Breast cancer is the most common cancer in women worldwide, including in the Japanese population. In Japan, 90,000 (1 in 9) persons are affected annually, and about 14,000 die from breast cancer each year. How to treat these cancers and improve the results of treatment is a very important issue. For early-stage breast cancer that is operable, it is common to perform surgery first and then combine chemotherapy and radiotherapy as needed based on the results of histopathological examination. With more widespread breast cancer screening in Japan, the number of breast cancers detected at an early stage is increasing. The above-mentioned methods are often used to treat breast cancer detected by screening. However, for a variety of reasons, it is also true that treatment is delayed in quite a few locally advanced (stage III) breast cancers. Locally advanced breast cancer has high rates of distant metastasis and local recurrence, and its prognosis is poor. So-called multimodal treatment is generally recommended, whereby combined local treatment (surgery, radiotherapy) is administered after pre-operative systemic chemotherapy. Locally advanced breast cancer is often difficult to treat and there are very few reports on its treatment and prognosis. In this study, we investigated the treatment and prognosis of locally advanced breast cancer at our institution.

Patients

Seventy-six women with locally advanced (stage III) breast cancer and no distant metastasis who underwent definitive surgery at Hiratsuka Municipal Hospital between January 2007 and September 2020 were enrolled. Women who had not undergone resection surgery, those who had bilateral breast cancer, and those with cancers in multiple organs were excluded. Information on clinical and pathological factors, treatment details, and the prognosis was retrospectively collected from the medical records. The study was approved by the institutional review board of Hiratsuka City Hospital. All patients provided written informed consent.

Statistical analysis

Groups were compared using Fisher’s exact test and the t-test. Multivariate analysis was performed using logistic regression. Disease-free survival was measured from the time of the first surgery until the date of death or final follow-up. Survival curves were constructed using the Kaplan–Meier method. The statistical significance of between-group differences was assessed using the log-rank test. All statistical analyses were performed using JMP Pro version 10 for Mac OS (SAS Institute Japan Ltd., Tokyo, Japan). P-values <0.05 were considered statistically significant.

The patient demographics and clinical characteristics are shown in Table 1. The median patient age was 62.5 years (range, 31-101). Fifteen women (20%) were premenopausal and 61 (80%) were postmenopausal. One patient (1%) had T1 disease, 9 (12%) had T2, 18 (24%) had T3, and 48 (63%) had T4. The N stage was N0 in 9 patients (12%), N1 in 47 (62%), N2 in 11 (14%), and N3 in 9 (12%). The clinical stage was IIIA in 25 cases (33%), IIIB in 41 (54%), and IIIC in 10 (13%). The median tumor diameter was 5.3 cm (range, 1.5-11.0).

The median number of lymph node metastases was 3 (range, 0–30). Fifty-five patients (72%) were hormone receptor-positive, 21 (28%) were hormone receptor-negative, 11 (16%) were HER2-positive, and 64 (84%) were HER2-negative. The subtype was luminal in 49 cases (64%), luminal HER2 in 5 (7%), HER2 in 6 (8%), and triple-negative in 16 (21%).

The treatment details are shown in Tables 2 and 3. The surgical treatment was mastectomy in 62 cases (82%) and partial mastectomy in 14 (18%). Sentinel lymph node biopsy was performed in 15 cases (20%) and axillary lymph node dissection in 60 (79%). Chemotherapy was administered preoperatively in 47 patients (61%) and postoperatively in 34 (45%). Forty-eight (87%) of 55 hormone receptor-positive patients received postoperative endocrine therapy and 9 (82%) of 11 HER2-positive patients received anti-HER2 agents. Eighteen patients (24%) did not receive chemotherapy and 3 (4%) did not receive any medication. Chemotherapy consisted of anthracycline and a taxane in 44 patients (76%), anthracycline alone in 7 patients (12%), and a taxane alone in 4 patients (7%). Postoperative radiotherapy was performed in 9 (64%) of 14 patients after partial mastectomy and in 22 (35%) of 62 patients after mastectomy. Thirty-one patients (41%) received multimodal treatment with chemotherapy, surgery, and radiotherapy. The median observation period was 43 months (range, 1-175).

There were 25 recurrences. The initial recurrence was local in 9 cases, distant metastasis in 18, and both local recurrence and distant metastasis in 3. There were 18 deaths, 16 of which occurred as a result of the primary illness and 2 from multiple causes. Patients with recurrence were significantly more likely to be premenopausal and to have 4 or more lymph node metastases (Table 4).

Median recurrence-free survival was 38 months and the 5-year recurrence-free survival rate was 65.6%. In univariate analysis, menopausal status and number of lymph node metastases significantly affected the likelihood of recurrence-free survival; however, in multivariate analysis, only number of lymph node metastases remained a significant factor (Table 5). The 5-year overall survival rate for all cases was 77.9%.

Patients with locally advanced (stage III) breast cancer are at high risk of systemic disease but should be treated with curative intent. Locally advanced breast cancer includes large tumors, especially those with skin infiltration and/or extensive metastasis to regional lymph nodes. The initial treatment is the same in all cases. In general, multimodal treatment consists of adding local treatment after systemic drug therapy. Preoperative chemotherapy is considered standard regardless of tumor subtype [1]. Preoperative endocrine therapy is considered acceptable for hormone receptor-positive locally advanced breast cancer in elderly patients with organ damage, those in whom adverse events associated with chemotherapy need to be avoided, and those in poor general condition. Given that there is no difference in the prognosis according to whether chemotherapy is administered preoperatively or postoperatively, upfront surgery is acceptable in patients with operable locally advanced breast cancer who are not concerned about breast preservation [2].

Preoperative chemotherapy

The standard preoperative chemotherapy regimen for HER2-negative disease and operable early-stage breast cancer is a sequential combination of an anthracycline-containing regimen and a taxane [3]. In HER2-positive cases, first an anthracycline-containing regimen and then a taxane plus a simultaneous combination regimen containing an anti-HER2 agent are used. It is desirable to administer both unless there is a specific reason, such as advanced age or a significant comorbidity. Dose-dense chemotherapy may also be considered. In the broad sense, dose-dense chemotherapy entails smaller drug doses and a shorter dosing interval without concomitant use of a granulocyte colony-stimulating factor (G-CSF) preparation. In the narrow sense, it is a method in which the type and dose of drug are the same and the dosing interval is shortened by using a G-CSF preparation in combination. Dose-dense chemotherapy with a G-CSF preparation is recommended in patients with adequate bone marrow function [4-6]. In addition to these standard regimens, attempts have been made to develop more potent treatment regimens for locally advanced breast cancer with a poor prognosis.

Locoregional therapy

The local treatment options are surgery alone, radiotherapy alone, and surgery plus postoperative radiotherapy after preoperative chemotherapy; however, surgery plus postoperative radiotherapy is recommended. Studies of locally advanced breast cancer have found no significant difference in the local recurrence rate or survival time between patients who undergo surgery alone or radiotherapy alone after chemotherapy [7,8]. However, when endocrine therapy or chemotherapy was administered after surgery, the local recurrence rate was significantly reduced by addition of radiotherapy [8]. A retrospective analysis of clinical trials that examined the outcomes of preoperative chemotherapy for locally advanced breast cancer found that the local recurrence rate and survival time were improved in patients who received postoperative radiotherapy [9]. In other retrospective studies, patients who underwent surgery and radiotherapy after preoperative systemic chemotherapy had a better prognosis than those who received only one treatment modality alone.

Mastectomy is a common surgical option, although partial mastectomy may be possible in some cases. In the present study, the partial mastectomy rate was 18%, which is low compared with the rate of 70% for all breast cancer cases at our hospital. Mastectomy was often selected because of large tumors and skin infiltration.

Axillary lymph node dissection is generally performed. In the case of N0 disease, a sentinel lymph node biopsy may be acceptable. All cases of locally advanced N0 breast cancer are T4b, so skin infiltration is relatively mild, and preoperative chemotherapy has been successful in some cases. The extent of dissection should be determined by imaging after chemotherapy. Basically, dissection up to level 2 is recommended. If lymph node metastasis is extensive, dissection to the subclavian lymph node should be performed as needed.

The rate of metastasis to the internal thoracic lymph nodes may be as high as 28%–52% in patients with positive axillary lymph node metastasis and up to 20% in those with negative axillary lymph node metastasis but with a medial breast mass. However, it has been found that extended mastectomy with internal thoracic lymph node dissection does not improve the recurrence rate or the survival rate when compared with pectoralis major-preserving mastectomy. Internal thoracic lymph node dissection is not currently performed because of the complexity of the procedure and the widespread use of breast-conserving surgery [10]. In contrast, the Danish Breast Cancer Cooperative Group 82b and c study [11] and a meta-analysis of randomized controlled trials by the Early Breast Cancer Trialists’ Collaborative Group [12] confirmed that irradiation of the chest wall, including the internal thoracic lymph node region, improves not only local control but also overall survival. Therefore, radiotherapy rather than internal thoracic lymph node dissection is considered to be the main treatment for this area. The same applies to the supraclavicular lymph nodes, which are normally treated by postoperative radiotherapy rather than excision.

Although radiotherapy is administered as part of multimodal treatment, there have been no relevant prospective randomized controlled studies on radiotherapy after preoperative chemotherapy. However, some retrospective studies have been reported, including one in patients in the National Surgical Adjuvant Breast and Bowel Project B-18 and B-27 trials who underwent total mastectomy without radiotherapy after preoperative chemotherapy.

The clinical stage and the efficacy of chemotherapy have been shown to be significant predictors of lymph node recurrence [13]. A retrospective analysis of data from six prospective clinical trials conducted at the MD Anderson Cancer Center compared the outcomes between a group of 542 patients who received postoperative radiotherapy and a group of 134 patients who did not [14]. The 10-year local/regional lymph node recurrence rate was significantly higher in the non-irradiated group (22% vs 11%; p=0.0001). However, there was no significant difference in the 10-year overall survival rate between the two study groups. In the same study, a retrospective analysis of 106 patients who underwent total mastectomy after preoperative chemotherapy and achieved a pathological complete response found that those with clinical stage I–II disease in both groups had no local or regional lymph node recurrence for up to 10 years whether or not they received postoperative radiotherapy. However, the local and regional lymph node recurrence rate was significantly higher in patients with stage III disease who did not receive radiotherapy (p=0.040) [14]. By contrast, in another study that included 52 cases of clinical stage II–III ypN0 breast cancer for which preoperative chemotherapy was effective for lymph node metastasis, multivariate analysis did not show a significant correlation of presence or absence of radiotherapy with the recurrence-free survival rate, local/regional lymph node non-recurrence rate, or overall survival rate [15]. Unfortunately, all these reports are subject to bias in terms of background factors and treatment selection, so the strength of the evidence is considered to be very weak. At present, the recommendation is to determine the indication for postoperative radiotherapy according to the stage before preoperative chemotherapy, even if it is successful.

If partial breast resection is performed, the remaining breast is irradiated. The lymph node area should be irradiated if lymph node metastasis remains. However, even if there is no lymph node metastasis, it is better to perform irradiation according to the stage before chemotherapy.

The post-mastectomy irradiation rate at our facility was low during the study period, being performed in 64% of cases after partial mastectomy and in only 35% after mastectomy. However, although there was no effect on recurrence-free survival, the possibility that post-mastectomy radiotherapy helped to suppress local lymph node recurrence cannot be ruled out. Our finding of a local recurrence rate of 12% at our institution suggests that our treatment should be more aggressive and that multimodal treatment should be promoted. Radiotherapy is basically administered after surgery. However, if the tumor is still present after preoperative chemotherapy, preoperative irradiation may be considered to facilitate resection surgery.

Preoperative irradiation has been studied in the past [16]. Although our present study focused on patients in whom radical surgery was possible, preoperative irradiation may still be effective in unresectable cases. According to one report, the effect of radiation after resection is small [17]. However, preoperative irradiation is not often performed at present in Japan.

This study has some limitations in that it was performed at a single center, had a retrospective design, and included a small number of cases with a short observation period. The results obtained from our analysis are very likely to be different if a larger number of cases are collected. It should be remembered that this is a retrospective study with a small number of cases in a single institution. Further studies that include a large number of cases drawn from a database and a longer observation period may provide a clearer picture with regard to the most effective treatment for locally advanced breast cancer.

Locally advanced breast cancer has high local recurrence and distant metastasis rates and a poor prognosis. Multimodal treatment, namely, a combination of local treatment after preoperative systemic chemotherapy, is recommended. At our facility, the proportion of patients who receive radiotherapy has been very low. Although radiotherapy had no statistically significant effect on the prognosis, there is a good chance that irradiation will improve the outcome. In this study, being premenopausal and the presence of 4 or more lymph node metastases were significant factors affecting recurrence-free survival. Patients with locally advanced breast cancer require multimodal treatment that includes radiotherapy, especially those with 4 or more lymph node metastases.