Abstract

Introduction: Neoadjuvant chemotherapy (NACT) is a prevalent treatment strategy for patients with locally advanced breast cancer (LABC). Achieving a pathologic complete response (pCR) is a critical determinant of favorable outcomes. To enhance response rates, some clinicians have incorporated radiotherapy (RT) prior to surgery.

Methods: This observational cohort study aimed to investigate the initial outcomes and complication rates of preoperative radiotherapy (PRT) in breast cancer (BC) patients who did not achieve a complete response post-NACT. Between January 2017 and January 2020, 216 patients who were clinical T1-3, lymph node-positive, non-metastatic, and received NACT were analyzed. After the final dose of chemotherapy, patients were evaluated clinically and radiologically. Among them, 123 patients were non-complete responders. Of these, 37 patients received PRT according to the guidelines.

Results: Following PRT and surgery, 7 (18.9%) patients showed pCR in the breast and 14 (37.8%) in the axilla. HER2-positive and triple-negative breast cancer (TNBC) patients were significantly associated with complete response following PRT in the breast and axilla (p = 0.029). Post-surgical infection was detected in 11 (29.7%) patients, with factors such as a body mass index greater than 25 kg/m2 significantly affecting surgical site infection rates (p = 0.036). The implant loss rate was 16.7% (n = 2), and there was no grade 3 or higher RT-related skin toxicity.

Conclusion: This study demonstrated that PRT for non-complete responder patients improves pCR rates in the breast and axilla, allowing almost 38% of patients to have successful breast-conserving surgery, and lowering axillary lymph-node dissection rates without an increase in major complications. Clinical trials: ClinicalTrials.gov: NCT05274594.

 

Introduction

Neoadjuvant chemotherapy (NACT) has significant clinical value in inoperable and locally advanced breast cancer (LABC)1, converting it into an operable tumor2, 3. Not only is NACT now commonly used in patients with largely operable tumors to downstage the primary tumor and increase breast conservation rates (7–12%), but it also moves those patients from having a mastectomy to having breast-conserving surgery (BCS)4. Additionally, NACT shows the impact of systemic therapies on the biology of breast tumors5, such as additional Capecitabine adjuvant therapy being effective against human epidermal growth factor receptor 2 (HER2)-negative BC in patients with residual cancer following NACT6. Moreover, previous research has indicated that BC patients who achieved pathological complete response (pCR) after NACT showed significantly better overall survival (OS) and disease-free survival (DFS), particularly for HER2-positive and triple-negative breast cancer (TNBC)7, 8, 9.

In our institution, we have two basic treatment approaches for patients with non-metastatic and lymph node-positive or large breast tumors: either starting with surgery followed by systemic therapy or initiating systemic therapy first as NACT and then followed by surgery. Currently, NACT is widely used specifically for selected groups of BC patients, such as those with HER2-positive or TNBC subtypes, even for early-stage (stage II and stage I-lymph node positive) patients. NACT aims to achieve a complete response in the breast or in axillary lymph nodes in order to preserve the breast and/or axilla. As the goal is achieving complete response, several physicians have started considering administering radiotherapy (RT) before surgery to increase the complete response rate, which is called preoperative radiotherapy (PRT). Historically, PRT dates back to the late 1940s for BC10, but it has been a hot topic, especially in the last years.

Recently, studies have been conducted on NACT patients irrespective of their response during or at the end of chemotherapy treatment. To our knowledge, this is the first clinical study focusing specifically on NACT patients who did not achieve a clinical complete response (cCR) at the end of their chemotherapy treatment. In this single-center observational cohort study, we aim to present the initial results and complication rates of PRT administration in non-complete responder patients after NACT.

Methods Study Design

This retrospective observational cohort study was conducted between January 2017 and January 2020 and was registered in the database of clinicaltrials.gov (NCT05274594). The study was approved by the local ethics committee of Istanbul University, Istanbul Faculty of Medicine (No: 2021-536891). Initially, 216 BC patients who were T1-3, N+, M0, and to whom NACT was initiated were followed up. Later, 93 patients were excluded due to their clinical response. The study continued with 123 patients who had no cCR in the breast and/or axilla after NACT. Eighty-six patients who didn’t consent to have NART were excluded. Finally, 37 patients who received NACT were enrolled in the study depending on their order of admission. Every participant signed a written informed consent prior to enrolling in the study.

NACT Treatment Protocol

The NACT regimen was 4 cycles of anthracycline and cyclophosphamide with 12 cycles of a taxane-based regimen. Trastuzumab for 12 months was also added if pathologically HER2-positive. This protocol was the same as planned for the postoperative protocol and it was decided by the medical oncologist of the patient. Within the molecular subtype grouping, luminal A patients were defined as hormone receptor-positive, HER2-negative with low Ki-67 (

Severe infection was defined as any surgical site infection that required hospitalization, whereas mild infection was defined as a surgical site infection that was managed as ambulatory treatment. pCR was defined as no residual invasive or in-situ tumor in the final pathology following neoadjuvant treatments. cCR was defined as no sign of residual tumor mass, and the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria were used to determine cCR11. Patients were evaluated for the clinical response after the end of the last PRT (median 6 weeks).

Patient Selection and Evaluation

Initially, clinical T1-3, axillary lymph node-positive (N+) (biopsy-proven), and non-metastatic patients with any molecular subtype were included in the study. After the final dose of their chemotherapy, patients were evaluated clinically by physical examination, mammography, ultrasound, and magnetic resonance imaging (MRI) to evaluate tumor response. Patients who achieved complete response in the breast were excluded from the study. Non-complete responder patients who provided consent for the study received PRT as defined in the PRT protocol section of this study. The flow diagram for patient selection is detailed in Figure 1 . Every patient was discussed in the preoperative multidisciplinary breast surgical oncology meeting before and after neoadjuvant treatment. The method of surgery was discussed in these meetings by a group of expert breast surgeons, plastic and reconstructive surgeons, radiation oncologists, medical oncologists, and radiologists. Patients were individually evaluated for breast conservation, mastectomy, or mastectomy with reconstruction. Likewise, the method of axillary surgery was also discussed in these meetings. The indications for mastectomy were initially multi-centric tumors, large tumor volume relative to breast volume that is not allowing a good cosmetic result, patients with BC-related gene mutations, and extensive in-situ components. Reconstruction with implant was also recommended to all mastectomy patients.

× Figure 1 . Flow diagram for patient stratification of the study cohort . NACT : Neoadjuvant Chemotherapy, NART : Neoadjuvant radiotherapy. Figure 1 . Flow diagram for patient stratification of the study cohort . NACT : Neoadjuvant Chemotherapy, NART : Neoadjuvant radiotherapy. Preoperative Radiotherapy Protocol

Radiotherapy was delivered via 4-6 MV X-ray beam energies and intensity-modulated radiotherapy (IMRT), volumetric modulated arc therapy (VMAT), or forward planning IMRT (field in field – FinF) treatment techniques. PRT was planned for patients who would have BCS as 42.5 Gy in 16 fractions (with 10 Gy in 5 fractions sequential boost doses), 50 Gy in 25 fractions (with 10 Gy in 5 fractions sequential boost doses), or 50.4 Gy in 28 fractions (with 59.9 Gy in 28 fractions simultaneous integrated boost doses), involving whole breast irradiation plus nodal irradiation (including supraclavicular and axillary lymph nodes - Level I, II, III). If mastectomy was scheduled following PRT, irradiation was planned with the same treatment doses (whole breast irradiation plus nodal irradiation) as in BCS, but boost dose delivery was left to the radiation oncologist’s preference. RT to the mammary internal lymph nodes was delivered at the discretion of the radiation oncologist and according to the tumor characteristics such as clinical stage or tumor location. Surgery was planned six weeks after the end of PRT.

Statistical Analysis

During the statistical analysis, the HER2-positive group and the TNBC group were evaluated together because of the small sample size (total of 11 patients), considering that these two groups are more chemo-sensitive than the hormone-positive groups. Categorical and continuous variables were summarized using descriptive statistics (e.g., median, range, frequency, and percentage) and were compared using the Pearson chi-square or Fisher’s exact tests, respectively. The effects of clinical variables on the pCR, surgical site infection, and implant loss were analyzed by univariate analysis. The statistical level of significance was defined as p

Table 1.

Demographic, pathologic, and clinical characteristics of the patients

Total (n = 37) n % Median Age 50 (28 - 63) Age Group ≤ 50 21 56.8 > 50 16 43.2 Body Mass Index (kg/m 2 ) Normal (18.5 - 24.9) 11 29.7 Overweight (25 - 29.9) 12 32.4 Obese (≥ 30) 14 37.8 AJCC Clinical T Stage II 22 59.5 III 15 40.5 AJCC Clinical N Stage I 31 83.8 II 6 16.2 AJCC Clinical Stage II-B 18 48.6 III-A 19 51.4 ER Positive 30 81.1 Negative 7