INTRODUCTION
Approximately 10%–30% of patients with breast cancer experience locoregional recurrence (LRR) after primary therapy despite careful local treatment, systemic adjuvant therapies, and/or radiotherapy [1-3]. Unlike distant metastasis, most cases of LRR are operable. Management of the recurrence is aimed at controlling local disease via surgical excision and the selective use of radiation therapy, depending on prior treatment [4-6]. However, the challenge remains whether local treatment alone is sufficient and what additional adjuvant therapies should be considered post-surgery.
Breast cancer LRR indicates a biologically resistant disease to first-line adjuvant treatment. An isolated tumor recurrence is a marker of concurrent occult systemic disease. Without adequate adjuvant treatment, repeated LRRs may occur at shorter intervals. A second LRR can have a poor prognosis, with a 3-year overall survival rate of approximately 50%, similar to that of distant metastasis [7]. Also, distant metastases after breast cancer LRR occur in 20%–80% of cases and the prognosis for these patients is distinctly poor relative to those with primary breast tumor [8-12]. To improve the prognosis of patients with breast cancer LRR, a combination of systemic and local treatment options has been proposed. Furthermore, to optimize the benefit of additional treatment, we need to be confident in distinguishing LRRs that will likely progress to distant metastasis from those that are less likely to progress [11,13].
Established standards or clinical study results to guide systemic treatment in these patients are very limited [13]. Having already undergone complex adjuvant treatment for their primary breast cancer, the treatment of patients with LRR is challenging. Importantly, treatment decisions need to be made with consideration of the patient’s treatment history, time of recurrence, and the sequencing of remaining treatment options [14].
This review aimed to summarize the factors influencing prognosis in breast cancer LRR, review randomized controlled trials (RCTs) assessing the benefits of systemic treatment following LRR resection, and explore systemic treatment strategies for the management of breast cancer LRR.
LRR PROGNOSIS AND PREDICTIVE FACTORS
The prognosis of LRR is poor. Approximately 50% of patients develop additional recurrent disease, and 30%–60% of patients die from metastatic disease within 5 years of recurrence. The National Surgical Adjuvant Breast and Bowel Project performed a multivariate analysis on patients who participated in 5 node-positive trials, treated with breast-conserving therapy and doxorubicin-based adjuvant systemic therapy [9]. In this study, the 5-year disease-free survival (DFS) and overall survival (OS) rates after an ipsilateral breast tumor recurrence (IBTR) were 51.4% and 59.9%, respectively. Failures beyond the breast, defined as other locoregional recurrences (oLRRs), conferred a far worse outcome. Only 18.8% of patients became free of the distant disease and only 24.1% remained alive 5 years after oLRRs. The relative risk (hazard ratio [HR]) of death for those who developed an IBTR was 2.58 (95% confidence interval [CI], 2.11–3.15) compared with those who did not, and 5.85 (95% CI, 4.8–7.13) for those who developed an oLRR compared with those who did not. Table 1 summarizes the DFS and OS rates after recurrence from selected studies [9,11,15-34]. As shown in Table 1, the prognosis for patients with LRR shows a 5-year DFS of 24%–60% and OS of 42%–80%. These percentages are significantly worse than those of patients with typical primary breast cancer. Of note, patients who experience LRR tend to have later-stage primary disease.
There is a good example to compare the prognosis of primary tumors and LRR. Studies have differentiated true recurrences from primary tumors in cases of in-breast recurrence and examined the differences in prognosis. The following factors suggest a new primary tumor: change in the biomarker profile and/or histopathology of the disease, while recurrence is in a different quadrant of the breast compared with the primary tumor and associated with changes in gene-expression profiles. Investigators from MD Anderson Cancer Center evaluated 397 patients with an in-breast recurrence and classified approximately half as having a new primary tumor and half as having a true recurrence (based on tumor location, histologic subtype, and biomarker profile). The new primary tumor cohort had a better 10-year survival and metastatic disease was less common than patients classified as true recurrence, but were more likely to develop contralateral breast carcinoma [35]. A similar study from Yale University compared 70 patients classified as having a new primary tumor with 60 patients classified as having a true recurrence. Again, those with a new primary tumor had a better overall 10-year OS (75% vs. 55%; p = 0.0001) and distant DFS (85% vs. 41%; p = 0.0001) [36].
Prognostic factors for LRR to distant disease or death are shown in Table 2, along with approximate HR from various studies [11,33,37,38]. Regional recurrence, along with a short disease free interval (DFI), unresectable disease, initial node metastatic disease, and estrogen receptor (ER) and progesterone receptor (PR) status, are factors that can predict the prognosis after LRR. Anderson et al. [11] analyzed the adjusted HRs for mortality associated with IBTR and found that oLRRs occurred more often in ER–negative patients than in ER-positive patients (p = 0.002 and p = 0.0001, respectively).
Subtypes are an important prognostic consideration in patients with breast cancer LRR. Montagna et al. [38] in their multivariate analysis found that both ER-negative breast cancer (as mentioned above) and the triple-negative breast cancer (TNBC) subtype are important prognostic factors. In particular, the TNBC subtype was determined to be a high-risk factor for PFS with an HR of 2.87 compared to the luminal type. This highlights the need for additional chemotherapy in patients with ER-negative LRR.
By comprehensively assessing various risk factors, prediction models for additional systemic treatment decision-making have been introduced. At Asan Medical Center, 11,236 patients diagnosed with breast cancer between 1989 and 2008 were analyzed. Among them, 500 patients who showed isolated LRR (ILRR) were investigated to identify the significant prognostic indicators of the risk of subsequent distant metastasis and breast cancer-specific mortality after ILRR. The identified indicators include lymph node (LN) (+) at diagnosis, a DFI < 30 months, and a regional LN (+) at ILRR onset. By scoring these risk factors, patients with LRR can be categorized into low, intermediate, high, and extremely high-risk groups to aid in additional treatment decisions [32].
A similar study was recently published in Japan. The researchers investigated the risk factors for distant metastasis after ILRR diagnosis and developed a model to predict the probability of distant metastasis after ILRR. Seven prognostic factors associated with poor distant metastasis-free survival (DMFS) after ILRR among patients with breast cancer were identified: ILRR receptor status (ER-positive/PR-negative/HER2 [human epidermal growth factor receptor-2]-negative tumor), shorter DFI (DFI shorter than 48 months), recurrence site (chest wall recurrence with or without regional node, and isolated regional node recurrence), non-resection of ILRR, nodal stage in the primary tumor (N2 or N3), computed tomography for the primary tumor, and no endocrine therapy for the ILRR. The study highlighted the importance of PR negativity and demonstrated that the characteristics of the recurrent tumor’s immunohistochemistry are more important than those of the primary tumor in determining the prognosis when breast cancer LRR occurs [33].
CLINICAL TRIALS REGARDING OPTIMAL SYSTEMIC TREATMENT STRATEGY FOR LRR
The increased likelihood of developing metachronous distant metastases after an ILRR mandates consideration of systemic therapy. The long-term prognosis for these patients is affected by the time interval between the index cancer and ILRR, as well as the stage of disease at presentation. There were several early studies conducted in the 1960s and 1980s that aimed to compare the prognosis of LRR disease after resection, by dividing patients into groups receiving either observation or drugs, such as actinomycin-D and alpha-interferon. These studies had a very small target patient number (n =30–50), making it difficult to draw meaningful conclusions. The attempted studies are summarized in Table 3. Many of the subsequent studies also managed to accrue only a small number of patients compared to their initial plans. The number of patients with LRR has been decreasing, making it challenging to plan and conduct randomized controlled studies to investigate different treatment modalities.
Two major trials have addressed the concept of systemic therapy after LRR. First, Swiss Group for Clinical Cancer Research 23/82 studied the use of tamoxifen in 167 postmastectomy ER-positive recurrences [30]. A statistically significantly improved 5-year DFS rate was observed, favoring tamoxifen over placebo (61% vs. 40%, Gehan–Wilcoxon p = 0.008). Second, the chemotherapy for isolated locoregional recurrence of breast cancer (CALOR) trial was an open-label randomized trial for patients with completely excised ILRR [39,40]. To the best of my knowledge, the CALOR study, published 10 years ago, is the only RCT to explain the necessity of chemotherapy for ILRR in breast cancer.
The CALOR trial began in 2001 with an original sample of 977 patients. However, due to a low accrual rate, the sample size and the target number of DFS events were down-adjusted twice. Consequently, by 2010, only 162 patients (58 with ER-negative and 104 with ER-positive recurrences) were randomly assigned to the investigator’s choice of adjuvant multidrug chemotherapy or no chemotherapy. For hormone-sensitive tumors, chemotherapy was followed by endocrine therapy. If the recurrence occurred while a patient was on endocrine therapy, a change in the endocrine therapy was advised. HER2-directed therapy was optional. Radiation was mandatory for those with positive margins and recommended for those who had not received radiation as part of their initial treatment. The primary endpoint was DFS. OS and DFI were secondary endpoints. The initial outcome assessments were performed after a median follow-up of 5 years. The results showed a 12% DFS improvement with chemotherapy versus no chemotherapy (69% vs. 57% (HR, 0.59 [95% CI, 0.35–0.99]); p = 0.046) [39]. Adjuvant chemotherapy was found to be significantly more effective for women with ER-negative disease (5-year DFS HR, 0.32; 95% CI, 0.14 to 0.73; favoring chemotherapy) with a less certain benefit for patients with ER-positive disease (5-year DFS HR, 0.94; 95% CI, 0.47 to 1.89). The final analysis, performed at a median follow-up of 9 years, confirmed the initial findings. In sum, chemotherapy significantly improved 10-year DFS in patients with ER-negative ILRR (70% for the chemotherapy subgroup vs. 34% for the no chemotherapy subgroup; HR, 0.29; 95% CI, 0.13 to 0.67) [40]. The benefit of chemotherapy was not detected in the ER-positive cohort (10-year DFS, 50% vs. 59% in patients treated with or without chemotherapy, respectively; HR, 1.07; 95% CI, 0.57 to 2.00). In the subgroup with ER-negative disease, OS at 10 years was 73% with chemotherapy versus 53% without chemotherapy (HR, 0.48; 95% CI, 0.19 to 1.20). OS for those with ER-positive disease was 76% versus 66%, respectively (HR, 0.70; 95% CI, 0.32 to 1.55). In a multivariable analysis, the interaction between ER expression and chemotherapy effect was statistically significant only if the ER status of the ILRR was considered, highlighting that the receptor status of the ILRR, rather than the primary tumor, should guide systemic recommendations. In general, these data support using adjuvant chemotherapy for patients who have undergone resection for an isolated ER-negative LRR.
For ER-positive recurrences, the benefit of chemotherapy remains unclear, and treatment recommendations should be individualized, taking into account patient preferences. It would not be unreasonable to consider chemotherapy for motivated patients with luminal B-type recurrences, those with clear endocrine resistance, or those whose prior treatment lacked a contemporary drug option. The size of the recurrence is not a significant determinant of subsequent prognosis. In fact, 67% of ILRR were less than 2 cm. For those without chemotherapy, the 5-year DFS was 69% for ER-positive patients and 35% for ER-negative patients.
ALGORITHM FOR MULTIDISCIPLINARY MANAGEMENT AND GUIDELINES FOR BREAST CANCER LRR
When deciding on the treatment for patients with LRR, there are issues, such as whether repeat radiotherapy and sentinel lymph node biopsy are indicated. This review aimed to focus on systemic treatment only. There are many algorithms and guidelines for systemic treatment in patients with breast cancer LRR. Most advise that different approaches to systemic treatment options are needed depending on the resectability. Figure 1 illustrates a treatment decision algorithm for LRR that we have developed based on recurrence site, resectability, and subtype.
Systemic treatment approaches for resectable LRR
First, additional treatment is determined based on the LRR location. For resectable LRR lesions in the breast, chest wall, or axillary LN, surgical removal followed by additional systemic treatment (similar to the adjuvant regimen used for the primary tumor) can be considered based on the subtype. According to the National Comprehensive Cancer Network (NCCN) Panel, after local treatment, patients with a local recurrence may only benefit from a limited duration of systemic chemotherapy or endocrine therapy, similar to that outlined in the adjuvant chemotherapy section. The Health Insurance Review and Assessment Service in Korea (HIRA) also states that in patients with breast cancer LRR, adjuvant therapies may be administered after curative surgery to prevent further recurrences. For these patients, in Korea, reimbursement is possible for drugs indicated for adjuvant settings under HIRA, as well as for drugs used in palliative settings for recurrent cases.
Considering the CALOR study, the survival rate of patients with ER-negative breast cancer may be improved by chemotherapy. There are no clear guidelines on administering additional systemic treatment when the size of the recurrent lesion in LRR exceeds a certain threshold. However, given that the prognosis for LRR breast cancer is significantly worse than that of primary breast cancer, more aggressive treatment beyond the standard adjuvant therapy for primary tumors may be necessary. The choices of chemotherapy agents for patients with ER-negative breast cancer LRR include all drugs used in adjuvant therapy. However, if the recurrence occurs within one year of completing the previous treatment, it is recommended to use a different agent due to the potential for drug resistance.
Patients with ER-positive breast cancer LRR would have likely undergone long-term adjuvant therapy with hormone therapy for more than five years. For these patients, it is crucial to determine whether the recurrence occurred during treatment or afterward. If recurrence occurs during hormone therapy or within one year of completing the treatment, drug resistance to the treatment drug must be considered when decision-making. In such cases, switching to a different hormone therapy, adding agents like CDK 4/6 inhibitors, or considering chemotherapy may be necessary. Table 4 provides treatment examples for ER-positive breast cancer LRR post-resection. The examples are categorized by menopausal status and timing of recurrence according to HIRA reimbursement guidelines. Here, only primary agents available for use are listed, excluding secondary or subsequent agents.
At the 18th St. Gallen International Breast Cancer Conference in 2023, the panelists were surveyed regarding treatment for LRR after breast cancer surgery [41]. For patients with strong ER+ and/or HER2-breast cancer, who develop LRR during adjuvant aromatase inhibitor therapy following adjuvant chemotherapy, there was a discussion about the necessity of additional chemotherapy after definitive local therapy. Approximately 63% of the panelists responded that they would not administer chemotherapy, while 28% indicated they would. Those who did not support the use of chemotherapy were likely influenced by the CALOR trial findings, which specified that for patients with ER-positive lesions, chemotherapy is of no significant benefit. Nevertheless, some patients with ER-positive breast cancer may still require chemotherapy following surgical resection of the LRR lesion. Decisions are best tailored to the individual patient based on the presence of previously discussed clinical prognostic factors, nomograms, or prediction models, and even multigene assays.
At the same meeting, adjuvant systemic therapy recommendations were also discussed for a patient who presented with an ILRR while on adjuvant aromatase inhibitor therapy [41]. The recurrence was fully excised in terms of a definitive local therapy. Most of the panelists advised a second adjuvant endocrine treatment, while 2% suggested otherwise. Considering the potential biological reasons for endocrine resistance, such as ESR1 mutation or PIK3CA mutation [42,43], a two-thirds majority suggested switching to an alternative endocrine approach (65%) by delivering SERMs (tamoxifen, 33%) or SERDs (fulvestrant, 33%), with or without CDK 4/6-inhibitors [44,45] (29% and 36%, respectively). In total, 34% of those surveyed supported adding a CDK 4/6 inhibitor to any of the endocrine treatment options. However, a substantial proportion (24%) indicated switching to tamoxifen alone as their preference, while one-fifth (20%) recommended fulvestrant in combination with a CDK 4/6 inhibitor. Additionally, a minority (16%) suggested switching to an alternative aromatase inhibitor (nonsteroidal to exemestane or vice versa). Only 6% supported using the same aromatase inhibitor plus a CDK 4/6 inhibitor, while 11% abstained from commenting. Table 4, provides treatment therapies that can be reimbursed under the HIRA system in Korea, demonstrating that the options we have are limited compared to the variety of choices presented in global consensus meetings.
A similar type of consensus survey was performed in the United A similar type of consensus survey was performed in the United Kingdom [46]. For example, treatment options were proposed for a 65-year-old female, who underwent breast cancer surgery 7 years ago and received adjuvant doxorubicin and cyclophoaphamide followed by taxol chemotherapy due to high risks associated with Oncotype DX. The panel investigated the treatment decision-making process for a scenario where the patient developed a 1.5 cm skin-flap recurrence, which was resected with clear margins. If the recurrent tumor is a Grade II, ER+, HER2- invasive ductal carcinoma with no LN involvement, 38% of the surveyed physicians indicated that they would not administer chemotherapy, while 50% would consider chemotherapy in some cases. For the same subtype and grade of recurrent lesion, if LN metastasis is found, over 50% of physicians would provide chemotherapy. Furthermore, if it is a TNBC subtype, over 80% would always treat using chemotherapy.
If the recurrence occurs during endocrine treatment at 3 years (and not 7 years later) 67% of the physicians would consider chemotherapy. A short recurrence interval is considered a risk factor for subsequent distant metastasis and survival. Additionally, to assess potential resistance to the previous treatment regimen, it is important to consider if recurrence occurred during the previous treatment or after more than 12 months post-treatment.
Regarding the decision to perform genomic signature testing for patients with ER-positive breast cancer LRR after definitive local therapy to determine the need for chemotherapy, only 9% of the physicians stated they would conduct genomic testing, while 84% indicated that they would not. The main reasons cited for not performing genomic testing included the ability to make chemotherapy decisions based on tumor grading, Ki-67, PR status, and patient age. Of note, our previous experience with genomic testing in the adjuvant setting, showed that it has the potential to predict recurrence and prognosis beyond clinical factors. We anticipate that future studies will provide more conclusive results.
Systemic treatment approach for unresectable LRR
For patients with unresectable disease, systemic therapy should be the initial treatment approach.
Recurrent unresectable LRR disease is challenging to cure and is treated similarly to stage IV distant metastatic disease. The NCCN guidelines categorize both conditions under the same index for recommending therapeutic agents. The medication choice is significantly influenced by the subtype and the degree of response to previous treatments. The NCCN guidelines state that patients whose disease progresses after a year from the end of adjuvant endocrine-based therapy and those who present with de novo Stage IV/metastatic breast cancer are eligible for first-line endocrine therapies. For disease progression on or within 12 months of completing adjuvant endocrine therapy, or for disease progression during first-line endocrine therapy for metastatic disease, second-line endocrine therapy, either as monotherapy or in combination with a targeted agent, is recommended. These recommendations are consistent with the HIRA criteria.
For the ER-positive lesions, an aromatase inhibitor plus a CDK 4/6 inhibitor is recommended as first-line therapy [47-50]. There is controversy on the choice of CDK 4/6 inhibitor as there are no head-to-head comparisons between the agents, and current phase 3 randomized studies examined differing study populations. Additionally, for disease progression on adjuvant endocrine therapy or early relapse within 12 months of adjuvant endocrine therapy completion, fulvestrant plus a CDK 4/6 inhibitor is recommended as first-line treatment [51-56].
For the HER2 type, the preferred regimen is pertuzumab plus trastuzumab plus docetaxel/paclitaxel [57]. For TNBC, if PD-L1 combined positive score (CPS) ≥ 10 regardless of germline BRCA mutation status, pembrolizumab plus chemotherapy (albumin-bound paclitaxel, paclitaxel, or gemcitabine and carboplatin) is recommended as first-line therapy [58]. If germline BRCA1/2 mutation is present and PD-L1 CPS < 10, PARPi (olaparib, talazoparib) [59,60] or platinum agents (cisplatin or carboplatin) [61] are recommended. If PD-L1 CPS < 10 and no germline BRCA1/2 mutation, chemotherapy agents, such as anthracycline, paclitaxel, capecitabine, gemcitabine, vinorelbine, and eribulin, are recommended.
Furthermore, biomarker testing is necessary to determine whether to try FDA-approved drugs for unresectable/stage IV disease. For the HR-positive/HER2-negative type, PIK3CA activating mutation using NGS or PCR (blood or tumor tissue if blood negative) can be treated with alpelisib plus fulvestrant. For PIK3CA or AKT1 activating mutations or PTEN alterations, capivasertib plus fulvestrant is recommended. For ESR1 mutation, elacestrant is used. In all breast cancer subtypes, olaparib or talazoparib is used If germline BRCA1 or BRCA2 mutation is present. Larotrectinib [62] or entrectinib are considered [63] if neurotrophic tropomyosin receptor kinase gene fusion is present, while pembrolizumab or dostarlimab-gxly is used if microsatellite instability-high/mismatch repair deficient [64] is found.
Additionally, for unresectable LRR, neoadjuvant regimens aimed at subsequent resection may be considered. In this case, the response to previously used agents and the time since last treatment (e.g., whether more than one year has passed) are comprehensively considered. This typically includes patients with supraclavicular and/or internal mammary recurrences and chest wall recurrences that require bony chest wall resection for complete extirpation. Using systemic therapy first can convert some patients from non-resectable to resectable disease, thus leaving a smaller tumor burden for patients who are candidates for postoperative radiation. Furthermore, retrospective analyses demonstrate superior outcomes for supraclavicular nodal recurrences treated with chemotherapy plus locoregional therapy [65,66]. Buchholz et al. [14] suggested that if the patient is a candidate for surgery, chemotherapy, and radiation, our preference is to mark the sites of resectable disease and proceed initially with systemic therapy. Current practice favors neoadjuvant systemic therapy followed by consolidation with radiation at the point of maximal response. These approaches have limited the role of surgical intervention, but resection should be considered on a case-by-case basis.
CONCLUSION
The management of breast cancer LRR poses significant challenges due to its association with biologically resistant disease and a high likelihood of concurrent occult systemic disease. The CALOR trial has highlighted the benefits of adjuvant chemotherapy in improving prognosis for patients with ER-negative LRR. However, the benefit of chemotherapy for ER-positive LRR remains unclear and should be individualized based on patient-specific factors.
For resectable LRR, treatment decisions should consider the location and subtype of the recurrent lesion/s, and any previous treatment. For patients with ER-negative breast cancer LRR, aggressive chemotherapy may be of benefit. In contrast, patients with ER-positive LRR lesions may require modifications to their endocrine therapy or the addition of CDK 4/6 inhibitors to enhance outcomes. For unresectable LRR, initial systemic therapy to reduce tumor size and enhance resectability, followed by potential surgical intervention, is recommended. This approach aims to reduce tumor burden and improve the efficacy of subsequent treatment.
Future studies should focus on developing more precise predictive models to identify patients at high risk of distant metastases and tailor systemic treatment accordingly. Additionally, exploring genomic signatures in LRR could provide further insights into optimizing treatment strategies. There is no “one-size-fits-all” approach to the management of breast cancer LRR. Furthermore, the challenge of conducting clinical trials in this setting remains.
