In this review, we focus primarily on describing locoregional and systemic management strategies for isolated locoregional recurrences manifesting as isolated first-failure events following mastectomy or breast-conserving therapy.
Advances in the treatment of breast cancer have decreased the rate of isolated locoregional recurrences (ILRRs) over time. Surgery, radiation therapy, and systemic therapies are used to manage these failure events and their associated poor prognosis. Operable ipsilateral breast tumor recurrences (IBTRs) are treated by either salvage mastectomy or, in select cases, repeat lumpectomy. Axillary nodal recurrences and postmastectomy chest wall relapses are commonly amenable to surgical resection, too. Repeat sentinel node mapping may be undertaken after IBTRs and chest wall recurrences. Aberrant lymphatic drainage, especially after previous mastectomy, is frequently observed. Adjuvant radiation is recommended for most ILRR cases; the dose and volume must be adjusted for prior to receipt of therapy. Implementation of adjuvant systemic therapies after ILRR should be based on the expression of molecular markers in the recurrent tumor. Administration of chemotherapy for estrogen receptor–negative ILRR is indicated, since it significantly decreases the rate of distant metastases.
Much of the available data on the long-term risks of isolated locoregional recurrences (ILRRs) in breast cancer are derived from studies carried out in the 1980s and 1990s, when first-line primary interventions consisted of modified radical mastectomy or lumpectomy and axillary node dissection followed by whole-breast radiation therapy.[1-6] Significant advances have occurred since then, changing the landscape in which an ILRR occurs. Implementation of sentinel lymph node biopsy (SLNB), routine use of systemic therapies, and the adoption of partial breast irradiation (PBI) after lumpectomy are foremost. Additionally, downstaging with neoadjuvant chemohormonal regimens, in combination with increasing use of postmastectomy radiation therapy (PMRT) and regional nodal irradiation (RNI), have enhanced the effectiveness of locoregional treatments, while limiting the use of more extensive surgery.
In this review, we focus primarily on describing locoregional and systemic management strategies for ILRRs manifesting as isolated first-failure events following mastectomy or breast-conserving therapy. Over the last 3 decades, findings from only two prospective randomized trials-the Swiss Group for Clinical Cancer Research (SAKK) 23/82 trial and the Chemotherapy as Adjuvant for Locally Recurrent breast cancer (CALOR) trial-have provided information on the benefits of adjuvant systemic therapies after ILRR.[7,8] The National Comprehensive Cancer Network (NCCN) classifies ILRRs into three groups based on prior therapy: 1) recurrences that occur after breast-conserving surgery plus radiotherapy, 2) those that occur after mastectomy and level I/II axillary lymph node dissection (ALND) with PMRT, or 3) those that occur after mastectomy and level I/II ALND without PMRT. Given current clinical practices regarding the extent of nodal surgery and RNI, it is perhaps more practical to discuss the management of the breast separate from the nodes.
An ILRR represents the reappearance of breast cancer in the region of the ipsilateral breast/chest wall or the draining regional lymph node basins. The majority are isolated first-failure events, with the remainder accompanying or following distant metastases. Most ILRRs are locally limited and operable. Historically, recurrences after mastectomy were discovered on clinical examination as skin changes, palpable masses, or lymphadenopathy. Many recurrences can be asymptomatic, appearing as a subtle change in skin color. Others may be more symptomatic, with a fullness or mass in the operative field, increasing discomfort, and limited or painful range of motion of the upper extremity. However, diffuse skin involvement or invasion into surrounding structures, such as the periosteum, intercostal muscles, or brachial plexus, at the time of recurrence can render patients inoperable, irrespective of the primary cancer type.
Local relapses after breast-conserving surgery can occur within the breast tissue itself or the chest wall, nodal basins, or skin. Most ipsilateral breast tumor recurrences (IBTRs) are detected on physical exam or by routine mammographic or MRI surveillance. Surgery- and radiation-induced changes in the breast may decrease the reliability of the physical exam. Over 90% of IBTRs after breast-conserving surgery for invasive breast cancer are invasive again, irrespective of radiation therapy. The majority are localized within 3 cm to 5 cm of the tumor bed.[10-13] In contrast, only 50% of IBTRs after ductal carcinoma in situ (DCIS) are invasive. The location of the IBTR; time to recurrence; and prior treatment, such as PBI, are some of the factors that define the biological significance of the recurrence. IBTRs occurring in another quadrant or exhibiting different histology may represent a new primary tumor rather than a true recurrence or growth of persistent disease, especially if they appear after a long interval.[13,15-19] Diffuse skin involvement can be the only manifestation of relapse and is analogous to the same presentation in mastectomy-treated patients (Figure 1).
Postmastectomy recurrences involve the chest wall, skin, or regional lymph nodes. Invasive recurrences can be localized or diffuse and involve the skin, subcutaneous tissues, chest musculature, or extranodal soft axillary tissue. Invasive recurrences rarely occur after mastectomy for DCIS. Invasion into the ribs or sternum is considered largely inoperable and has a poor prognosis, similar to distant metastases. Prosthetic and autologous tissue breast reconstruction can theoretically interfere with the detection of small recurrences. However, mammographic screening of the reconstructed breast after mastectomy is not superior to physical exam. Although annual PET or CT scans may detect nodal recurrences before they are palpable, there are no data to support routine implementation after primary treatment.
Nodal recurrences most commonly manifest in the ipsilateral axilla on physical exam or radiologic tests. In current practice, most patients will have had only sentinel node resection for their primary cancer surgery, with the exception of clinically node-positive patients, who may have also received regional and axillary irradiation. The biological significance of nodal recurrences may not all be the same, and the approaches to these failures must be tailored to prior interventions as we detail below.
Relapses in the interpectoral, internal mammary node, and infraclavicular (level III axillary node) basins are uncommon. Inclusion of supraclavicular nodal failures in the ILRR classification has been controversial, but is currently classified as N3c disease.[22,27,28] The contralateral axilla may be considered an area for ILRR, a consequence of postoperative aberrant lymphatic drainage following a SLNB or complete lymphadenectomy.
Amelia B. Zelnak, MD, MSc
The management of locoregional recurrence (LRR) in breast cancer remains a challenge, as it requires input from multiple disciplines: surgery, radiation oncology, and medical oncology. In breast oncology, we have grown accustomed to making decisions regarding adjuvant therapy based on clinical trials that enroll and collect data from thousands of patients. However, clinical trials studying LRR in breast cancer have been difficult to perform due to the heterogeneity of the patient population.
In this issue, Wapnir and Khan review the current literature that can be used to guide clinical decisions, including results from the only two prospective randomized trials on LRR conducted in the past 3 decades. They found that the literature supports excision of recurrent disease, when possible. Patients should receive radiation therapy, if not already performed, and be considered for re-irradiation based on the individual clinical scenario.
As the authors noted, the Swiss Group for Clinical Cancer Research (SAKK) trial evaluated the benefit of tamoxifen after excision and radiation among 167 patients with postmastectomy LRR. Adding to the evidence is the Chemotherapy as Adjuvant for Locally Recurrent breast cancer (CALOR) trial, which evaluated the benefit of chemotherapy amongst 162 patients with isolated LRR. Patients who experience LRR have an increased chance of developing distant metastatic disease, and both of these trials showed that additional systemic therapy can reduce this risk. Regarding recurrent disease that is hormone receptor (HR)-negative,
results from the CALOR trial show that systemic chemotherapy, preferably doublet therapy, provides a clear benefit. Although a statistically significant improvement in disease-free survival after systemic chemotherapy was not seen amongst HR-positive patients, we cannot draw a firm conclusion from such a small patient sample.
Decisions regarding the role of systemic chemotherapy should take into consideration many factors, including HR status and other characteristics of the tumor, timing of the recurrence after initial treatment, prior response to systemic therapy, and the patient’s tolerability of therapy. There is no “one size fits all” approach to the management of LRRs in breast cancer, and the challenge of conducting clinical trials in this setting still remains. Thankfully, improvements in therapy have reduced the rate of LRRs so that fewer patients have to face this challenge.
FINANCIAL DISCLOSURE: Dr. Zelnak has no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.
Dr. Zelnak is a Medical Oncologist at Northside Hospital Cancer Institute in Atlanta, Georgia.
Over the last decade, tumor biology has emerged as one of the most powerful determinants of locoregional recurrence. The incidence of IBTRs and chest wall or regional node recurrences varies based on the stage of disease at presentation and adjuvant treatments.[5,6] Young age, nodal positivity, larger tumors, and hormone receptor–negative tumors have been associated with a higher risk of recurrence.[30-34] However, this rate has been dropping. Tumor biology impacts the interval to ILRR; the median time to ILRR is longer for estrogen receptor (ER)-positive (6.8 years) vs ER-negative (3.6 years) cancers. Triple-negative breast cancers have a higher early local failure rate compared with ER-positive cancers, with a 5-year cumulative incidence of 4.2% and 5.4% for lumpectomy and mastectomy, respectively.[36,37] Notably, ILRR events among patients with ER-positive cancers continue over a 20-year period.
The molecular profiling of tumors has shed further light on the biological behavior of breast cancer, including the risk of locoregional recurrence.[39,40] A high Oncotype DX Recurrence Score, indicative of a patient’s risk for distant metastases in ER-positive carcinomas, is also associated with a higher risk of locoregional recurrence.[41-43]
Many studies have described the relationship between lumpectomy margins and local recurrence.[44-46] This was verified in a systematic review of 33 trials encompassing 28,162 patients. Those with close/positive margins had an odds ratio for IBTR of 1.96 compared with 1.0 for those with negative margins (defined as no tumor on ink). Wider negative margins were not associated with superior local control. In this same analysis, a radiation boost to the lumpectomy cavity reduced IBTR rates, but it did not completely overcome the effect of microscopic positive margins.
Omission of breast irradiation is associated with higher rates of locoregional recurrence and earlier manifestation of recurrence. In a pooled analysis of 15 trials, the annual risk of IBTR ranged from 0.4% to 2.1% with radiation therapy compared with 1.4% to 5.7% without radiation therapy. The Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) conducted a meta-analysis of 17 randomized trials involving 10,801 women. A 10-year reduction in the risk of IBTR, from 35% to 19.3%, was seen with breast radiation therapy.
The risk of ILRR is related to the extent of initial nodal involvement. Thus, patients with more positive nodes experience higher rates of locoregional failure. The rate of nodal recurrence for patients who have negative sentinel nodes or low-burden nodal involvement is less than 2%.
Adjuvant systemic therapies have been instrumental in enhancing local control of disease, which is exemplified by the decreasing trends in 10-year cumulative risks observed in the National Surgical Adjuvant Breast and Bowel Project (NSABP) trials.[5,6,42,52,53] Targeted therapies-such as the anti–human epidermal growth factor receptor 2 (HER2) agent trastuzumab-have greatly contributed to reducing locoregional recurrences in both lumpectomy- and mastectomy-treated populations. Use of neoadjuvant chemotherapy is linked to a complete pathologic response in triple-negative and HER2-positive breast cancers, but not necessarily in endocrine-responsive cancers.
ILRRs are associated with an unequivocal high risk of developing distant metastases and, consequently, poor survival.[3-6,56] For example, 50% of mastectomy-treated patients in Danish Breast Cancer Group trials who experienced an ILRR then developed distant metastases within 2 years. In 1990, Halverson et al treated postmastectomy ILRRs with radiation therapy and reported 5-year and 10-year survival rates of 43% and 26%, respectively. IBTRs, too, have been largely viewed as indicators of future risk for distant metastases.[11,58] The 5-year distant disease–free survival (DDFS) after an IBTR was 67% in node-negative patients vs 51.4% for node-positive patients in pooled analyses of NSABP trials.[5,6] Strikingly worse was the 5-year DDFS for non-IBTR ILRR-28% in node-negative patients and 19% in node-positive patients. Among nodal recurrences, the 5-year DDFS rates were 31.5% for axillary recurrences and 12.1% for supraclavicular events. Globally, early recurrences, defined as within 24 months, have a far worse prognosis than those occurring after more than 48 months.[5,6]
Second ILRRs are common after treatment of an ILRR, only exceeded by distant failures.[59,60] In the CALOR trial, these second relapses occurred at a median interval of 1.6 years, and prognosis after this event was poor compared with those experiencing distant metastases.
The type of biopsy performed to diagnose a recurrence depends on the location of the recurrence. Internal mammary or supraclavicular recurrences are safer to sample via fine needle aspiration, whereas other sites are amenable to core needle biopsy sampling. Metastatic disease must be ruled out concurrently with a diagnosis of ILRR via CT or PET/CT scans. Obtaining an updated family history and considering genetic testing or re-testing, given the more informative multigene panels available today, are equally important. Hormone receptor and HER2 testing should be repeated for any recurrence, so that systemic therapies are guided by the molecular characteristics of the recurrence rather than the primary occurrence.
Salvage strategies for any ILRR should account for the index cancer presentation, pattern, and location of the recurrence, as well as prior therapies. Clinical management of an ILRR has been focused on surgical removal of recurrent disease whenever possible, selective use of radiotherapy, and systemic treatments. Outside of systemic therapy, no prospective randomized clinical trial data exist to ascertain the benefit of local treatment strategies. We address this discussion in four broad categories of recurrences: post–breast-conserving therapy, postmastectomy, nodal recurrences, and inoperable recurrences.
Mastectomy as a strategy. Salvage mastectomy remains the standard of care for an IBTR after initial lumpectomy and whole-breast adjuvant radiotherapy (Figure 2 and Figure 3). Concerns about skin viability and the time interval following radiation treatments must be considered when selecting a postmastectomy breast reconstruction procedure. Nipple-sparing salvage mastectomies have recently been reported with satisfactory technical and oncologic results.[61-64]
The reported locoregional control rates after salvage mastectomy are highly variable; they range from single digits to as high as 30% to 50%.[65-67] Therefore, PMRT should be considered, even though there are no high-level data on its use in the salvage setting after initial breast-conserving therapy with whole-breast radiation therapy. In cases with positive mastectomy margins, PMRT is likely beneficial. Because the majority of irradiated tissue is removed during a salvage mastectomy, and the remnant chest wall and skin have a relatively high tolerance for radiotherapy, re-irradiation is feasible and can also be considered for patients whose index cancer was associated with biologically more aggressive cancers (eg, multiple positive nodes). The IBTR may be accompanied by concurrent nodal relapse, necessitating the inclusion of nodal basins, which is further complicated if the initial adjuvant radiotherapy for breast-conserving therapy included RNI. In these patients, the brachial plexus constrains the re-irradiation dose, posing significant morbidity risks. Still, with today’s highly conformal radiotherapy techniques, brachial plexus dose carve-outs can be attempted for women with particularly high-risk presentations that warrant re-irradiation to the regional nodal basins. This should be considered only after a multidisciplinary consensus, with documentation of patient consent after a thorough discussion of the inherent risks.
Repeat breast-conserving therapy as a strategy. Kurtz and colleagues first described the use of repeat lumpectomy for IBTR in 1989. In a nonrandomized comparison, without the routine benefit of systemic therapies, the locoregional failure rate was 36% compared with 12% after salvage mastectomy. Others have reported a wider range of second ILRR rates, from 7% to 38% at 51 to 120 months of median follow-up.[68-73] In contrast, Gentilini et al found that recurrent tumors measuring < 2 cm that recurred 48 months or later had low subsequent second ILRR rates with repeat lumpectomy alone.
Re-irradiation of the breast has been reported by several groups. Most of these series used PBI as a method to limit the volume being radiated.[75,76] Of note, in the CALOR trial, 16 of 89 IBTR cases (18%) received repeat lumpectomy, and only 2 reported breast re-irradiation. During a median follow-up of 5 years, a second ILRR occurred in 2 repeat lumpectomies (12.5%) compared with 6 of 73 salvage mastectomies (8.2%).
Three noteworthy studies involving breast re-irradiation provide insight into this topic. One study by Hannoun-Levi et al is significant for its large size (N = 69) and long follow-up (median of 50 months); the second is a prospective series by Chadha et al.[77,78] Both were done with low-dose-rate multicatheter implants at centers with considerable brachytherapy experience, and both reported excellent outcomes in terms of local control and toxicity. A third study by Arthur et al-considered the current highest level of evidence for repeat breast-conserving therapy-is the Radiation Therapy Oncology Group (RTOG) 1014 trial, which utilized external-beam conformal PBI. Treatment was completed in 58 of the 65 accrued patients, and systemic therapy was administered in 51.7%. There were two local recurrences, for a 3-year estimate of 3.7% and a breast preservation rate of 94.8%. At a median follow-up of 3.64 years, there were 4 patients (6.9%) with late grade 3 treatment-related adverse events. A larger follow-up trial is now being developed by NRG Oncology to build on the experience of RTOG 1014.
The local salvage strategy for ILRR after mastectomy is guided by the extent of recurrence and prior radiotherapy. In general, the aim is to attempt removal of all gross disease, understanding that microscopically negative margins are not applicable posteriorly on the chest wall or for resection of nodal recurrences. Postoperative radiotherapy should be administered to all previously unirradiated locoregional sites, with consideration of re-irradiation to irradiated sites on a case-by-case basis, as previously discussed.
Operable ILRR of the chest wall. Simple primary closure or advancement of dermal subcutaneous tissues to cover chest wall defects after wide excision are preferable. Skin grafts are sometimes unavoidable if the patient is not a good candidate for a rotational flap or autologous tissue transfer. Autologous tissue offers better coverage and aesthetically superior reconstruction results. Either pedicled or free tissue flaps are commonly used. Administration of radiation therapy after reconstruction can aggravate skin changes, contracture, and fibrosis of soft tissue flaps. In general, reconstructions in a previously irradiated field are associated with a higher complication rate.
Axillary recurrences most commonly involve remaining nodes, but can also appear within the fat or connective tissue of the axilla. Ascertainment of prior nodal involvement and the extent of axillary node surgery for the index cancer is key. If a level I and II ALND was performed during the initial cancer operation, then surgery is aimed at resection of the recurrent tumor only. Conversely, if SLNB or limited lymphadenectomy (defined as fewer than 6 to 8 nodes) was performed, then a completion ALND is indicated. Exploration of the interpectoral and level III nodes should be included. Nodal recurrences fixed to the chest wall, axillary vein, or brachial plexus are not considered operable. A minority of supraclavicular recurrences can be treated surgically, but systemic therapy and radiation therapy are the preferred approach.
Axillary reoperations, even after a prior SLNB, may increase the likelihood of arm and breast lymphedema. Reverse mapping of arm-draining lymphatics has been described in the context of routine nodal staging as a means of identifying and sparing lymphatics and nodes draining the arm.[82,83] This approach may be considered as an adjunct to re-operation for limited nodal recurrences.
Nodal restaging. The merit of repeat sentinel node mapping after postmastectomy recurrences or IBTRs is debated.[29,84,85] The controversy rests on whether this procedure unmasks unsuspected disease, aids in maintaining locoregional control if positive nodes are discovered, or influences the choice of systemic therapy. Moreover, the proponents of repeat SLNB argue that decisions regarding the use of regional irradiation may be directed by these findings. Maaskant-Braat et al conducted a meta-analysis of published studies reporting repeat lymphatic mapping and SLNB among 692 patients with a locoregional recurrence. Sentinel nodes were successfully identified in 65.5% and 68.9% of patients who underwent lumpectomy and mastectomy, respectively. Aberrant drainage patterns, namely to the contralateral axilla, have been found in 17.4% of cases with a prior SLNB compared with 69.2% after ALND. Overall, the success rate of repeat SLNB after a previous SLNB for a primary cancer was 81% compared with 52.2% (P < .0001) if performed after a prior ALND. Contralateral axillary sentinel nodes can be resected when repeat mapping drains to that basin. Although controversial, if positive, completion ALND and/or RNI could be considered. However, long-term outcome data are unavailable with respect to local control and subsequent distant metastases.
Systemic therapy is indicated for inoperable ILRR at presentation. Diffuse erythema; papular, rash-like skin changes; and thickened, edematous-appearing skin are akin to an inflammatory presentation of cancer. Large, bulky recurrences of the chest wall may appear amenable to surgical resection if not fixed, but should preferably be downstaged with systemic therapy first. Extensive chest wall resections and complex reconstructions are possible, but have fallen out of favor over time.[86,87] Recurrences that invade musculoskeletal or neurovascular structures are challenging. Typically, the prognosis of these patients is poor; thus, surgery should be undertaken as a palliative measure and with consideration of the presence of distant disease.
Supraclavicular or internal mammary lymph node recurrences can be difficult to resect. Hence, the preferred treatment approach has shifted to the use of adjuvant treatments. Pedersen et al reported outcomes for 305 patients with supraclavicular recurrences, including 38% with synchronous sites of locoregional recurrence treated between 1977 and 2003. Combination locoregional and systemic therapy and locoregional therapy alone resulted in remission rates of 67% and 64%, compared with 40% for systemic therapy alone. However, the 5-year rates of progression-free survival and overall survival were poor: 15% and 24%, respectively. In a multivariate analysis, the type of treatment and the histologic grade of differentiation were the only independent prognostic factors. 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 can be considered on a case-by-case basis.
For patients who did not receive PMRT during initial management, the general consensus is that comprehensive radiation should be administered to the chest wall and draining lymph node basins in the axilla and supraclavicular and infraclavicular regions, and to the internal mammary nodes after an ILRR. Patients who received chest wall radiation therapy only for a postmastectomy chest wall recurrence had inferior outcomes compared with patients treated comprehensively to the chest wall and regional lymphatics. Long-term local control rates, in the range of 40% to 80%, attest to the efficacy of radiation therapy in the salvage setting. Willner et al reported a 5-year overall survival rate of 42% among 145 patients with an ILRR after a modified radical mastectomy. The 5-year overall survival rate for those with an isolated axillary recurrence was 50%.
On multivariate analysis, the site of recurrence and number of recurrent chest wall nodules had the strongest influence on survival. Additional variables influencing survival included time to recurrence, age at recurrence, sustaining local control at the sites of recurrence and of the primary tumor, and the presence of tumor necrosis in the primary tumor. As previously discussed, re-irradiation of patients who received PMRT may be warranted, and it is feasible in certain situations with the appropriate technology and expertise.
The high 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. Two major trials have addressed the concept of systemic therapy after a locoregional recurrence. First, SAKK studied the use of tamoxifen in 167 postmastectomy ER-positive recurrences. A statistically significantly improved 5-year disease-free survival (DFS) rate was observed favoring tamoxifen over placebo (61% vs 40%). Second, the CALOR trial recruited 162 patients between 2003 and 2010 with ILRRs and randomly assigned patients to the physician’s choice of chemotherapy. Endocrine therapy was required for ER-positive recurrences. Locoregional radiation tailored to prior radiation history was recommended, but was mandated for cases with microscopically positive margins. Although the study was small and did not meet its original accrual goals, the findings were robust for the ER-negative cohort. The most common first-failure event was distant metastases. Chemotherapy significantly improved the 10-year DFS rate, from 34% for the no-chemotherapy subgroups to 70% for the chemotherapy subgroups; the hazard ratio (HR) was 0.29 (95% CI, 0.13–0.67). No benefit of chemotherapy could be ascertained in the ER-positive cohort (10-year DFS rate, 50% vs 59%, respectively; HR, 1.07; 95% CI, 0.57–2.00). In multivariable analyses, the hormone receptor status of the ILRR was the best predictor of a chemotherapy benefit, underscoring that the receptor status of the recurrence should always be evaluated and utilized as a guide in the selection of systemic therapy.
Locoregional control of breast cancer has improved in both mastectomy- and lumpectomy-treated populations, resulting in fewer locoregional recurrences. Management should be largely individualized and tailored to the extent of disease, the molecular profile of the recurrence, and prior adjuvant treatments. Moreover, for most clinical scenarios of ILRR, there may be multiple reasonable salvage strategies that multidisciplinary teams should carefully discuss and present to the patient. Finally, surgical excision and locoregional radiation should be considered in nearly all subgroups of patients, along with recommendations for systemic therapy.
Financial Disclosure: Dr. Wapnir served on a one-time Advisory Board for Amgen, Cardinal Health, Genomic Health, and Tolmar. Dr. Khan has no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.
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