatment specimens were compared. Five biopsy specimens (62.5%) were positive for TP. After administration of docetaxel, 6 of 8 cases (75.0%) revealed significant enhancement of reactivity for TP. Increased reactivity was recognized diffusely as well as focally in carcinoma tissues. From these results, we believe that administration of docetaxel to breast cancer patients evokes enhancement of immunohistochemical reactivity for TP in breast carcinoma cells in situ. Furthermore, we consider that docetaxel treatment might improve efficacy of additional doxifluridine and capecitabine therapy.

The mechanisms of antitumor effects of luteinizing hormone-releasing hormone agonist (buserelin) in 7, 12-dimethylbenz(a)anthracene-induced rat mammary cancer.

We evaluated the mechanism of antitumor effects of buserelin, which is one of LH-RH agonists, on a hormone dependent breast cancer model, using 7,12-dimethylbenz(a)anthracene (DMBA)-induced rat mammary cancer. Rats developing solid mammary tumors within 5-7 weeks following the DMBA administration were divided into groups weekly, and treated without delay. The tumor bearing rats were randomized into five groups with regard to tumor size or average weight (15 rats per group). Each group received one of the following treatments during 4 weeks: a) no treatment (NT); b) ovariectomy (Ovx); c) buserelin; d) Ovx and 17beta-estradiol (E2) (Ovx+E2); e) Ovx+E2+buserelin. Tumor regression immediately began at one week after both buserelin treatment and ovariectomy. A significant reduction of tumor size was observed in both buserelin-treated rats and Ovx rats compared with NT rats (p<0.01). No significant difference of tumor size was observed between buserelin-treated rats and ovariectomized rats. No reduction of tumor size was observed in Ovx+E2 rats and Ovx+E2+buserelin rats. Although the mean uterine wet weight of the buserelin group was significantly higher than that of the Ovx group, it was significantly lower than that of the NT group. The mean uterine wet weight of the NT group, the Ovx+E2 group and the Ovx+E2+buserelin group was similar and was significantly higher than that of the Ovx group. Buserelin did not inhibit exogenous estrogen-dependent tumor growth in DMBA-induced rat mammary cancers. These results suggest that buserelin has no direct effects on DMBA-induced rat mammary cancers, and the main mechanism of action of buserelin for tumor-reduction is due to ovarian estrogen deficiency.

A novel aromatase inhibitor, vorozole, shows antitumor activity and a decrease of tissue insulin-like growth factor-I level in 7, 12-dimethylbenz[a]anthracene-induced rat mammary tumors.

Effects of vorozole, a potent and specific non-steroidal aromatase inhibitor, were evaluated on female Sprague-Dawley (SD) rats with 7, 12-dimethylbenz[a]anthracene (DMBA)-induced mammary tumors. Vorozole at a dose of 0.25, 1.0 and 4.0 mg/kg was orally administered once a day for 28 consecutive days. A significant regression in tumor size was observed in each treated group at 1, 2, 3 and 4 weeks after the start of treatment compared with control group. Tissue insulin-like growth factor I (IGF-I) in the DMBA-induced tumors in each treated group significantly decreased in a dose-dependent fashion compared with control group. These results show the mechanism of vorozole in DMBA-induced rat mammary tumors.

Antitumor effects of SEF19, a new nonsteroidal aromatase inhibitor, on 7,12-dimethylbenz[a]anthracene-induced mammary tumors in rats.

The antitumor and endocrine effects of a new nonsteroidal aromatase inhibitor, 2-(imidazol-1-yl)-4,6-dimorphorino-l, 3, 5-triazine (SEF19) were examined in female Sprague-Dawley rats bearing estrogen dependent 7,12-dimethylbenz[a]anthracene(DMBA)-induced mammary tumors, and the effects were compared with those of CGS20267. The rats bearing DMBA-induced mammary tumors within 6-15 weeks after the DMBA administration were divided into the treatment groups once a week every week, and they were treated with SEF19, CGS20267 and vehicle for 4 weeks. One hundred rats were sacrificed 4 hours after the last administration, and the remaining 60 rats were sacrificed after a 4-week recovery period. During the treatment and recovery period, the tumor size was generally smaller in the SEF19 and CGS20267-treated subgroups than in the control subgroup. Tumor sizes in the subgroups treated with high doses of SEF19 (25 mg/kg/day and 50 mg/kg/2 days) were reduced to the size of the CGS20267-treated subgroup. The CGS20267-treated rats showed decrease in the serum estradiol level and an increase in the serum testosterone level. Their uterine weights were reduced. SEF19 treatment failed to show any effect on the serum levels of estrone, estradiol, testosterone and androstenedione, but it suppressed uterine weight in a dose-dependent manner. After the recovery period, no effect was detected in the serum concentrations of steroid hormones and the weight of the organs. At every dose used in the present study the aromatase inhibitory activity of SEF19 was weaker than that of CGS20267, but the inhibitory effect on mammary tumor growth of SEF19 at high doses was comparable to that of CGS20267. We conclude that the antitumor effect of SEF19 is not due to aromatase inhibition but mainly to its direct cytotoxicity.

A combination chemoendocrine therapy of mitoxantrone, doxifluridine, and medroxyprogesterone acetate for anthracycline-resistant advanced breast cancer.

Between January 1993 and October 1995, 34 patients with anthracycline-resistant advanced breast cancer were treated with a combination chemoendocrine therapy of mitoxantrone (MIT), doxifluridine (5'-DFUR) and medroxyprogesterone acetate (MPA). Of 34 patients, 28 were evaluable for efficacy of this combination therapy, and 30 including 2 for whom data were incomplete were assessed for adverse drug reactions. Adriamycin (ADM) was used for pretreatment in 12 patients, 4'-epi-ADM in 6, and THP-ADM in 12. In the eligible patients, 8.0 mg/m2 MIT was administered intravenously every 4 weeks, and 600 mg MPA and 600 mg 5'-DFUR were given orally every day. The median follow-up period was 25 weeks (range 2-90 weeks). The median cumulative dose of mitoxantrone was 66 mg (range 12-121 mg). Of the 28 patients, 11 (39.3%) responded to this combination therapy. As for response in relation to predominant site of lesion, 1 of 5 soft tissue lesions (20%) and 8 of 12 bone metastases (66.7%) showed a partial response, and one complete response and one partial response (25.0%) were seen in eight lung lesions. None of three pleural lesions responded to this therapy. The median duration of response was 31 +/- weeks (range 12-82 weeks). Adverse drug reactions were controllable or tolerable. Combined chemoendocrine therapy with a low dose of MIT is a well-tolerated and moderately effective regimen for the treatment of anthracycline-resistant advanced breast cancer.

Comparison of breast-conserving therapy with mastectomy for treatment of early breast cancer.

The aim of this study was to compare the survival and recurrence rates of patients undergoing breast-conserving therapy with the rates of those undergoing mastectomy. Between August 1991 and June 1994, 229 patients were enrolled in this study, although one was later excluded because the tumor was histologically diagnosed as benign. A total of 119 patients with clinical stage TIS, I or II underwent breast-conserving therapy and 109 patients received mastectomy. Mastectomy was utilized more than breast-conserving therapy in the case of clinical stage II, greater age, larger tumor size or shorter distance between the tumor and the nipple. Twenty-seven patients (23.1%) of the 117 receiving breast-conserving surgery were surgical margin positive. There was no significant difference in the distance between the tumor and the nipple, tumor size or clinical stage in the incidence of surgical margin positive cases. Mean follow-up time of the breast-conserving therapy group and the mastectomy group was 42.4 and 39.7 months, respectively. There was no significant difference in the overall survival and disease-free survival between breast-conserving therapy and mastectomy. After adjustment for the clinical stage, there was no significant difference in the prognosis between breast-conserving therapy and mastectomy.

Phase II trial of mitoxantrone, doxifluridine and medroxyprogesterone acetate as second-line treatment for anthracycline-resistant metastatic breast cancer.

Sixteen patients with anthracycline resistant metastatic breast cancer were treated with a combination of mitoxantrone (MIT), doxifuridine (5'-DFUR) and medroxyprogesterone acetate (MPA). The median dose of anthracyclines was 360 mg (range 20-540 mg). Eligible patients received 7.0 mg/m2 of MIT every four weeks 600 mg of 5'DFUR were given orally every day. Eight (50.0%) out of 16 patients showed partial response. Six (54.5%) out of 11 bone lesions, 4 (80.0%) out of 5 lung lesions and 1 (20.0%) out of 5 soft tissue lesions responded to this treatment. The median response duration was 26 weeks (range 4-52). Hematological and gastrointestinal toxicity were tolerable. Alopecia was not observed. Tachycardia was noted in patients receiving more than 80 mg of MIT; however, digitalis controlled the symptom. The combined treatment with MIT is useful for anthracycline-resistant metastatic breast cancer.

Subcutaneous mastectomy with axillary dissection plus breast reconstruction using latissimus dorsi myocutaneous flap (or latissimus dorsi muscle) for breast cancer.

Subcutaneous mastectomy with axillary dissection plus breast reconstruction using latissimus dorsi myocutaneous flap (or latissimus dorsi muscle) was carried out for 8 patients with breast cancer. These consisted of 1 patient with non-invasive ductal carcinoma, 5 with stage I (4 invasive ductal carcinomas and 1 invasive lobular carcinoma) and 2 with stage II (1 invasive ductal carcinoma and 1 invasive lobular carcinoma). Cancer cells were recognized histopathologically in the resection margins of the small mammary gland resting under the nipple in only 1 case, and the remaining 7 cases underwent a curative resection. In the prognosis, 7 patients were disease-free and 1 showed a local recurrence. The patient with local recurrence showed no metastasis after the resection of the local lesion. The cosmetic results of this operation were excellent in all patients. This operation was effective both for these patients with breast cancer who did not want to undergo breast conserving surgery or modified radical mastectomy and for those who were excluded from the criteria of breast conserving surgery from the prognostic and cosmetic points of view.

Oral high-dose medroxyprogesterone acetate treatment for recurrent breast cancer.

Oral high-dose medroxyprogesterone acetate (MPA) treatment (600, 800, 1200 mg/day or changed dosage) was given to 49 patients with recurrent breast cancer from January 1979 to December 1992. The overall response rate to MPA was 38.8% (19/49). The response rate in the soft tissue was significantly higher compared with that in bone metastases or in visceral metastases. MPA was effective on patients both with or without previous treatment. Several side effects were recognized, but they were mild and tolerable. These results demonstrate that MPA is effective when used as first line or second line treatment.

Clinical significance of first line treatment in recurrent breast cancer.

From 1962 to 1992, 279 patients with recurrent breast cancer were treated. Of these, the cases with resected lesions, imperfectly evaluated cases and cases where information was lacking were excluded, and 185 recurrent breast cancers were evaluable at the first line or subsequent treatment. Sixty-seven (36.2%) out of 185 cases responded to first line treatment, while the remaining 118 cases did not respond. In the 67 responder cases at the first line treatments, 16 (23.9%) responded to second line or third line, however, in the 118 nonresponder cases, only 13 (11.0%) responded to next or subsequent treatment. The incidence of responder in the second line or third line treatment was significantly higher in the first line responder group than in the first line nonresponder group. Furthermore, overall survival of first line responders was significantly better than that of first line nonresponders. There was no significant difference in the survival after recurrence between responders and nonresponders in the first line chemotherapy, chemoendocrine treatment or radiotherapy, however, a significant difference was seen between the two groups in the first line endocrine treatment. These results suggest that first line treatment may select the treatment sensitive (especially, truly hormone-dependent) recurrent breast cancers which show a better prognosis.

Nonpalpable breast cancer.

Thirty-seven patients with nonpalpable breast cancer treated between 1981 and 1992 were analysed. Twenty-five (68%) of the patients were detected by microcalcification of mammogram, 8 by nipple discharge and 4 by other means. Biopsy was carried out in all patients to get a final diagnosis and histopathological examinations were performed using continuous sections (especially the section with microcalcification). The incidence of noninvasive carcinoma was 59% (22 cases) and the remaining invasive carcinomas were 3 minimal lesions less than 0.5 cm, 3 lesions from 0.5 to 1.0 cm, 3 diseases more than 1.0 cm, and 6 invasive carcinomas with noninvasive ductal carcinoma predominant. Modified radical mastectomy was performed in 16 cases, partial glandectomy in 10 and other surgery including subcutaneous mastectomy in 11. All of the patients with nonpalpabl breast cancer showed a good prognosis because of early detection and early treatment. Mammography was useful to detect nonpalpable breast cancers with microcalcification.

A new triphenylethylene derivative, TAT-59; hormone receptors; insulin-like growth factor 1; and growth suppression of hormone-dependent MCF-7 tumors in athymic mice.

TAT-59 ((E)-4-[1-[4-[2-(dimethylamino)ethoxy]-phenyl]-2-(4- isopropyl)phenyl-1-butenyl]-phenyl-monophosphate) treatment was performed on hormone-dependent MCF-7 tumors in athymic mice. TAT-59 given at 1, 5, and 20 mg/kg inhibited the estrogen-stimulated growth of MCF-7 tumors in athymic mice in a dose-dependent fashion. The most clear decrease in tumor growth was shown in the TAT-59 alone group, although it was not dramatic. Average serum concentrations of DP-TAT-59((Z)-[1-[4-[2-(dimethylamino)- ethoxy]phenyl]-2-(4-isopropyl)phenyl-1-butenyl]-4-hydroxybenzene) and DM-DP-TAT-59(desmethyl-DP-TAT-59), metabolites of TAT-59, increased in a dose-dependent manner. Much higher levels of DP-TAT-59 and DM-DP-TAT-59 were shown in tumors (target tissues of estrogen) as compared with muscles (nontarget tissues of estrogen) or serum. A serum concentration of DP-TAT-59 or DM-DP-TAT-59 corresponding to the physiologic levels of serum estradiol in premenopausal women was sufficient to inhibit the estrogen-stimulated growth of MCF-7 tumors in mice. TAT-59 induced a dose-dependent increase in estrogen receptor levels in the MCF-7 tumors. In contrast, it prevented the estradiol (E2)-induced increase in progesterone receptor levels in a dose-dependent manner. Insulin-like growth factor 1 levels measured in the MCF-7 tumors significantly decreased in the TAT-59 alone group and in the no treatment group as compared with the E2 alone group. These results show the pronounced antiestrogenic action of TAT-59 on hormone-dependent MCF-7 tumors in athymic mice.

Subcutaneous mastectomy with axillary dissection for early breast cancer.

From 1983 to 1990, subcutaneous mastectomy with axillary dissection was carried out for 46 patients with early breast cancer including three bilateral breast cancer patients (four breasts). Cancer cells were recognized histopathologically in the resection margins of small mammary gland resting under the nipple in four cases, and the remaining 42 cases underwent a curative resection. Multicentric lesions were found out histopathologically by continuous sections in five cases (six breasts). There was no difference in the prognosis using the case-control comparison method between 34 patients with ipsilateral invasive carcinoma who underwent a subcutaneous mastectomy in this study group and 34 patients who underwent a radical or modified radical mastectomy in the control group. Cosmetic results of the subcutaneous mastectomy were evaluated in 37 patients, and 9 were excellent, 17 were good, 9 were not so good and 2 were poor. Subcutaneous mastectomy with axillary dissection was an effective operation for early breast cancer including multicentric lesions and some non-invasive ductal carcinomas from the prognostic and cosmetic standpoints.

Effect of toremifene on the growth, hormone receptors and insulin-like growth factor-1 of hormone-dependent MCF-7 tumors in athymic mice.

Toremifene given in different sizes of silastic capsules was used to treat MCF-7 tumors in athymic mice. Toremifene inhibited the estradiol-stimulated growth of MCF-7 tumors in athymic mice. Average serum concentrations of toremifene obtained using a sustained-release preparation of the drug (in 0.5-, 1.0-, and 2.0-cm silastic capsules) increased gradually in a capsule-size-dependent fashion. Much higher levels of toremifene or N-demethyl-toremifene were detected in tumors (target tissues of estrogen) as compared with muscles (non-target tissues of estrogen). The concentration of toremifene in serum (i.e., 10-30 ng ml-1) was sufficient to inhibit the estrogen-stimulated growth of MCF-7 tumors at physiological (i.e., 200-400 pg ml-1) serum estradiol concentrations in premenopausal women. No significant difference in estrogen receptor (ER) levels was found between the estradiol-alone group and the toremifene-treated groups. However, the ER levels in the toremifene-alone group and the no-treatment group (no toremifene or estradiol) tended to increase as compared with the estradiol-alone group. Toremifene blocked the estradiol-induced increase in progesterone receptor levels in a dose-dependent fashion. Insulin-like growth factor-1 (IGF-1) levels in the MCF-7 tumors significantly decreased in the toremifene-alone group as compared with the estradiol-alone group. These results show the antiestrogenic action of toremifene on hormone-dependent MCF-7 tumors in athymic mice.

Antitumor effect of medroxyprogesterone acetate (mpa) on 7,12-dimethylbenz(a)anthracene-induced rat mammary-carcinoma depends upon the mpa concentration in tumors of rats.

Medroxyprogesterone acetate (MPA) in doses of 1 mg, 5 mg or 10 mg, was orally administered daily for four weeks to rats with 7,12-dimethylbenz(a)anthrace (DMBA)-induced mammary carcinoma. All rats were sacrificed after four weeks and MPA concentration was determined in serum, tumor and muscle. MPA concentration in the tumor was much higher compared with that in the serum or in the muscle in each treatment group. There was no difference between responder group and non-responder group in MPA concentration in the serum, however, MPA concentration in the responder group was significantly higher than that in the non-responder group in all the tumors of the treatment groups. These results suggest that antitumor effect of MPA on DMBA-induced rat mammary tumors depends upon the MPA concentration in the tumor of the rat.

PSK (krestin) potentiates chemotherapeutic effects of tamoxifen on rat mammary carcinomas.

A total of 20 mg of 7,12-dimethylbenz[a]anthracene (DMBA) was administered orally to 41 female Sprague-Dawley (SD) rats (control group), and 60 mg/kg of Krestin (PSK) were orally administered daily to 38 rats (PSK group) after DMBA administration. The average development period (9.6 weeks) of DMBA-induced tumors in the PSK group was significantly longer (P < 0.02) than that (7.9 weeks) in the control group. Average estrogen receptor (ER) levels of established tumors were almost the same between these two groups. However, the chemotherapeutic effect of tamoxifen (TAM) was significantly enhanced by PSK pretreatment.