Introduction

Idiopathic Granulomatous Mastitis (IGM) is an under-recognized inflammatory and auto-immune breast disease1 that presents significant management challenges due to its varied clinical manifestations and lack of a standardized treatment protocol. This disease often requires long-term management and is prone to high relapse rates after surgical interventions. The treatment landscape for IGM has traditionally included corticosteroids (CSs) due to their efficacy in managing inflammation1. However, the relapse rates and their long-term use is associated with severe metabolic side effects, prompting a shift towards non-steroidal immunosuppressive agents such as Methotrexate (MTX) and Azathiopurine (AZA)2. While MTX is frequently used for its steroid-sparing benefits and has shown high remission rates in several studies, the role of AZA remains less defined, although it is valued for its ability to reduce corticosteroid dosage effectively3.

The complicated clinical course of the disease highlights the necessity of personalized treatment plans tailored to the individual needs of each patient. While immunosuppressive therapies have shown promising results, there remains a critical need to rigorously evaluate the benefits and risks associated with these treatments to enhance clinical outcomes for IGM patients. This study aims to investigate the efficacy and safety of immunosuppressive therapy, including corticosteroids and other agents, in the management of IGM. Through extensive long-term data collection and analysis, our research seeks to provide deeper insights into treatment responses and contribute to the development of evidence-based clinical guidelines for this complex condition.

Methods

Study design and patient population

The study was utilized as a retrospective analysis of a prospectively collected data including a total of 505 patients who were treated and followed-up at the Breast Surgery Clinic of Bursa Uludag University with a diagnosis of IGM between January 2011 and December 2022. Patients aged 18 years or older with a confirmed diagnosis of IGM were included in this study (n = 355). Diagnosis was based on clinical, radiological, and histopathological findings, performed by experienced breast surgeons and pathologists in accordance with established diagnostic criteria. Only patients with a definitive diagnosis confirmed by biopsy and at least one follow-up visit within the last 6-months at the breast clinic were included. Patients with other breast diseases or incomplete medical records were excluded.

The study involved both primary and recurrent cases of IGM. Patient demographics, including age at diagnosis, gender, and co-morbidities, were recorded. Clinical data such as breast involvement, presenting symptoms, diagnostic methods, and treatment modalities were collected from the medical records. Treatment modalities included 1st -line, 2nd -line, and 3rd -line therapies, as well as surgical interventions when indicated. Recurrence rates, therapy duration, and progression-free time were recorded. Patients who experienced relief of symptoms, had no lesions associated with IGM on imaging, and maintained a disease-free interval of at least 3 months meeting these criteria were considered as having achieved a state of progression-free status.

All participants in this study provided informed consent for inclusion. This consent covered both participation in the research and the collection of de-identified data. Specific consent for publication of identifying information or images was not applicable, as no patient names, images, or other personal identifiers were included in the study. The study protocol was approved by the Ethics Committee of Uludag University (Approval Date: 15.12.2021, Decision Number: 2021/100), in alignment with the principles outlined in the Declaration of Helsinki.

Clinical management of the disease and follow-up

The management of IGM involved different therapy lines, and patient follow-up was considered essential to monitor treatment response and ensure optimal outcomes.

1st -line observation therapy

1st -line therapy was given to patients at earlier stages with a painful, small (< 2 cm) non-complicated lesions for conservative measures to manage symptoms and control disease progression. This included close observation, pain management, and local wound care, with empiric antibiotics administered when an associated infection was suspected. Antibiotic regimens included amoxicillin-clavulanate as monotherapy, dicloxacillin or cephalexin combined with metronidazole for suspected anaerobic infections, or doxycycline monotherapy if cultures were positive for Corynebacterium spp. Routine scheduled clinical assessments were conducted to monitor the patient’s response to treatment and to determine the need for further intervention.

2nd -line Anti-inflammatory and immune suppressive corticosteroid therapy

In cases where 1st -line therapy was insufficient or when moderate to severe disease is present, 2nd -line therapy was initiated. Second-line therapy aimed to suppress the immune response and control disease activity. This typically involved the use of steroid therapy, such as low-dose or high-dose prednisolone. Low-dose steroid therapy was given of 16–20 mg of prednisolone per day orally for 4 to 6 weeks, followed by a gradual dose tapering over a three-month period in patients with small unilateral lesions (< 5 cm) with small drainage or ulceration. The dosage and duration of steroid therapy were determined based on the individual patient’s response and disease severity. High-dose steroid therapy in this study involved the administration of 0.5-1.0 mg/kg/day of prednisolone with or without 3rd -line therapy drugs to patients with multiple lesions, lesions ≥ 5 cm in diameter, bilateral lesions, or disease characterized by significant cutaneous ulceration, drainage, or fistulas.

3rd -line immune suppressive therapy

3rd -line therapy was necessary for patients who experience disease recurrence, complicated disease or have an inadequate response to previous therapies and advanced disease. In cases of recurrences and treatment response failure, further escalation of treatment was recommended, including the addition of alternative immunosuppressive agents or referral to specialized disciplines such as rheumatology, pulmonology, and infectious diseases for advanced management options. MTX, AZA, Cyclophosphamide (CP), and Cyclosporine (CSA) were utilized as 3rd-line therapy drugs to manage IGM and optimize treatment outcomes. MTX therapy was initiated in advanced disease along with high-dose steroid therapy, providing an opportunity to taper the steroid dosage while on MTX treatment. MTX was typically administered at a dosage of 5–15 mg per week along with daily Folic acid supplementation for a duration of 6 to 24 months to alleviate symptomatic disease and prevent early recurrences. As the steroid dose was gradually tapered, MTX was continued in conjunction with low-dose steroids, typically at a dosage of 4 mg/day, for extended durations in cases of advanced disease. This combination approach allowed for better disease management and prolonged treatment efficacy.

The choice between AZA and MTX, or their combination, was based on individual patient factors and treatment response. AZA therapy, either as a standalone treatment or in combination with other agents, aimed to suppress the immune system and control disease activity. AZA therapy involved an induction phase of 1 mg/kg/day orally in single or divided q12 doses, followed by a maintenance phase with a gradual reduction of the daily dose by 0.5 mg/kg/day every 4 weeks after reaching the effective therapeutic dose. In the latter stage of treatment, once the effective dosage of AZA was reached, steroid therapy was discontinued, and AZA continued as the sole therapeutic agent in the treatment regimen. AZA therapy was safely administered during pregnancy and in patients with liver and renal impairment. To evaluate treatment efficacy, adjust dosage or regimen if needed and to ensure disease control, patients were monitored with close and regular assessments.

Surgical therapy

The mainstay therapy of IGM was conservative involving non-steroidal anti-inflammatory and analgesic drugs and immune suppressive therapy with corticosteroids and immune suppressive agents. However, in cases where patients were unresponsive to medical therapy or had a complicated clinical course, surgical therapy such as such as abscess drainage, wide local excision, and mastectomy provided an additional therapeutic benefit in the management of IGM. These surgical procedures were employed across all therapy lines, including 1st-line, 2nd-line, and 3rd-line treatments, aiming to address treatment-resistant disease and improve patient outcomes. These procedures provided the disease control, relief of symptoms, and reduced the risk of complications. The decision to practice surgical intervention was made based on careful evaluation of the patient’s clinical condition and treatment response. Surgeons worked closely with the multidisciplinary team to determine the appropriate timing and extent of surgical intervention, considering the individual patient’s needs and treatment goals.

Follow-up

Patient were followed up with routine scheduled clinical assessments, including physical examinations, symptom evaluations, and laboratory investigations for 4 to 6 weeks intervals, for monitoring treatment response and disease progression. Radiological imaging, such as ultrasound, or MRI, for 3 to 6 months intervals provided valuable insights into disease extent, treatment response and the presence of any complications. Patients were educated and counselled to ensure that they were well-informed about their treatment options, potential side effects, and the need for compliance with therapy. Psychological support and counseling were considered to address the emotional and psychological aspects associated with the management of idiopathic granulomatous mastitis.

Statistical analysis

Statistical analyses were performed using IBM SPSS Statistics for Windows, Version 25.0. (Armonk, NY: IBM Corp). Categorical variables, such as therapy groups and recurrence outcomes, were summarized with frequencies and percentages.

A chi-square test of independence assessed the association between therapy type and recurrence rates among the five groups:

  1. 1.

    Corticosteroid (CS) therapy alone.

  2. 2.

    Methotrexate (MTX) plus CS therapy.

  3. 3.

    MTX plus azathioprine (AZA) therapy.

  4. 4.

    AZA therapy alone.

  5. 5.

    AZA plus CS therapy.

When the overall chi-square test was significant, pairwise chi-square tests with Bonferroni correction were conducted to identify specific group differences. The significance level was adjusted to α = 0.005 to account for multiple comparisons.

Recurrence rates were calculated as the percentage of patients experiencing recurrence within each therapy group. P-values less than 0.05 were considered significant, except in pairwise comparisons where the adjusted α was applied. All tests were two-tailed, and assumptions of the chi-square test were verified.

Results

Clinical manifestation

Among 505 patients during 12-year follow-up, 29.7% (n = 150) had 1st -line conservative therapy, and 70.1% (n = 355) had 2nd -line and 3rd -line immune suppressive therapy.

The mean age on diagnosis of patients who had immune suppressive treatment was 36.14 ± 8.08 (Range: 21–66 years) and all patients were female. The right breast was affected in 43.4% (n = 154) of patients, the left in 52.4% (n = 186), and both breasts in 4.2% (n = 15). The most common symptom on admission was a palpable, painful mass with skin changes such as thickening, edema and redness in 47% (n = 167) of the cohort. A significant number of patients also showed signs of abscess formation (34.6%, n = 123) and fistula development with purulent discharge (16.9%, n = 58). The median duration to the diagnosis was 2 months (Range:1–36 months) in symptomatic patients. All patients had breast ultrasound and diagnosis of IGM were performed by tru-cut bx in 83.7% (n = 297) of the patients, and fine needle aspiration cytology in 1.7% (n = 6) while incisional biopsy in 14.6% (n = 52). The median size of the index inflammatory mass or abscess was 35 mm (Range: 8–110 mm).

In terms of co-morbid diseases, the majority of patients (75.8%, n = 269) did not have any underlying medical conditions. Only a small percentage of patients, 2.81% (n = 10), had attending rheumatological and autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus, familial mediterranean fever, and psoriatic arthritis. Among these individuals, erythema nodosum was diagnosed in 2.25% (n = 8) of cases.

The median number of pregnancies among the patients were 2, with a range of 0 to 5. Eight patients experienced IGM during pregnancy. However, one pregnancy had to be terminated due to the teratogenic effects of the therapy. Furthermore, 21.7% (n = 77) of the patients were diagnosed with IGM within the first 5 years following lactation, and 3.38% (n = 12) of them developed the condition during lactation. Clinical and demographic characteristics of the patients with risk factors were demonstrated in Table 1.

Table 1 Demographic and clinical characteristics of patients with IGM who were treated with immune suppressive therapy.
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Immune suppressive treatment

Medical treatment options varied among the patients who received immune suppressive treatment. Among the 355 patients, 29.3% (n = 104) underwent 2nd -line steroid therapy while 70.7% (n = 251) had 3rd -line immunosuppressive therapy. The median duration of follow-up for the patients in this study was 24 months, with a range of 3 to 137 months. A total of 21.4% (82) of the patients exhibited progressive disease that was unresponsive to initial treatment, resulting in recurrences prior to receiving the final therapy. These patients were referred to later line therapies and the overall recurrence rates decreased to 3.1% with 3rd -line immune suppressive therapy. The median progression-free time was observed as 17 months (Range: 3-134 months) during 12-year follow-up. The multi-modal therapy management of the IGM was demonstrated in Table 2.

Table 2 Multi-modal therapy characteristics of patients with IGM.
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The overall mean duration of 2nd -line steroid therapy for all patients in the study was 6 months (Range: 1–48 months). 54.8% (n = 57) of the patients received low-dose prednisolone therapy, and 75.4% of them (n = 43) experienced no disease recurrence during the follow-up period. In contrast, 24.6% (n = 14) of patients in this subgroup had disease recurrence and subsequently required later-line therapy. 45.2% (n = 47) were administered high doses of prednisolone, and 66% (n = 31) was disease-free. However, 36% (n = 16) of patients receiving high-dose steroid therapy had to be referred for later-line immunosuppressive therapy due to progressive disease. When comparing the low-dose and high-dose steroid therapy groups, there was no significant difference in terms of therapy duration (3.9 ± 2.28 months vs. 4.15 ± 2.89 months, p = 0.781) and disease recurrence rates (p = 0.199).

The 3rd -line immune suppressive therapeutic modalities employed for IGM were diverse. Particularly, 35.9% (n = 90) of patients received initial immunosuppressive drug alone, 34.3% (n = 86) received immunosuppressive therapy in combination with corticosteroids, and 29.9% (n = 75) referred later-line immunosuppressive therapy after failing to respond to adjunctive corticosteroid treatment.

The overall median duration of 3rd -line therapy in combination with corticosteroids was 6 months, with a range of 1 to 48 months. 26.7% (n = 43) of the patients received low-dose prednisolone, and 83.7% of them experienced no disease recurrence during the follow-up period. In contrast, 16.3% (n = 7) of patients in this subgroup had disease recurrence and subsequently required later-line therapy. 73% (n = 118) were administered high doses of prednisolone. Among this group, 72% (n = 85) experienced no disease recurrence during the follow-up period. However, 28% (n = 33) of patients receiving high-dose steroid therapy had to be referred for later-line immunosuppressive therapy due to disease recurrence. When comparing the low-dose and high-dose steroid therapy groups, there was no significant difference in terms of disease recurrence rates (p = 0.152). However, the median duration of combined prednisolone therapy differed significantly between the two groups. The high-dose therapy group had a longer median therapy duration compared to the low-dose therapy group. Specifically, the median duration of therapy in the low-dose group was 4.5 months (Range:1–18 months), while the median duration in the high-dose group was 6 months (Range: 1–48 months) (p = 0.002).

34.3% (n = 86) of the patients received MTX therapy in combination with prednisolone. The median duration of MTX therapy was 8 months, with a range of 3 to 24 months. During MTX therapy, it was observed that 20% of the patients (n = 17) experienced progressive disease. As a result, these patients were referred for further therapy, which included the addition or switch to AZA. The specific treatment approach was tailored based on the individual patient’s response and the need to effectively manage the recurrence of the disease. A subset of 8.4% (n = 21) underwent a combination therapy involving both MTX and AZA. However, only one patient experienced disease recurrence during the follow-up period while on combination therapy.

Among the patients who received 3rd -line immune suppressive therapy, a significant proportion of 55.4% (n = 141) underwent treatment involving AZA. Within this subgroup, 61.8% of the patients (n = 86) received AZA therapy alone, without the addition of any other immunosuppressive agents. The median duration of AZA as a sole drug was 12 months, (Range: 1 to 40 months). Recurrence rate of AZA alone therapy was 4.65% (n = 4). Additionally, 29.1% (n = 56) of the patients who received a combination of AZA and CSs, a recurrence rate of 9.09% (n = 5) was observed.

Among patients receiving immunosuppressive therapy for IGM, the recurrence rates varied significantly between different treatment regimens (p < 0.001). The group treated with CS therapy alone exhibited the highest recurrence rate at 28.84%. The addition of MTX and AZA reduced the recurrence rates to 19.76% (p = 0.143) and 9.09% (p = 0.004), respectively. Notably, AZA monotherapy used as a third-line therapy option significantly lowered the recurrence rate to 4.65% compared to CS-containing therapies (p < 0.001 and p < 0.002). The immune suppressive therapy regimens, recurrence rates and pairwise comparison of treatments were demonstrated in Tables 3 and 4.

Table 3 The immunosuppressive therapy regimens and recurrence rates of patients with IGM.
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Table 4 Pairwise comparisons of recurrence rates between therapy groups.
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To evaluate the impact of medical therapies alone, we analyzed data excluding patients who underwent surgery, resulting in a cohort of 243 non-surgical patients. Among these, 191 patients (78.6%) received 1st-line therapy, with only 50 patients (20.6%) achieving remission. A total of 138 patients (56.8%) received CS therapy as a 2nd-line treatment, with remission observed in 45 patients (18.5%). In contrast, 3rd-line therapy with immunosuppressive agents was administered to 148 patients (60.9%), demonstrating significantly improved outcomes, with only 2 recurrences reported during follow-up. In comparison, 1st-line and 2nd-line therapies were associated with 31 recurrences (12.8%) during the follow-up period. These findings highlight the efficacy of 3rd-line immunosuppressive therapy in achieving sustained remission and reducing recurrence rates in patients managed without surgical intervention.

Adverse effects were reported in 11 patients, accounting for 3.1% of the study cohort (n = 355), necessitating adjustments to their treatment regimens. Among patients treated with MTX, 6 (1.7%) experienced adverse effects: two had gastrointestinal intolerance and were switched to AZA, one developed nausea and vomiting on oral MTX and was transitioned to subcutaneous MTX, one experienced hair loss and was switched to AZA, one reported abdominal pain, nausea, and erythema nodosum and was switched to AZA, and one developed immunosuppression, leading to a switch from AZA to oral MTX and eventually to subcutaneous MTX due to continued gastrointestinal intolerance. For CS therapy, 3 patients (0.8%) experienced adverse effects: one had blood glucose dysregulation and was switched to MTX, one developed leukocytosis and transitioned to MTX, and one had a full-body rash and was switched to AZA. Additionally, one patient (0.3%) on MTX became pregnant and was transitioned to AZA.

Discussion

This study provided invaluable data to the literature regarding the effectiveness of multidisciplinary, multimodal therapy for IGM within a large patient cohort, with a median follow-up of 24 months over a 10-year experience at a tertiary breast clinic. Close monitoring with observation, medical therapy including both steroid and immunosuppressive, and surgical interventions were combined meticulously. The initial conservative approach observation and symptomatic management was performed for uncomplicated and smaller lesions. The more aggressive 2nd-line and 3rd-line therapies including CSs and other immunosuppressive agents like MTX, AZA, CSA and CP were employed based on disease severity and response to initial treatments. Among the entire cohort, 21.4% of the cases on initial treatment presented with progressive disease experiencing complicated clinical course and recurrences. However, later-line therapies significantly decreased the recurrence rates to 3.1%. The median progression-free time was observed as 17 months (Range:3-134 months) with 3rd-line immunosuppressive therapy. Additionally, this study demonstrated the largest cohort involving AZA therapy in the literature, to our knowledge, as an emerging 3rd-line therapy regimen with the lowest side effects and recurrence rates either alone or in combination with other immunosuppressive drugs. These outcomes underscore the efficacy of escalating to more intensive immunosuppressive regimens in the management of IGM within a multidisciplinary, multimodal individualized treatment approach.

IGM is an under recognized inflammatory disease of the breast that lacks a standardized treatment approach and often requires long-term follow-up regarding high risk of recurrence. Additionally, in terms of adverse reactions or resistance to CSs, alternative treatments such as MTX, AZA, and other immune suppressive agents are considered4. Kim et al.5 presented a case with recurrence following CS dose tapering, where initial AZA therapy was not tolerated and switched to MTX therapy which was maintained for a year without side effects and recurrence. Thereafter, MTX proved to be a viable alternative for managing complex IGM cases, especially in patients who relapsed after CS use and were concerned about long-term side effects, with successful outcomes reported in individual cases6,7.

MTX monotherapy is currently considered as a feasible option for the management of IGM. Schmajuk et al. reported the first successful cases with moderate weekly oral doses of MTX monotherapy, highlighting the need for further research to determine optimal dosing and treatment duration8. Recently, Kundaktepe et al. achieved full recovery in 81.25% of patients with dosage adjustments in relapsed cases over a treatment duration to a year9. Only 4.69% of patients experienced side effects that required switching to subcutaneous treatment. To evaluate the effectiveness of MTX within a multi-modal treatment approach, Ringsted et al. conducted a comparative study between MTX therapy and CS therapy in patients with systemic inflammatory symptoms, either alone or combined with surgery. In this cohort, 14% of these patients presented with inflammatory arthritis or arthralgia, and 18% had erythema nodosum. The study demonstrated an 80% rate of relapse-free remission with MTX treatment, compared to 42% with CS therapy alone and 66% for CS therapy combined with surgery. These findings highlighted the potential effectiveness MTX’s for IGM patients, particularly those with additional inflammatory conditions10. Furthermore, Kehribar et al. conducted a retrospective study involving 33 female patients who had a combination of CSs and MTX therapy11. The study presented remission in 87.9% of cases, and notably, no relapses were observed during a 24-month follow-up period. These studies provided the efficacy of combined treatment regimen in ensuring long-term remission for IGM patients.

Our study involved 355 patients who received immunosuppressive therapy during a median follow-up period of 24 months (range: 3-137 months). Of these, 29.3% underwent 2nd-line steroid therapy, while 70.7% received a 3rd-line therapy regimen. CS therapy alone showed a higher rate of progressive disease associated with recurrence, at 29%. The duration of both low-dose and high-dose CS therapy was similar (p = 0.781), and the recurrence rates did not significantly differ (p = 0.199). Additionally, 34.3% of patients in the 3rd-line immunosuppressive therapy group received a combination of MTX and CS, with 80% achieving remission within a median therapy duration of 8 months. These results were consistent with the current literature, confirming that the median therapy duration was appropriate. However, 29.9% of the patients received an additional therapy regimen after failing to respond to initial immunosuppressive treatment; their therapy was tailored as combination therapy with MTX plus AZA, AZA plus CS, or AZA alone. A subset of 8.4% underwent a combination therapy involving both MTX and AZA and during the follow-up period, only one patient experienced disease recurrence while on combination therapy. The combination therapy of MTX and AZA appeared to be effective in managing the severe complicated disease and reducing the risk of recurrence as most patients in this subgroup-maintained disease control.

AZA is a potent immunosuppressive drug widely used for autoimmune and rheumatologic disorders. However, to date, it is frequently preferred as an adjunctive therapy option in the management of IGM. Several studies have demonstrated its effectiveness especially in combination with CS as a maintenance strategy to alleviate prolonged CS side effects. Konan et al. demonstrated promising results with 73% complete response rate using combination therapy, which also facilitated a rapid reduction in CS dosages12. Another study by Tekgoz et al. investigated the role of AZA in patients with recurrent IGM who did not respond to initial MTX and CS therapy13. The two out of three patients achieved clinical and radiological remission within the first nine months of AZA treatment, although one patient requiried the administration of cyclosporine A due to progressive disease. Among seven patients treated with AZA, five of them had complete remission and two had partial remission with a median time of 9.33 months. Although these findings confirm the potential role of AZA in the treatment of IGM, further research involving larger patient cohorts is necessary to ascertain its efficacy.

Our study represents the largest dataset to date assessing the effectiveness of AZA in the multi-modal management of IGM. This cohort includes 162 patients, comprising 45.62% of those receiving immunosuppressive therapy. Among these patients 53.08% had AZA as monotherapy, while 33.95% and 12.96% had in combination with CS and MTX, respectively. While the CS therapy alone group presented with the highest recurrence rates (28.84%), the addition of MTX and AZA reduced the recurrence rates to 19.76% (p = 0.143) and 9.09% (p = 0.004), respectively. Remarkably, the use of AZA as a standalone agent in the treatment of complicated disease significantly lowered the recurrence rate to 4.65%. These findings underscore that AZA, whether used alone or in combination with other agents, provides a more sustained immunosuppressive effect in the management of IGM, particularly when administered as a primary long-term treatment modality.

Our study has several limitations. The retrospective analysis of prospectively collected data may introduce selection bias and limit the ability to compare outcomes across treatment modalities. Although the follow-up duration and remission rates in each therapy group were consistent with existing literature, the lack of randomization and control groups makes it challenging to account for confounding variables. Additionally, our findings are based on a relatively homogenous patient cohort, reflecting the demographics of the population treated at our institution. While this provides valuable insights into the management of IGM in this context, it limits our ability to evaluate the role of ethnicity in disease incidence and treatment outcomes. Recent studies have highlighted significant ethnic disparities, with Hispanic and Latino populations showing a six-fold higher prevalence of IGM compared to non-Hispanic groups. These studies also reveal variations in treatment patterns, such as increased methotrexate use (P < 0.05), lower steroid use (P < 0.05), and higher rates of incision and drainage (P < 0.05) in these populations14. To address these, future research should include more diverse patient cohorts and conduct prospective, randomized controlled trials to further explore ethnic disparities, develop individually tailored treatment strategies, and validate findings in broader populations beyond a single tertiary breast clinic.