Radiotherapy (RT) is a cornerstone of breast cancer (BC) treatment, hypofractionated radiotherapy (HypoF) emerging as a safe and effective fractionation. However, the role of molecular profiles (MP) in predicting the impact of different RT regimens on locoregional recurrence-free survival (LRFS) remains poorly understood. Personalized RT, tailored to tumor biology, could enhance outcomes by optimizing fractionation schemes for individual subtypes.
MethodsRetrospective cohort study included 290 breast cancer patients treated with adjuvant RT in 2016. Patients were classified by MP (luminal A, luminal B, HER2+, and triple-negative), and received either conventional (50 Gy/25 fractions) or hypofractionated (40.5 Gy/15 fractions) radiotherapy. Descriptive, univariate, and multivariate analyses were performed, and Kaplan–Meier survival curves with log-rank tests were used to assess LRFS.
ResultsOf the 290 patients, most patients received conventional RT (51.7%), while 48.3% received hypofractionation. Luminal A showed the longest LRFS (68.2 months), but no significant difference was observed between subtypes (p = 0.058). The five-year LRFS was highest in luminal A patients (CF: 94.4%, HypoF: 98.5%), with no significant difference (p = 0.183). Notably, triple-negative patients had better LRFS with HypoF (100%) compared to CF (73.1%) (p = 0.017).
ConclusionLuminal A subtypes exhibited higher LRFS regardless of RT type, while triple-negative BC patients achieved better outcomes with HypoF. Overall, higher LRFS were associated with BCS and HypoF treatments. These results highlight the importance of tailoring RT strategies to molecular subtypes to optimize outcomes. Further validation through larger studies is essential.
Breast cancer (BC) remains one of the most prevalent and significant causes of cancer-related mortality in women globally [1,2]. While early detection and advancements in treatment have improved survival rates, locoregional recurrence (LR) continues to pose a major challenge [3]. Radiotherapy (RT) is a fundamental part of the treatment of BC patients, reducing the incidence of LR from 27% to 8% after breast conservative surgery (BCS) and from 49% to 14% after modified radical mastectomy (MRM) [4]. Conventional fractionated radiotherapy (CF), typically delivering 50 Gy in 25 fractions, has been the standard of care [5]. However, hypofractionated radiotherapy (HypoF), which delivers a higher dose per fraction in fewer sessions (e.g., 40.5 Gy in 15 fractions), has gained traction as a safe and effective alternative, offering benefits in terms of patient convenience, cost-effectiveness, and reduced treatment time [6,7]. This has been demonstrated by studies like the Royal Marsden Hospital/Gloucestershire Oncology Centre (39 Gy/13 fractions) [8], Ontario Clinical Oncology Group (42.6 Gy/16 fractions) Standardization of Breast Radiotherapy Trial (START) A (39 Gy/13 fractions) [7], and START B (40 Gy/15 fractions) [6]. In these studies, the risk of LR ranged from 12.1% to 5.2% in the CF group (50 Gy/25 fractions) and from 9.6% to 3.8% in the HypoF group, without increased cardiac or pulmonary toxicity, radiodermatitis or cosmesis involvement [9]. In the age of precision medicine, it is needed to identify which specific population subsets are most appropriate for this HypoF treatment and, conversely, whether certain groups should be excluded from HypoF treatment [10].
Despite these advantages, evidence regarding the differential effects of CF versus HypoF on locoregional recurrence-free survival (LRFS) is still emerging. In recent years, molecular profiling (MP) of BC has become a key factor in personalizing treatment strategies. The molecular subtypes of BC luminal A, luminal B, human epidermal growth factor receptor 2 (Her2+), and triple-negative breast cancer (TNBC) have distinct biological characteristics and varying responses to treatments such as chemotherapy and RT [11]. These molecular subtypes influence the prognosis and the potential for LR, thus providing an opportunity for tailoring therapy based on the tumor's genetic and molecular makeup [10]. Previous studies have suggested that molecular subtypes could impact the effectiveness of RT [9,11]. However, the relationship between MP, HypoF, and LRFS has not been extensively explored. In Mexico, there are no reports on this matter, even though it could provide valuable insights into treatment optimization. Therefore, this study aims to determine the relationship between MP, RT treatment (CF versus HypoF), and LRFS in women diagnosed with BC in 2016 at Centro Médico Nacional del Noreste.
MethodsA retrospective comparative cohort study was carried out at the Centro Médico Nacional del Noreste in Monterrey, Mexico. The study involved 290 women diagnosed with BC (stages I–III based on histopathological diagnosis) who underwent treatment with BCS or MRM and adjuvant treatment from January to December 2016. Patients with metastatic disease, synchronous second primary tumors, autoimmune or inflammatory diseases, those who did not complete adjuvant RT treatment or had incomplete information in their electronic records, and male patients were excluded.
Data were retrieved from the pathology department, and the patients' files were reviewed to determine if they could be included. Some pathology reports examined did not have complete MP; therefore, the tissue blocks were retrieved, and the pathology department completed the profile. The patients were randomly treated with CF (150 patients treated with 50 Gy/25 fractions) or HypoF (140 patients treated with 40.5 Gy/15 fractions) with a conformal 3D technique. The treatment volumes were breast or chest wall and regional lymphatics areas according to medical indication.
The molecular classification was based on estrogen receptor (ER), progesterone receptor (PR), Ki-67 proliferation index, and Her2+ receptor status determined by immunohistochemistry. The luminal classification was recorded as positive (whether it was weakly or strongly expressed) or negative. The Her2+ was recorded as positive or negative in all the patients, and the Ki-67 proliferation index was recorded as high (15% or higher) or low (less than 15%).
At the end of the treatment, patients were scheduled for a follow-up appointment one month later to assess potential toxicities. During the first two years, visits were scheduled every three months; between the third and fifth years, appointments were held every six months, and from the fifth year onward, they were conducted annually. During the first five years, a chest X-ray, mammography, and bilateral breast ultrasound were requested every six months. From the fifth year onward, these studies are conducted annually. Recurrence was considered when the reappearance of cancer after at least six months following radical treatment. Whereas an LR was considered as the reappearance of cancer in the breast, axillary lymph nodes, or ipsilateral supraclavicular lymph nodes. Clinical, histopathological, and treatment information was collected from all the patients.
The Chi-square test/Fisher's exact test was used to compare patient, tumor, and treatment characteristics distribution. Univariate proportional hazard models were used to assess factors associated with LR, and variables with a p < 0.05 were performed in a multivariate logistic regression analysis. The survival curves were obtained with the Kaplan–Meier method, and the differences were analyzed with the log-rank test. All analyses were performed using the SPSS v 30.0 statistical package (IBM, Armonk, NY, USA).
The Comité de Ética en Investigación of Centro Médico Nacional del Noreste in Monterrey, Mexico approved this study (R-2023-1901-011). The ethics committee waived informed consent as the study was based on an existing administrative database with no direct patient contact.
ResultsThe clinical characteristics of 290 women with BC (average age: 54, range: 31–84 years) treated with CF or HypoF are summarized in Table 1. Ductal carcinoma was the predominant histological subtype, representing 42.4% in the CF group and 43.1% in the HypoF group. The distribution of clinical stages was similar between the two groups. Stage IIIA was the most common, followed by IIB and IIA. Tumor size was similar in all groups, with most patients having T2 tumors, followed by T1. Lymph node status showed N0 in 16.6% of the CF group and 13.4% of the HypoF group, while N1 was the most common (15.5% in CF, 17.2% in HypoF). Overall, clinical characteristics, including histology, tumor size, stage, lymph node status, and receptor status, were similar between the CF and HypoF groups, with no significant differences. Whereas recurrence rates differed between groups, the CF group had a higher LR rate (7.2%) than the HypoF group (2.3%). In general, 80.7% of the patients had no recurrence, 6.1% had LR, 3.4% experienced both locoregional and distant recurrence and 9.7% distant recurrence. The CF group showed a higher LR rate, indicating a potential advantage of HypoF in reducing recurrence.
Clinical and tumor characteristics of the patients.
| Conventionaln (%) | Hypofractionationn (%) | Totaln (%) | p-value | |
|---|---|---|---|---|
| Histology | 0.221 | |||
| Ductal | 123 (42.4) | 125 (43.1) | 248 (85.5) | |
| Lobular | 15 (5.1) | 6 (2.0) | 21 (7.1) | |
| Mucinous | 2 (0.6) | 1 (0.3) | 3 (0.9) | |
| Metaplastic | 1 (0.3) | 2 (0.6) | 3 (0.9) | |
| Other | 9 (3.1) | 6 (2.0) | 15 (5.1) | |
| Clinical Stage | 0.151 | |||
| IA | 16 (5.6) | 20 (6.8) | 36 (12.4) | |
| IIA | 25 (8.6) | 25 (8.6) | 50 (17.2) | |
| IIB | 26 (8.9) | 30 (10.3) | 56 (19.2) | |
| IIIA | 35 (12) | 31 (10.6) | 66 (22.6) | |
| IIIB | 22 (7.5) | 15 (5.1) | 37 (12.6) | |
| IIIC | 26 (8.9) | 19 (6.5) | 45 (15.4) | |
| Tumor size | 0.377 | |||
| T1 | 38 (13.1) | 40 (13.8) | 78 (26.9) | |
| T2 | 60 (20.6) | 64 (22) | 124 (42.6) | |
| T3 | 35 (12) | 21 (7.2) | 56 (19.2) | |
| T4 | 17 (5.9) | 15 (5.2) | 32 (11.1) | |
| Lymph node | 0.349 | |||
| N0 | 48 (16.6) | 39 (13.4) | 87 (30) | |
| N1 | 45 (15.5) | 50 (17.2) | 95 (32.7) | |
| N2 | 37 (12.8) | 34 (11.7) | 71 (24.5) | |
| N3 | 20 (6.9) | 17 (5.9) | 37 (12.8) | |
| Molecular subtype | 0.919 | |||
| Luminal A | 71 (24.4) | 67 (23.1) | 138 (47.6) | |
| Luminal B | 38 (13.1) | 31 (10.7) | 69 (23.7) | |
| HER2+ | 15 (5.2) | 15 (5.2) | 30 (10.3) | |
| Triple Negative | 26 (9) | 27 (9.3) | 53 (18.3) | |
| Surgical treatment | 0.561 | |||
| MRM | 102 (35.1) | 83 (28.6) | 185 (63.7) | |
| BCS | 48 (16.5) | 57 (19.6) | 95 (2.7) | |
| Recurrence | 0.026 | |||
| No recurrence | 114 (39.3) | 120 (41.4) | 234 (80.7) | |
| Local | 7 (2.4) | 1 (0.3) | 8 (2.7) | |
| Locorregional | 9 (3.1) | 1 (0.3) | 10 (3.4) | |
| Locoregional and distance | 5 (1.7) | 4 (1.7) | 10 (3.4) | |
| Distance | 15 (5.2) | 13 (4.5) | 28 (9.7) |
HER2+: Human epidermal growth factor receptor 2 positive, MRM: Modified radical mastectomy, BCS: Breast conservative surgery. Data are the number of patients (percentages estimated based on the total included patients n = 290).
Univariate analysis showed no significant association between clinical stage, tumor size, or molecular subtype and LR. However, lymph node status was significantly associated with LR (p = 0.001), with higher recurrence rates in patients with advanced lymph node involvement (N1–N3) compared to those with N0 status. In contrast, no significant association was found between molecular subtype and LR (p = 0.058), as recurrence rates remained consistent across all subtypes (Table 2).
Univariate analysis of factors associated with locoregional recurrence in breast cancer.
| Clinical features | Recurrencen (%) | Non-recurrencen (%) | p |
|---|---|---|---|
| Clinical Stage | 0.228 | ||
| IA | 1 (0.3) | 35 (12.1) | |
| IIA | 2 (0.7) | 48 (16.5) | |
| IIB | 4 (1.4) | 52 (17.9) | |
| IIIA | 9 (3.1) | 57 (19.6) | |
| IIIB | 5 (1.7) | 32 (11) | |
| IIIC | 6 (2.1) | 39 (13.4) | |
| Tumor size | 0.172 | ||
| T1 | 4 (1.4) | 74 (25.5) | |
| T2 | 10 (3.4) | 114 (39.3) | |
| T3 | 8 (2.8) | 48 (16.5) | |
| T4 | 5 (1.7) | 27 (9.3) | |
| Lymph node | 0.001 | ||
| N0 | 1 (0.3) | 86 (25.5) | |
| N1 | 3 (1) | 92 (31.2) | |
| N2 | 15 (5.2) | 56 (19.3) | |
| N3 | 8 (2.8) | 29 (10) | |
| Molecular subtype | 0.058 | ||
| Luminal A | 5 (1.72) | 133 (45.9) | |
| Luminal B | 8 (2.8) | 61 (21) | |
| HER2+ | 7 (2.4) | 23 (7.9) | |
| Triple Negative | 7 (2.4) | 46 (15.8) | |
| Radiation therapy fractionation | 0.015 | ||
| Conventional | 20 (7.8) | 130 (44.4) | |
| Hypofractionation | 7 (1.7) | 133 (46.1) |
HER2+: Human epidermal growth factor receptor 2 positive. Data are the number of patients (percentages estimated based on the total included patients n = 290).
Multivariate analysis showed no significant association between CF vs. HypoF; OR 0.320 (95% CI 0.102–1.007 p = 0.051), and lymph node involvement OR 1.639 (95% CI 0.429–6.307 p = 0.472).
CF treatment was associated with higher recurrence rates compared to HypoF, indicating that HypoF may reduce LR. Therefore, lymph node involvement, surgical treatment, and HypoF were significant predictors of LR, while clinical stage, tumor size, and molecular subtype showed no significant correlation. These findings underscore the importance of lymph node status and RT regimen in predicting LR in BC patients.
The Kaplan–Meier survival curve illustrates the cumulative survival proportions over time (in months) for four BC subtypes (Luminal A, Luminal B, Her2+, and TNBC) (Fig. 1). Luminal A has the highest survival rate (96.4%), reflecting the most favorable prognosis. Luminal B has a slightly lower survival rate (88.4%) but is still better than the Her2+ (76.7%) and TNBC subtypes (86.8%) p value (0.058). Her2+ subtype has the steepest decline in survival and the lowest cumulative survival percentage after 70 months of follow-up, indicating the worst prognosis. These results highlight the prognostic differences between the subtypes and emphasize the importance of subtyping in determining treatment and management strategies.
The 70-month follow-up for LRFS rates, categorized by RT type and molecular subtype, showed no significant differences between CF and HypoF for luminal A, luminal B, and Her2+ subtypes (Table 3). However, for TNBC patients, HypoF significantly improved outcomes, with 100% LRFS compared to 73.1% for CF (Table 3, Fig. 2D). The overall recurrence rate for TNBC patients was 13.2%, with a total LRFS of 86.8% after a 70-month follow-up period (Fig. 2). These results suggest that HypoF may be as effective as CF across subtypes and may provide enhanced benefits in more aggressive tumor profiles, such as TNBC and Luminal A.
70-month follow-up locoregional recurrence-free survival (LRFS) according to adjuvant radiotherapy fractionation.
| Molecular subtype | Cases n (%) | Recurrence n (%) | LRFS (%) | p-value |
|---|---|---|---|---|
| Luminal A | 0.183 | |||
| Conventional | 71 (51.4) | 4 (5.6) | 94.4% | |
| Hypofractionation | 67 (48.5) | 1 (1.5) | 98.5% | |
| Total | 138 (100) | 5 (3.7) | 96.4% | |
| Luminal B | 0.200 | |||
| Conventional | 38 (55.1) | 6 (15.7) | 84.2% | |
| Hypofractionation | 31 (44.9) | 2 (6.5) | 93.5% | |
| Total | 69 (100) | 8 (11.6) | 88.4% | |
| HER2+ | 0.841 | |||
| Conventional | 15 (50) | 4 (26.6) | 73.3% | |
| Hypofractionation | 15 (50) | 3 (20) | 80.0% | |
| Total | 30 (100) | 7 (23.3) | 76.7% | |
| Triple Negative | 0.017 | |||
| Conventional | 26 (49) | 7 (26.9) | 73.1% | |
| Hypofractionation | 27 (51) | 0 (100) | 100% | |
| Total | 53 (100) | 7 (13.2) | 86.8% |
LRFS: Locoregional recurrence-free survival, HER2+: Human epidermal growth factor receptor 2 positive. Data are the number of patients (percentages estimated based on the total included patients n = 290).
This study of 290 women diagnosed with EBC provides important insights into the clinical features of this disease. The results show that stage IIIA ductal tumors, tumor size of T2, and positive progesterone and estrogen receptors were the most common features (Table 1). The predominance of ductal tumors is consistent with the existing literature, which states that invasive ductal carcinoma (IDC) is the most common form of BC [12,13]. The classification of most tumors as stage IIIA indicates advanced disease, which usually requires aggressive treatment approaches [13,14]. This emphasizes the importance of early detection and screening, as early-stage cancers generally have a better prognosis. The distribution of tumor size, with T2 tumors (>2 cm but ≤5 cm) being the most common, is consistent with stage IIIA classification. The presence of lymph nodes (N1–N3) indicates that cancer has spread beyond the primary tumor, increasing the risk of both local and distant recurrence and death (p < 0.001) [15]. This indicates a delayed diagnosis has grown beyond the early stage but remains localized [14,15]. Larger tumors may correlate with lymph node involvement, which could influence the choice between surgery and adjuvant therapies [14]. The high positivity rates for progesterone and estrogen receptors (over 60%) underscore this group's endocrine sensitivity to tumors. This characteristic opens up possibilities for hormonal therapies such as tamoxifen or aromatase inhibitors, which are crucial for improving survival rates and minimizing recurrence in hormone receptor-positive BC [16].
This study's outcomes provide insights into the influence of MP on LRFS in BC, highlighting key differences in outcomes between CF and HypoF treatments. The LR across molecular subtype categories (Table 2) are similar to the reported by Lalani et al. [10] (1.7% luminal A, 3.0% luminal B, 2.9% Her2+, and 6.0% TNBC), and previous studies using different methods for MP [10,17]. Our findings showed that LR rates did not differ between patients treated with HypoF and CF across BC molecular subtypes in the assessed population during 70-month follow-up. The same result has already been reported in previous studies, which attributed this to their limitations, such as a small sample size and a small number of events [18]. However, this outcome is consistent in a study involving 5868 women with invasive BC treated with CF (1439) or HypoF (4429) after 12 years of follow-up [10]. These findings support the extensive application of HypoF to all BC molecular subtypes. Therefore, studies to establish the relationship between MP and LR should include molecular gene expression tools for profiling categorizations.
Notably, in the subset of patients with TNBC, evidence regarding the benefits of HypoF for locoregional control remains scarce. Based on the findings of this study, it is critical to further investigate the underlying radiobiological mechanisms involved in this interaction. A higher dose per fraction may enhance the immune response in TNBC tumors, potentially improving LRFS [19]. This study represents one of the first to propose this potential benefit and serves as a foundation for more extensive studies to validate these findings.
The low percentage of LR observed in patients receiving HypoF suggests that this treatment may enhance tumor control [20]. This finding aligns with recent studies indicating that HypoF regimens can be as effective as conventional schedules regarding local control while improving patient convenience [14,21]. In addition to clinical efficacy, HypoF may offer economic advantages. By reducing the number of treatment sessions, healthcare systems can potentially lower costs associated with radiation therapy, including facility use, staffing, and patient transportation [22]. This consideration is crucial in an era where healthcare resources are increasingly strained.
ConclusionsThis retrospective cohort study emphasizes that immunohistochemical profiling of BC does not predict HypoF or CF sensitivity or LRFS. Luminal A subtypes exhibited higher LRFS regardless of RT type, while triple-negative BC patients achieved better outcomes with HypoF. Treatment selection was pivotal, as patients treated with BCS and HypoF had a lower risk of local recurrence compared to CF. Further research with larger, multi-center studies and genetic tools is essential to validate these findings and refine future breast cancer guidelines for CF and HypoF treatments.
Ethics approval and consent to participateThe Comité de Ética en Investigación of Centro Médico Nacional del Noreste in Monterrey, Mexico approved this study (R-2023-1901-011). The ethics committee waived informed consent as the study was based on an existing administrative database with no direct patient contact.
FundingNone.
The authors declare no conflict of interest.
