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Background/aim: This phase II trial evaluated the efficacy and safety of neoadjuvant nab-paclitaxel plus cyclophosphamide (CPA) plus trastuzumab (AbraC-HER) in patients with early HER2-positive breast cancer., Patients and Methods: This was a single-arm, open-label, single-center prospective phase II study. The primary endpoint was pathological complete response rate (pCR rate). The secondary endpoints were clinical antitumor efficacy and the frequency and severity of adverse events., Results: Fifty-nine patients were enrolled in this study. pCR (ypT0/is ypN0) was achieved in 29 patients (49%). The overall response rate was 88.1% (52/59) in all patients. Dose reductions because of adverse events occurred in 3 patients (5.1%) and relative dose intensity was 98%. Compared to Abra-HER, AbraC-HER induced fewer adverse effects., Conclusion: Treatment with nab-paclitaxel plus CPA plus trastuzumab was tolerable and effective with a high pCR rate. This AbraC-HER neoadjuvant therapy may be a feasible new treatment option for patients with early HER2-positive breast cancer., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Aim: Treatment strategies for patients with human epidermal growth factor 2 (HER2)-positive metastatic breast cancer (MBC) have significantly progressed. The use of trastuzumab, a monoclonal antibody targeting the HER2 (human epidermal growth factor 2) protein, in combination with chemotherapy improves survival in patients with HER2-positive breast cancer. S-1, an oral combination of fluorouracil derivatives, is widely used in Japan and is more convenient than intravenous drugs. However, little is known about the combination of S-1 and trastuzumab in patients with HER2-positive MBC., Patients and Methods: We conducted a single-arm, open-label, multicenter prospective phase II study to evaluate the efficacy of an S-1 plus trastuzumab regimen for HER2-positive MBC. S-1 was administered orally [80-120 mg, based on body surface area (BSA)] twice a day for 14 consecutive days in a 3-week cycle. Patients with BSA of <1.25 m 2 received a total of 80 mg of S-1, those with BSA ≥1.5 m 2 received 120 mg, and the remaining received 100 mg daily in two divided doses. Trastuzumab was administered intravenously at 8 mg/kg on day 1 of the first cycle and at 6 mg/kg on day 1 of subsequent cycles, i.e., every 3 weeks., Results: Between December 2008 and March 2013, 10 patients were enrolled and received a median of 17 (range=3-76) cycles of treatment. Overall response and clinical benefit rates were 60.0% and 90.0%, respectively. Progression-free survival was 15.8 (95% confidence interval=9.4-29.6) months and overall survival was 45.5 (95% confidence interval=37.1-62.2) months. Grade 3/4 adverse events included were neutropenia and hyperglycemia in one patient each (10.0%). There was no clinically significant cardiotoxicity., Conclusion: The combination of S-1 and trastuzumab was tolerable and had excellent efficacy with good response and disease control in this study. S-1 plus anti-HER2 therapy is a feasible treatment option for HER2-positive MBC., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

A phase II clinical trial was conducted to examine the clinical and pathologic efficacy and safety of neoadjuvant paclitaxel with or without trastuzumab in women with advanced or metastatic breast cancer. A total of 49 patients with advanced or metastatic breast cancer (clinical stage IIB -IV) were included. Patients with HER2-negative tumors received weekly paclitaxel 80 mg/m2 (days 1, 8, 15) followed by a 1-week break for 4 cycles. Patients with HER2-positive tumors received weekly paclitaxel 80 mg/m2 (days 1, 8, 15) followed by a 1-week break and a trastuzumab 4 mg/kg loading dose, intravenously, followed by 2 mg/kg weekly for 4 cycles. The age of the patients was 51.6 +/- 1.6 years (mean +/- SE) and the size of their tumors was 5.8 +/- 0.4 cm (mean +/- SE). Thirty-two patients had HER2-negative tumors and 17 had HER2-positive tumors. Of 49 patients, 13 (26.5%) had a clinical complete response and 24 (49.0%) had a clinical partial response. Five (10.2%) patients had a pathological complete response (pCR) and three (6.1%) patients had a near pCR in the breast. A total of eight (16.3%) patients had a pCR or near pCR in the breast. The pCR or near pCR rate was 3.1% in the HER2-negative group and 41.2% in the HER2-positive group. With a median follow-up of 28 months (range, 1-45), the 3-year overall survival was 88%. Clinical responders showed a significantly better overall survival than non-responders (p < 0.01). Pathological responders showed a better overall survival than non-responders. There was no significant difference in overall survival between patients with HER2-positive and -negative tumors. In conclusion, combined neoadjuvant weekly paclitaxel and trastuzumab achieved high clinical and pathological response rates for HER2 -overexpressing breast cancers, despite the omission of an anthracycline.

The aim of this study was to evaluate both the risk factors of local recurrence and the prognostic significance of local recurrence in relation to surgical treatment and/or radiation therapy of breast cancer. A total of 1574 primary breast cancer patients, undergoing surgical treatment and/or radiation therapy between 1980 and 2001, were included in this study. Radical mastectomy was performed in 1144 patients, subcutaneous mastectomy in 141 and breast-conserving therapy in 289. The clinical stage was significantly earlier in the subcutaneous mastectomy and breast-conserving therapy groups than in the radical mastectomy group. A positive surgical margin was observed in 9 (6.4%) out of 141 patients in the subcutaneous mastectomy group and 51 (176%) out of 289 in the breast-conserving therapy group. Local recurrence occurred more frequently in the subcutaneous mastectomy and breast-conserving therapy groups than in the radical mastectomy group. Independent prognostic factors in local recurrence were lymph node metastasis in the radical mastectomy group, and surgical margin in the subcutaneous mastectomy group and the breast-conserving therapy group. Independent prognostic factors in overall survival were local recurrence, lymph node metastasis and estrogen receptor status in the radical mastectomy group, and lymph node metastasis and estrogen receptor status in the breast-conserving therapy group. In conclusion, the surgical margin status is an important factor in the risk of local recurrence in patients who have undergone a subcutaneous mastectomy or breast-conserving therapy. The significance of local recurrence for overall survival may be different among these three treatments.

Local control was compared between patients who had undergone breast-conserving therapy with and without nipple resection. We explored whether there was any difference in local control between the two treatment methods for patients with early breast cancer. A total of 333 women with breast cancer, who had undergone breast-conserving therapy between 1991 and 2002, were included in this study. Surgery consisted of a wide local excision of the primary tumor with a 2-cm free margin as the minimum distance. When the tumor was located under the nipple or close to the nipple, breast-conserving surgery with nipple resection was selected. A total of 320 patients received breast-conserving surgery without nipple resection and radiation therapy (BCT) and 13 patients breast-conserving surgery with nipple resection and radiation therapy (BCT-NR). There were no significant differences in age, tumor size, nodal status, clinical stage, ER status, histological type or surgical margin status between the two groups. The surgical margin was positive in 55 (17.2%) out of 320 patients in the BCT group and in one (7.7%) out of 13 patients in the BCT-NR group. There was no significant difference in the breast-free survival between the two groups. In conclusion, breast-conserving surgery with nipple resection and radiation therapy may be the treatment of choice for early breast cancer patients with the tumor located under the nipple or very close to the areola.

The purpose of this study was to compare the results of 133 cases (131 patients) of subcutaneous mastectomy with axillary dissection between 1983 and 1999 and 910 cases of radical mastectomy during the same period. The median follow-up period of the subcutaneous mastectomy group and the radical mastectomy group were 66 months and 81 months, respectively. The age at operation was significantly (p<0.01) younger in the subcutaneous mastectomy group than in the radical mastectomy group and the clinical stage was significantly (p<0.01) earlier. Lymph node metastasis was significantly (p<0.01) higher in the radical mastectomy than in the subcutaneous mastectomy group. There was no difference in ER status between the two groups. There was local recurrence in 5 (3.8%) members of the subcutaneous mastectomy group and in 12 (1.3%) members of the radical mastectomy group. There was no difference in disease-free survival and overall survival between the two groups. Divided into two subgroups by lymph node status, there was no difference in disease-free survival and overall survival between the two groups. Local recurrence occurred more frequently (p<0.05) in the subcutaneous mastectomy group, however, than in the radical mastectomy group when no lymph node metastasis was found. Multivariate analysis using the Cox hazard model showed that operation method and lymph node status were independent prognostic factors for local recurrence, whereas, lymph node status and ER status were independent prognostic factors of disease-free survival. In conclusion, subcutaneous mastectomy presents a risk factor for local recurrence, but the survival rate of the subcutaneous mastectomy group is as favourable as the radical mastectomy group.

Screening mammography (MMG) for women aged 50 years and older has been widely accepted all over the world. However, the efficacy of screening mammography for women aged under 50 years has not been established. We compared mammographic findings of the patients under age 50 (the younger group) and those of patients 50 and older (the older group). From 1992 to 1997, 107 patients with early breast cancer (non-invasive and Stage I) were treated in our hospital. There was no difference between the groups in background. Of 53 patients in the younger group, 40 (75.5%) were diagnosed as having cancer using mammography, while 44 of 54 (81.5%) of the older group were diagnosed as having cancer. A total of 46 (86.8%) patients in the younger group were diagnosed using MMG and physical examination (PE), and 50 (92.6%) in the older group were diagnosed as cancer using MMG and PE. There was no difference in the successful diagnosis rate using mammography in the two groups. Breast cancer screening using MMG may also be useful for women aged under 50.

A consecutive series of 128 breast cancer patients detected by breast screening were enrolled in this study to analyze their age-dependent characteristics. They were classified into three groups; 40 years or less (young): 26 patients, 41-55 years (middle-aged): 67 patients and 56 years or over (old): 35 patients. The percentage of patients who had noticed breast abnormality by self-examination at the time of the breast screening increased from the young patients to the old without statistical significance. Nonpalpable breast cancer was more frequently (p < 0.05) observed in the young patients or the middle-aged rather than the old patients. The incidence of noninvasive carcinoma decreased from the young patients to the old without statistical significance. Decreased survival was seen in older patients rather than younger patients, without statistical significance. As a result, prognostic features were more favorable in patients aged 40 years or less than the other. Women aged 35-40 years should be recommended to attend breast screening.

We demonstrated that the prognosis of breast cancer patients who received adjuvant immunochemotherapy with Krestin (PSK) showed a tendency to be better than that of breast cancer patients receiving chemotherapy only. We retrospectively investigated the usefulness of HLA typing for selecting patients to receive adjuvant immuno-chemotherapy with PSK. One hundred and thirty-four patients with operable breast cancer were typed as HLA-A, -B, -C by a lymphocytotoxicity test. Patients without vascular invasion had no adjuvant therapy (NA group). Patients with vascular invasion in the tumor and/or in the metastatic lymph node were randomized into two groups. In group 1 (FEMP only), a combination chemotherapy of 100 mg of 5-fluorouracil (F), 50 mg of cyclophosphamide (E), 2 mg of mitomycin C (M), and 5 mg of predonisolone (P) was orally administered daily for 28 days (one course). In group 2 (FEMP+PSK), FEMP and 3.0 g of PSK were orally administered for 28 days (one course). Two courses a year of these agents were given for five years in both groups. Each group (NA, FEMP, FEMP+PSK) was stratified by the presence of HLA B40 type (B40(+)) or not (B40(-)). Five- and 10-year disease-free survival (DFS) rates (93%, 80%, respectively) of patients with B40(+) seemed to be better than those (83% and 51%) of patients with B40(-). In the NA group, 5- and 10-year DFS were 100% and 71% in patients with B40(+), 92% and 76% in those with B40(-), respectively. In the FEMP group (chemotherapy only), 5- and 10-year DFS of patients with B40(+) were both 84%. These were not statistically significant compared with those (82% and 33%) of patients with B40(-). On the other hand, in the FEMP+PSK group, 5- and 10-year DFS of patients with B40(+) were both 100%, and those of patients with B40(-) were 76% and 55%, respectively. DFS of patients with B40(+) was significantly better than that of patients with B40(-). It is concluded that HLA typing may be a predictive index in determining the use of immunochemotherapy combined with PSK for patients with operable breast cancer.

The hypothyroid state or nonthyroidal illness is often observed in patients with recurrent cancer. High levels of cytokines are frequently observed in critically ill patients. Recent studies have shown that interleukin (IL)-6 may be a cause of nonthyroidal illness. We reported the relationship between thyroid function and the prognosis of the patients with recurrent breast cancer. In this study, we measured the serum level of cytokines (IL-2, IL-6, IL-8) and thyroid function (free T3, free T4, and thyrotropin (TSH)) in 38 patients with recurrent breast cancer. All patients had received three or more different courses of therapy before they were entered the study. The patients were divided into three groups according to their response to therapy. There were 16 partial response (PR), 10 no change (NC) and 11 progressive disease (PD) patients. They did not receive any medication that influenced the thyroid hormone level other than medication for cancer. The IL-2 level was under the detectable limit in all groups. No abnormal levels of cytokines were observed in the PR group. IL-6 and IL-8 levels in the PD group were significantly higher than that in the NC group (p < 0.05). Significant negative correlation was observed between IL-6 and thyroid hormones (free T3, free T4). Patients whose IL-6 level was 20 pg/ml or more died within four months after the beginning of the treatment. We concluded that IL-6 may lead to a hypothyroid state in patients with recurrent breast cancer. A high level of IL-6 and IL-8 means the confusion of the defense system in hosts. Therefore, these cytokines will be predictive indicators of the therapeutic response and the prognosis of the patients with recurrent breast cancer.

Twenty-two patients with inflammatory breast cancer treated between 1962 and 1994 were analyzed. Before the introduction of multidisciplinary treatment with anthracycline agents between 1962 and 1981, 11 patients out of 14 were resected, however, a curative operation was performed for only 3 of these patients (29.3%). Ablative endocrine therapy, intraarterial infusion of anticancer drugs (mitomycin C or 5-fluorouracil), and radiation were carried out as the preoperative induction therapy for inflammatory breast cancer. All 14 patients died within 36 months. After the introduction of multi-disciplinary treatment with anthracycline agents between 1981 and 1994, preoperative induction chemotherapy or chemoendocrine therapy using anthracyclines was carried out on 7 out of 8 patients and the remaining patient received radiation. Of the former 7 patients, 6 (85.7%) underwent a curative operation. There was approximately a 35 percent cumulative survival rate observed 60 months after operation, and 3 patients out of the 7 lived for more than 5 years. To conclude, multidisciplinary treatment including systemic induction chemotherapy with anthracyclines was an effective treatment for inflammatory breast cancer.

Breast conserving surgery with nipple resection was carried out on 4 patients with early breast cancer because location of each tumor was very close to nipple. These consisted of 3 patients with state I invasive ductal carcinoma and 1 patient with stage II invasive ductal carcinoma. Cancer cells were not recognized histopathologically in the resection margins of each case and all cases underwent a curative resection with axillary dissection (up to level III). The rested areola in each case was made to be round-shaped by skin suture and the edge of the wound located in the center of areola looked like a small nipple. The cosmetic result of this operation were excellent in all patients. This operation may be effective both for these patients with early breast cancer locating under the nipple or areola and for those whose tumor was very close to nipple.

In this study, thyroid (T3, T4, free T3, free T4) and pituitary function (thyrotropin (TSH), growth hormone (GH), prolactin (PRL)) in 38 patients with recurrent breast cancer were examined. The patients were divided into three groups according to their response to the therapy. There were 16 partial response (PR), 10 no change (NC) and 11 progressive disease (PD) patients. The maximum and the minimum value for each hormone throughout the course of treatment were compared between three groups. The PD group showed significantly lower minimum T3 levels than the other two groups (p < 0.05). The maximum TSH level in the PD group was significantly higher than that of the other groups. The minimum TSH level in the PD group was significantly lower than that in the PR group (p < 0.05). The minimum TSH level in the NC group was also lower than that in the PR group. The maximum PRL level in the NC and the PD group was higher than that in the PR group (p < 0.05, p < 0.01, respectively). The tumors of the patients with temporal increase of TSH level were resistant to all subsequent therapies. These five patients died within four months followed by decreasing of the TSH level. It is concluded that thyroid and pituitary function, especially free T4, TSH and PRL, are predictive indicators of therapeutic response and the prognosis of the patients with 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.