Impact of immediate breast reconstruction on perioperative therapy: insights from a Japanese Nationwide Registry

Background Immediate breast reconstruction (IBR) is a common oncoplastic procedure used in breast cancer surgery. This study aims to investigate compliance with prosthetic breast reconstruction guidelines and its impact on perioperative treatment. Methods We reviewed data from the National Clinical Database-Breast Cancer Registry between January 2019 and December 2020. We compared perioperative treatment implementation between the IBR and non-IBR groups by subtype matching for age, menopausal status, T stage, N stage, and histology. Results A total of 8,860 patients with breast cancer who underwent IBR (6,075 breast prostheses, 2,492 autologous tissues, and 293 others) were identified. The compliance rate with the guidelines for prosthetic breast reconstruction was 97.7%. After matching, chemotherapy for luminal A-like diseases was significantly less frequent in the IBR group than in the non-IBR group (16.3% vs 20.5%, p < 0.001), and radiotherapy was less frequent in luminal A-like and HER2-positive patients (7.2% vs 9.0%, p = 0.010 and 7.1% vs 11.4%, p = 0.005, respectively). Among the 1–3 node-positive cases, fewer patients with prosthetic IBR received radiotherapy than those without IBR (15.7% vs 26.4%, p < 0.001). Conclusion Prosthetic breast reconstruction was performed with strict adherence to the Japanese guidelines. The implementation rates of chemotherapy and radiotherapy were lower in the specific IBR group than those in the non-IBR group. Therefore, large-scale, long-term follow-up data are required. Supplementary Information The online version contains supplementary material available at 10.1007/s12282-024-01604-3.


Introduction
Breast cancer is the most common cancer among adult women worldwide and in Japan.The number of newly diagnosed breast cancer cases in Japan has increased from 85,856 in 2013 to 97,142 in 2019 [1].Mastectomy is a standard radical surgery, along with breast-conserving surgery.However, it has severe cosmetic disadvantages.Immediate breast reconstruction (IBR) is an important treatment option for this demerit [2].The National Insurance Service of Japan covered IBR using breast prostheses in 2013, and breast reconstruction increased dramatically, from 1,050 in 2013 to 5,942 in 2018 [3].The prosthetic IBR fell to 3,678 in 2019 due to an interruption in the supply of prosthetic reconstructive materials based on concerns of breast implant-associated anaplastic large-cell lymphoma, but has since increased again, reaching 4,587 in 2021.
However, the oncological safety of IBR for locally advanced breast cancer has not been adequately studied [4].Therefore, the Japan Oncoplastic Surgery Society recommends the following requirements for using breast prostheses: 1) stage II or lower preoperative diagnosis, 2) no evidence of skin or pectoralis major muscle involvement, and advanced lymph node metastasis [3].However, compliance with these recommendations has not been investigated.In addition, there is concern that IBR may influence the implementation of standard adjuvant therapy.IBR is associated with a higher risk of postoperative complications, such as wound complications, infections, flap necrosis, and implant removal [5,6].Prolonged recovery from complications can delay or prevent subsequent therapy.In particular, radiation has been reported to increase IBR-related complications and cause a reduction in cosmetic appearance and patient satisfaction [7,8].
Given these gaps, our study aims to shed light on the impact of IBR on oncological outcomes and treatment compliance.The National Clinical Database-Breast Cancer Registry (NCD-BCR) covers surgeries performed in almost all surgical facilities in Japan.Detailed data on IBR were collected from the registry in 2019.This study was conducted to investigate compliance with the IBR guidelines and the implementation of standard perioperative therapy in Japanese patients with breast cancer who underwent IBR.

Patients
Surgical cases with breast cancer registered in the NCD-BCR database between January 2019 and December 2020 were reviewed.The exclusion criteria were male sex, bilateral breast cancer, stage IV disease, and a history of breastconserving surgery.A total of 86,797 patients were eligible for inclusion (8860 who underwent IBR and 77,937 who did not undergo IBR).We matched the IBR and non-IBR cases in a 1:1 ratio in terms of age, menopausal status, T stage, N stage, and histology by subtype to compare the implementation of perioperative therapy between the two groups.A flowchart of the process is shown in Fig. 1.

Statistical analysis
All statistical analyses were performed using SAS ver.9.4 (SAS Institute, Cary, NC, USA).Statistical comparisons of categorical variables were performed using the Chi-square or the Fisher exact probability tests.Continuous variables were compared using the Wilcoxon rank-sum test.Continuous variables are expressed as medians and 5-95th percentiles.Differences were considered statistically significant at two-tailed p values < 0.05.

Results
The characteristics of 8,860 patients with breast cancer who underwent IBR are presented in Table 1.Among them, 6,075 underwent IBR with breast prostheses, and 2,492 underwent autologous tissues.In the prosthetic and autologous IBR groups, 2.1% and 4.9% of the patients had T3-4 tumors, 5.9% and 10.4% had nodal metastases, and 5.0% and 9.9% underwent neoadjuvant chemotherapy, respectively.

Compliance with guidelines for breast prosthesis use.
Among 6,075 cases with prosthetic IBR, 33 were not evaluable for compliance with the IBR guidelines for prosthetic breast reconstruction, and 5,906 (97.7%) were compliant (Table 2).The reasons for non-compliance were stage III disease in 94 cases, skin or pectoralis major muscle involvement in 82 cases, and advanced lymph node metastases in 60 cases (including duplicates).Forty-four of 136 noncompliant patients received neoadjuvant chemotherapy.

Implementation of perioperative treatment
The implementation of perioperative therapy in the matched cases of invasive breast cancer is shown in Table 3, and the characteristics of the matched cases are shown in Supplementary Table S1.Chemotherapy was administered frequently in luminal B-like, HER2-positive, and triplenegative subtypes, with no significant difference between cases with and without IBR.Fewer luminal A-like tumors with IBR received chemotherapy than those without non-IBR cases (16.3% vs 20.5%, p < 0.001).Radiotherapy was provided less frequently in the IBR group than in the non-IBR group for luminal A-like and HER2-positive subtypes (7.2% vs 9.0%, p = 0.010 and 7.1% vs 11.4%, p = 0.005, respectively).Radiotherapy rates were approximately 2% lower for luminal B-like and triple-negative subtypes in the IBR group.Endocrine and anti-HER2 therapies were administered similarly in both groups.

Discussion
We investigated the current status of IBR in breast cancer surgery in Japan and its impact on perioperative treatment using the NCD-BCR.Autologous IBR tend to be performed for more advanced diseases.Prosthetic IBR was performed according to the Japanese guidelines.Perioperative treatment, particularly radiotherapy for N1 cases and chemotherapy for luminal A-like diseases, was less common in the IBR group than in the non-IBR group.
Breast reconstruction after mastectomy is a common oncoplastic procedure for restoring breast symmetry and improving health-related quality of life (HRQoL) and psychological damage in survivors of breast cancer [2,10].IBR does not affect the prognosis or incidence of local recurrence after mastectomy [11].However, in the Japanese Breast Cancer Society survey, 47.4% of physicians thought that IBR could mask local recurrence, and 27% thought it influenced prognosis [12,13].They were concerned about the delay or omission of adjuvant chemotherapy and radiotherapy.
Radiotherapy is a significant risk factor for complications after breast reconstruction, particularly for breast prostheses [14].In addition, radiotherapy impairs cosmetic outcomes, HRQoL, and patient satisfaction [7,8,15].Therefore, the negative impact of IBR on the administration of postmastectomy radiation therapy is a concern.Postmastectomy radiation therapy is recommended for node-positive breast cancer to reduce both recurrence and mortality of breast cancer [16].If the axillary lymph node is negative, radiotherapy is recommended for patients with T3-4 primary tumors [17].The Japanese Breast Cancer Society Clinical Practice Guidelines also recommend postmastectomy radiation therapy for patients with T3-4 or positive-node disease [9].No radiotherapy has reported as an independent risk factor for local recurrence in patients with IBR [18].Recently, the therapeutic effect of postmastectomy radiation therapy for patients with 1-3 positive nodes has been discussed based on advances in modern systemic therapy [19,20].In the Japan Clinical Oncology Group survey, postmastectomy radiation therapy was performed in only 20.3% of T1-2N1 cases in 2016 [21].Many physicians doubt the effectiveness of postmastectomy radiation therapy in patients with N1 disease.The recommendation for radiotherapy in T3-4N0 cases was not mentioned in the guidelines during the study period [22].Regarding the timing of radiotherapy administration, the waiting period for radiotherapy was longer in IBR cases than in non-IBR cases.Although a delay of 8-20 weeks in the initiation of radiotherapy after breast-conserving surgery is associated with worsening local recurrence and survival, the relationship between the timing of radiotherapy after mastectomy with IBR and clinical outcomes is uncertain [23,24].In this study, the systemic therapy was similarly administrated to matched patients with and without IBR, excluding chemotherapy for luminal A-like invasive diseases.The indication for chemotherapy for luminal disease is based not only on clinical risk but also on multi-gene assays.Determining appropriate chemotherapy administration for the luminal A-like subtype is difficult, except in definitive high-risk cases.Particularly in premenopausal women, who account for the majority of patients with IBR, the potential effects of ovarian function suppression are unclear.The ongoing NRG-BR009 (OFSET) trial will provide insight into the need for chemotherapy in premenopausal women with ovarian function suppression.The risk-benefit assessment of chemotherapy in relation to IBR may affect treatment decision-making in patients with luminal A-like disease.
Previous meta-analyses have demonstrated that neoadjuvant chemotherapy did not increase IBR-related complications and that IBR did not delay the administration of adjuvant chemotherapy [25][26][27].The Japanese Breast Cancer Society group survey demonstrated the oncologic safety of neoadjuvant chemotherapy in Japanese patients with IBR [28].Recently, the de-escalation of local therapy for remarkable responders has been discussed.NSABP B-51/RTOG 1304 trial (NCT01872975) demonstrated the oncological safety of omitting chest and regional radiotherapy after mastectomy in cN + /ypN0 patients who received neoadjuvant chemotherapy [29].The role of radiotherapy is changing with the development of systemic therapy, and IBR will be offered to more patients undergoing neoadjuvant chemotherapy in the near future.
This study has some limitations.First, this study was limited by its retrospective design.Second, the NCD-BCR had missing data, particularly regarding factors related to subtype classification.Third, this study had a short period for a database study, covering only 2 years.This is because data collection on IBR and subtype classifications began in 2019.However, this allowed the study to reflect recent Japanese trends and distinguish between luminal A-and B-like subtypes.Fourth, this study did not clarify the reasons for treatment administration or mention Japanese physicians faithfully complied with the guidelines for prosthetic breast reconstruction and tended to perform autologous IBR in advanced cases.Perioperative treatment was administered less frequently in specific IBR cases, especially radiotherapy in N1 cases and chemotherapy in luminal A-like cases.IBR should be performed considering cosmetics, HRQoL, complications, and potential prognostic risks.In the future, more patients should be given opportunities for IBR, including those who have received neoadjuvant chemotherapy.Large-scale prognostic and HRQoL data from long-term follow-up are required.

Table 1
Characteristics of breast cancer cases with immediate breast reconstruction BMI body mass index, HER2 human epidermal growth factor receptor type2, IBR immediate breast reconstruction

Table 2
Compliance of requirements criteria for artificial breast use * Including duplicates

Table 3
Perioperative treatment according to subtypes in matched cases of invasive breast cancer Despite the use of matching analysis to mitigate confounding factors, inherent selection biases may have persisted.Information about postoperative complications and HRQoL, which were not collected in the NCD-BCR database, may have affected treatment selection.The Japan Oncoplastic Breast Surgery Society group survey on HRQoL after IBR and postmastectomy radiation therapy is ongoing.Finally, this study lacks prognostic information.

Table 4
Radiotherapy implementation rate in radiotherapy-recommended cases *IBR immediate breast reconstruction * T3-4 or N1-3 cases based on Japanese Breast Cancer Clinical Practice Guideline † Clinical stage if receiving neoadjuvant chemotherapy ‡ p < 0.001 compared with non-IBR cases included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material.If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.