Yasuo Nomura

Steroid hormone receptors and clinical usefulness in human breast cancer

For more precise prediction of response to endocrine therapy in patients with advanced breast cancer, we investigated the correlation between the presence of combination of estrogen (ER), progesterone (PgR) receptors, or combination of ER, PgR, and androgen receptor (AR) and response to therapy. The patients with ER+, PgR+ tumors survived longer than those with ER+, PgR− or ER−, PgR− tumors. A better response rate with longer survival time was obtained in patients with tumors that had three positive receptors or PgR+ and/or AR+ in addition to ER+ than in those with tumors of other combinations.

Changes of steroid hormone receptor content by chemotherapy and/or endocrine therapy in advanced breast cancer

In several sequences during the progression of cancer, the authors assayed estrogen receptors(ER) in 940 breast cancers and progesterone receptors(PgR) in 773 cancers. The percentages of ER+ and PgR+ cancers diminished according to the progression of malignancy. Sequential assays of ER and PgR were carried out in primary tumors and in the metastatic tumors at the first recurrence in 42 patients. During the disease‐free interval, 10 (37%) of 27 ER+ tumors changed to ER‐ and all 15 ER‐ tumors remained negative. The hormone receptors were assayed before the treatments and after the tumor relapsed following regression or after the progression of cancer. The changes of ER and PgR in 99 patients with advanced breast cancer were studied according to the type of systemic treatments. Through endocrine therapy, marked changes from ER+ to ER‐, were noted (by antiestrogens, 47% [7/15]; by adreno‐oophorectomy, 61% [11/18]). Almost no breast cancers changed from ER‐ to Er+ during the endocrine therapy (by antiestrogen, 1/6; by adreno‐oophorectomy, 0/10). All of six PgR+ tumors changed to PgR‐ after therapy. By chemotherapy treatment, 44% (4/9) ER+ cancers became ER‐, while 19% (3/16) ER‐ tumors changed to ER+. After the simultaneous combination of chemotherapy and endocrine therapy, 67% (10/15) of ER+ cancers changed to ER‐, and 20% (2/10) of ER‐ tumors changed to ER+. Through the intervention of more than two kinds of chemotherapy and/or endocrine therapy between the first treatment and the last therapy, 79% (19/24) ER+ breast cancers changed to ER‐. Thus, ER and PgR contents of breast cancer gradually became negative as the malignancy progressed, and with some kinds of treatments particularly including endocrine therapy. The significance of changes in hormone receptors after therapy was discussed.

Postoperative adjuvant randomised trial comparing chemoendocrine therapy, chemotherapy and immunotherapy for patients with stage II breast cancer: 5-year results from the nishinihon cooperative study group of adjuvant chemoendocrine therapy for breast cancer (ACETBC) of Japan

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.

Relationship between estrogen receptors and risk factors of breast cancer in Japanese pre- and postmenopausal patients

SummaryThe relation between estrogen receptors (ER) in breast cancer and risk factors was studied in 456 Japanese patients. ER was shown to be positive in 55.3% (252/456) of patients. There was no difference in ER positivity between pre- and postmenopausal patients. In premenopausal patients, only the age at menarche and obesity showed some influence on the ER positivity of breast cancer. Among postmenopausal patients, on the contrary, ER(+) cancers were predominant in the patient groups that have been known to be higher in the risk of incidence of breast cancer. The factors included were the age at marriage, number of pregnancies, number of live children, and body weight. Of these, the body weight of patients was the strongest influence on the ER positivity in the postmenopausal patients. After excluding the effects of body weight, some of the reproductive factors such as number of pregnancies and number of live children were shown to be related to the ER status. These results may suggest the combination of lower incidence of breast cancer and lower percentage of ER(+) cancers in Japanese postmenopausal women as compared with the Western countries.

Meta-Analysis of Five Studies on Tegafur plus Uracil (UFT) as Post-Operative Adjuvant Chemotherapy for Breast Cancer

Meta-analysis of 5 studies on postoperative breast cancer cases (2 studies on surgery alone vs. tegafur plus uracil (UFT) and 3 studies on tamoxifen (TAM) alone vs. TAM + UFT) were carried out to evaluate the anticancer drug UFT in oral postoperative adjuvant chemotherapy. Of the 1973 patients enrolled, 1898 were eligible and 75 were excluded (exclusion rate 3.8%). There was no bias in major background factors in either the UFT-treated (965) or non-UFT-treated (933) groups. The reduction in the odds of death and the odds of recurrence were 17 ± 17% (p = 0.33) and 21 ± 11% (p = 0.060), respectively. Multivariate analysis using Cox’s proportional hazards model emphasized the effectiveness of UFT treatment for suppression of recurrence compared with non-treatment with UFT (p = 0.038). Suppression of recurrence was remarkable in the group treated with UFT for 2 years. (the reduction in the odds of recurrence: 23 ± 11%, p = 0.048) Stratified analysis was applied concerning recurrence, and improved results were obtained in premenopausal cases (the reduction in the odds of recurrence: 33 ± 11%, p = 0.019). These results suggested that UFT treatment for 2 years was effective as postoperative adjuvant chemotherapy for stage I – IIIA breast cancer for the prolongation of the reccurence-free survival period.

Evaluation of liver and bone scanning in patients with early breast cancer, based on results obtained from more advanced cancer patients

Abstract A prospective study on both bone and liver scanning was undertaken in patients with Stage I, II and III breast cancer immediately following the operation. In both series of scans the diagnostic values were evaluated in patients with more advanced breast cancer. No cases of occult metastases of the liver were identified, and 2.3% of 129 patients showed equivocal scannings with Stages I, II and III breast cancers and there were no patients with postoperative liver metastases. Ten of 114 (8.8%) patients with breast cancer at Stages I, II and III showed positive bone scans. However, 6 of them were excluded because of degenerative diseases or influences of operation, noted as the cause of a positive scan. Therefore, 4 of 114 (3.5%) patients showed abnormal positive scans which were otherwise unaccounted for. Out of these patients, only 1 had developed bone metastases. It may be that the bone and liver scans are restricted to patients who have a high risk of recurrence at the time of the operation, and that they could be used for the detection of early metastases during the follow-up study.

Phase II study of paclitaxel (BMS-181339) intravenously infused over 3 hours for advanced or metastatic breast cancer in Japan

A Phase II study of paclitaxel in patients with primary advanced or metastatic breast cancer was conducted by a cooperative study group consisting of 16 institutions in Japan. Paclitaxel at a dose of 210 mg/m2 was intravenously infused over 3 hours, along with premedication to prevent hypersensitivity reactions. The course was repeated at 21-day intervals. Of 62 eligible patients, 60 were evaluable for toxicity and 59 were evaluable for efficacy. Forty-five patients were previously treated with anthracyclines. Twenty-one of 59 patients (35.6%) had a major objective response including 2 CRs and 19 PRs (95% confidence interval, 23.6–49.1%). A response rate of 35.5% (CR1, PR10) was observed in 31 patients refractory to the anthracyclines containing prior metastatic chemotherapy. Median (range) time was 41 (6–100) days to onset of and median duration of response was 125 (36–305) days. Toxicities included leukopenia (grade 3, 4: 67%), anemia (grade 1–3: 80%), thrombocytopenia (grade 1: 8%), alopecia (grade 3: 43%), peripheral neuropathy (grade 1–3: 93%), arthralgia (59%), myalgia (46%), nausea and vomiting (40%), fever (33%), allergic reaction (grade 3: 2%) and hypotension (grade 3: 5%). All toxicities were tolerable and manageable. Paclitaxel intravenously infused over 3 hours demonstrated a significant antitumor activity for metastatic breast cancer. Furthermore, paclitaxel exhibited non-cross resistance to anthracycline. Paclitaxel administered as a convenient 3-hour infusion is effective for patients with metastatic breast cancer and has an acceptable toxicity profile.

Comparison of chemotherapy with or without medroxyprogesterone acetate for advanced or recurrent breast cancer.

The usefulness of CAF [cyclophosphamide (CPA)/doxorubicin (ADR)/5-fluorouracil (5-FU)] + medroxyprogesterone acetate (MPA) therapy for advanced/recurrent breast cancer was studied in a randomised trial at 56 institutions. Patients received CAF therapy [CPA: 100 mg, orally, days 1-14; ADR: 30 mg/m2, intravenously (i.v.), days 1 and 8; 5-FU: 500 mg/m2, i.v., days 1 and 8) in arm I, or CAF + MPA therapy (CAF + MPA 1200 mg, daily) in arm II. The response rate was significantly higher (P = 0.041) in arm II (53.5%, 46/86) than arm I (36.6%, 30/82). The response rate by tumour site was significantly higher for lymph node and bone lesions in arm II. Partial response duration and overall response duration were significantly longer in arm II. Incidences of anorexia and nausea/vomiting were significantly higher in arm I but in arm II, moon face, oedema and vaginal bleeding were significantly higher. Many patients in arm II demonstrated improvement in performance status and weight loss, suggesting a beneficial effect of MPA. The chemoendocrine therapy with CAF + MPA appears to be more beneficial than CAF alone in the treatment of advanced/recurrent breast cancer.

A phase I study of toremifene

A Phase I study of the new antiestrogenic drug toremifene was carried out in 27 Japanese women, using oral doses of 10–480 mg per day for one or five days. Serum concentrations reached a dose-dependent maximum 2–6 hours after each oral administration. Side effects were generally mild.

A randomized trial of adjuvant endocrine therapy, chemotherapy, and chemoendocrine therapy for operable breast cancer stratified by estrogen receptors

Based on estrogen receptor (ER) status and menopausal status, operable breast cancer (International Union Against Cancer [UICC] Stage I, II, and III) patients were randomized for adjuvant endocrine therapy, chemotherapy, and chemoendocrine therapy, and the effects on the disease‐free survival (DFS) and overall survival (OS) were compared. Adjuvant endocrine therapy was composed of tamoxifen (TAM) 20 mg/day orally for 2 years in postmenopausal patients. In premenopausal patients, oophorectomy (OVEX) was done before TAM administration. In the chemotherapy arm, the patients were given 0.06 mg/kg of body weight of mitomycin C (MMC) intravenously (IV) and then an oral administration of cyclophosphamide (CPA) 100 mg/body orally in an administration of a 3‐month period and a 3‐month intermission. This 6‐month schedule was repeated four times in 2 years. As the chemoendocrine therapy arm, TAM with MMC + CPA chemotherapy was added. The patients were randomized according to ER and menopausal status. Estrogen receptor‐positive (ER+) cancer patients were randomized to three arms: TAM ± OVEX, MMC + CPA, or MMC + CPA + TAM. For estrogen receptor‐negative (ER‐) patients, there were two arms: MMC + CPA, or MMC + CPA + TAM. The study started in September 1978, and 692 patients entered until the end of 1984 were evaluated. The median follow‐up was about 46 months. Totally, a 9.8% rate (68/692) of recurrence was noted, a 7.5% rate (52/692) of mortality. There were no significant differences in DFS or OS among the treatment arms in ER+ or ER‐ patients. There was significant differences in adverse effects such as bone marrow suppression, gastrointestinal disturbances, cytitis, hair loss between endocrine therapy and chemotherapy or chemoendocrine therapy groups. In this preliminary study, it was concluded that because of less adverse effects of endocrine therapy, it seems rational to select the operable breast cancer patients by the presence or absence of ER, namely, endocrine therapy for ER+ and chemotherapy for ER‐ cancer patients.