Surgery and radiation for locoregional recurrences of breast cancer

INTRODUCTION — After either mastectomy or breast-conserving therapy (BCT), defined as breast-conserving surgery (BCS; ie, lumpectomy or partial mastectomy) followed by whole-breast radiation therapy (WBRT), breast cancer can recur locally, regionally, and/or at distant metastatic sites. A local recurrence is defined as reappearance of cancer in the ipsilateral preserved breast, if BCT was initially undertaken, or in the chest wall, if mastectomy was performed. As many patients have reconstruction following mastectomy, a chest wall recurrence may appear above or below implants or within autologous tissue. In contrast, a regional recurrence denotes tumor involving the ipsilateral regional lymph nodes, usually the ipsilateral axillary or supraclavicular, and less commonly the infraclavicular and/or internal mammary. The term locoregional recurrence is used to indicate a recurrence in either the ipsilateral breast, chest wall, and/or regional nodal basin.

The primary management of breast cancer has changed considerably over the past decade, and this may alter the incidence, presentation, and management of locoregional recurrences. With advances in systemic adjuvant therapy that have led to better survival rates [1], recurrences are less frequent and are sometimes delayed for several years. Furthermore, the use of sentinel lymph node (SLN) biopsy rather than axillary lymph node dissection (ALND) as a method of staging the axilla may not only impact the incidence of regional recurrence but has also altered the approach to the patient with an isolated locoregional recurrence.

Aggressive multimodality treatment has the potential to provide long-term disease control for many patients who develop an isolated locoregional recurrence. Multidisciplinary evaluation and management of these cases appears to improve patient outcome and overall satisfaction [2].

The management of a locoregional recurrence after mastectomy or BCT for operable breast cancer will be reviewed here. The clinical manifestations and diagnosis of recurrent breast cancer are discussed in another topic. (See "Clinical manifestations and evaluation of locoregional recurrences of breast cancer".)

Systemic therapy for locoregionally recurrent breast cancer is discussed in another topic. (See "Systemic therapy for locoregionally recurrent breast cancer".)

Recommendations for post-treatment surveillance are discussed in detail elsewhere. (See "Overview of long-term complications of therapy in breast cancer survivors and patterns of relapse" and "Approach to the patient following treatment for breast cancer".)

SEQUENCING LOCAL AND SYSTEMIC THERAPIES — There are no prospective clinical trial data to guide the sequencing of treatments for patients with recurrent disease.

●For patients in whom an upfront resection is feasible, with acceptable risks of morbidity and anticipated cosmetic outcome, we proceed with initial surgery and use pathologic staging from the resection specimen to guide decisions regarding adjuvant systemic therapy.

●However, for patients whose resectability would be facilitated by downstaging, it is preferable to administer systemic therapy first, not only to facilitate successful locoregional treatment but also to be certain that early evidence of distant metastases does not emerge. In such patients, radiation alone generally cannot control the gross disease. As such, presentation at a multidisciplinary tumor board is recommended for many patients with locoregional recurrence. (See "Systemic therapy for locoregionally recurrent breast cancer", section on 'Timing of treatment'.)

●Radiation, when indicated, is performed after surgery when surgery is feasible and may occur after adjuvant chemotherapy. Decisions on whom should receive radiation are discussed in the sections below. (See 'Management of chest wall recurrence following mastectomy' below and 'Management of in-breast recurrence following BCT' below and 'Local management of lymph nodes' below.)

MANAGEMENT OF CHEST WALL RECURRENCE FOLLOWING MASTECTOMY — Combined-modality treatment has the potential to provide long-term disease control for some patients with an isolated chest wall recurrence. The approach to local therapies to the breast or chest wall for those who have evidence of distant disease is discussed elsewhere. (See "The role of local therapies in metastatic breast cancer".)

Surgical resection — Whenever possible, wide excision for solitary or multiple nodules that are amenable to resection is recommended. In patients who have had prior breast reconstruction, this may require removal of implants or takedown of autologous reconstruction. Even with complete resection, repeat chest wall recurrences are common (eg, 20 percent [3]), particularly in the absence of adjuvant chest wall radiation. Indications for radiation following resection of chest wall recurrences are discussed below. (See 'Radiation' below.)

In cases where resection may be facilitated by downstaging the locally recurrent disease, initial treatment with systemic therapy is preferable. Unfortunately, there may be cases where the patient is not a candidate for systemic therapy or the tumor fails to decrease in size. In these cases, more extensive surgery may be indicated. Often, skin grafts or rotational flaps may be necessary after complete excision [4]. In rare cases, chest wall resection may be necessary to obtain negative margins [5].

Adjuvant treatment — The approach to adjuvant radiation therapy (RT) depends on whether initial postmastectomy RT was administered (after the initial diagnosis of breast cancer).

Systemic therapy — Adjuvant systemic treatment is discussed elsewhere. (See "Systemic therapy for locoregionally recurrent breast cancer".)

Radiation

For those with no prior RT — For women who did not undergo prior postmastectomy RT, external beam RT is a standard treatment for an isolated postmastectomy chest wall recurrence. Outcomes from several retrospective series in which the majority of patients underwent excision followed by RT are available [6-16]. We also extrapolate from favorable local control outcomes in the setting of newly diagnosed breast cancer, in which postmastectomy radiation for high-risk disease has shown both overall and disease-free survival benefits.

Optimal RT management generally involves treatment to the entire chest wall and draining lymph node areas, even if the recurrence is localized to a small area of the chest wall. Limited treatment of the chest wall increases the risk for future rerecurrences in the chest wall as well as supraclavicular and axillary regions [9,13,17,18]. The RT techniques usually employed are similar to those used for newly diagnosed breast cancer. (See "Radiation therapy techniques for newly diagnosed, non-metastatic breast cancer", section on 'Whole-breast RT'.)

In general, long-term local control is achieved in 42 to 86 percent of patients, and the 5 and 10 year overall survival rates range from 35 to 82 and 26 to 62 percent, respectively. Unfortunately, only about one-third of treated patients remain free from distant metastases at five years.

The approach to nodal irradiation is discussed below. (See 'Adjuvant nodal irradiation' below.)

Select patients with previous RT — For patients who recur in the chest wall after a course of initial postmastectomy chest wall RT, full-dose reirradiation of the chest wall is generally not considered, because of concerns for long-term toxicity. Decisions regarding limited reirradiation are dependent on the features of each individual case. Our approach is as follows:

●Patients at low risk for additional local recurrence – Surgery alone may be an option in some patients in whom complete excision is expected. Acceptable results have been reported with more extensive surgery (very wide local excision of skin and subcutaneous tissue with partial or full-thickness chest wall resection) without RT in highly selected patients [19-21]. The likelihood of local control after surgery alone is highest when the recurrence pattern is a single nodule rather than multiple nodules, when surgical margins are negative, and for patients whose relapse-free interval is longer than two years [22-26]. Additionally, location of recurrence is a consideration; for example, patients with chest wall recurrence are more likely to undergo limited reirradiation compared with those with recurrences in the supraclavicular area, due to concerns for treatment-related brachial plexopathy in the latter group.

●Patients at high risk for additional local recurrence – For patients who remain at high risk of local recurrence (eg, those who have an incomplete excision, with or without neoadjuvant systemic therapy), retreatment of at least limited volumes with decreased total radiation doses are often offered, in order to maximize the opportunity for local control; whether survival is impacted is unclear. In general, if reirradiation is undertaken, we try to limit the dose to critical structures, including the brachial plexus, sometimes using a more superficial type of beam (eg, electrons) or twice-a-day irradiation (hyperfractionated RT) to reduce the significant risk of late side effects. The risk/benefit ratio in these situations must be individualized, taking into account the risk of additional recurrence, location of recurrence (and risk of retreatment), systemic options available, and time from the initial treatment.

The following represents the range of findings:

●One multi-institutional retrospective review of 81 patients who underwent reirradiation of the breast or chest wall (median reirradiation dose 48 Gy) for locally recurrent breast cancer reported an overall complete response rate of 57 percent at a median follow-up of 12 months (range 1 to 44) from the second radiation course [27]. At reirradiation, 80 percent received standard 1.8 to 2.0 Gy daily treatments, 20 percent received twice-daily RT, 54 percent were treated with concurrent hyperthermia, and 54 percent received concurrent chemotherapy. The one-year local disease-free survival rate was significantly higher for patients without gross disease at the time of reirradiation (100 versus 53 percent). Reirradiation was well tolerated as only four patients developed late grade 3 or 4 toxicity. Of 25 patients who had follow-up exceeding 20 months, no late grade 3 or 4 toxicities were noted.

●Local control rates of approximately 70 percent at one year have been noted in other small series of patients with a previously irradiated chest wall who were treated with limited irradiation fields to only the site of recurrent disease [18,27,28]. In general, treatment-related morbidity has been acceptable and limited to dry and/or moist desquamation with no evidence of soft tissue necrosis.

MANAGEMENT OF IN-BREAST RECURRENCE FOLLOWING BCT — Many patients who develop an ipsilateral breast tumor recurrence (IBTR) without distant disease have long-term and durable responses to local (surgical and/or radiation therapy [RT]) and systemic therapy. The optimal management of IBTR depends upon the management of the initial primary breast cancer (with or without RT), the overall medical condition of the patient, and the specific characteristics of the recurrence.

For patients who develop an IBTR, it is important to distinguish between a true recurrence and a new primary tumor, if possible, as it may have implications on the choice of treatment. (See "Clinical manifestations and evaluation of locoregional recurrences of breast cancer", section on 'Distinguishing a new primary from a recurrence'.)

While a mastectomy is the surgical standard of care for most patients with a local recurrence following breast-conserving therapy (BCT), repeat breast excision may be feasible for select patients who request breast conservation [29]. (See 'Preferred approach: Mastectomy' below.)

Preferred approach: Mastectomy — The standard approach for an IBTR after breast-conserving surgery (BCS) and RT is mastectomy, provided there is no evidence of distant metastatic disease. However, repeat BCT may be offered to a select group of patients, as discussed below. (See 'Repeat BCT as an alternative for select patients' below.)

Most series report an operability rate of approximately 85 percent; reasons for nonoperability include simultaneous distant metastases, locally extensive recurrences, or inoperable regional nodal disease [30-33]. Systemic therapy may be used prior to surgery to improve operability. (See "Systemic therapy for locoregionally recurrent breast cancer".)

Patients with skin involvement or an inflammatory type of recurrence have a poor prognosis [31,34]. These individuals, as well as those with locally fixed or large tumors, are usually treated with systemic therapy prior to locoregional therapy [35-37]. (See "Systemic therapy for locoregionally recurrent breast cancer", section on 'Timing of treatment'.)

Following a mastectomy for locoregional recurrence, the locoregional control rate (defined as the absence of further recurrence of breast or chest wall) ranges from approximately 50 to 95 percent [29,30,38-48]. Many patients with an isolated local recurrence treated with a subsequent mastectomy will survive at least 10 years; however, isolated local recurrence can be a harbinger of distant disease and early breast-cancer-related death [49,50]. Contemporary studies report that 10 year overall survival rates range from approximately 40 to 80 percent [29,38,40,45,46,51-53].

Is there a role for chest wall radiation? — There are no data that address the benefit of chest wall radiation at the time of mastectomy performed for recurrent disease.

In women who initially were treated with lumpectomy and whole breast radiation and then had a mastectomy at the time of recurrence, reirradiation may rarely be offered, if very-high-risk features are present (eg, T3, multiple involved lymph nodes or lymph node with extracapsular extension, positive margins, skin involvement), particularly to those with a long time interval from the prior radiation. By contrast, chest wall radiation is offered more commonly to women who undergo mastectomy for a recurrence of a cancer that was not initially treated with radiation.

Repeat BCT as an alternative for select patients — Repeat lumpectomy with or without breast radiation is an alternative to mastectomy for patients who experience a local recurrence, but this is not standard treatment [29,47,48,54,55]. This approach may be an option for select patients, according to the following treatment history:

Patients with no prior radiation — Patients who underwent BCS alone (without breast RT) may be candidates for repeat BCS followed by RT. In a retrospective review of patients who were initially treated with lumpectomy without radiation, repeat lumpectomy upon recurrence followed by adjuvant radiation was associated with a five-year local control rate of 82 percent (versus 32 percent among those treated with repeat lumpectomy only) [56]. In comparison, patients treated with a total mastectomy or a total mastectomy plus RT had local control rates of 60 and 52 percent, respectively.

Select patients with prior radiation — In general, for patients initially treated with BCS and radiation, recurrences are treated with mastectomy. Exceptions may be made in the following cases:

●The patient is not an appropriate surgical candidate for mastectomy due to comorbid disease. In such cases, more limited surgery or primary systemic therapy may be considered. (See "Overview of the approach to early breast cancer in older women", section on 'Nonsurgical candidates'.)

●The patient is older with hormone-receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative disease and is willing to complete a course of adjuvant endocrine therapy. Such patients may be treated with lumpectomy alone (for primary disease and recurrences), without radiation. (See "Adjuvant radiation therapy for women with newly diagnosed, non-metastatic breast cancer", section on 'Possible omission of RT for select ER-positive, HER2-negative cancers'.)

●Some, but not all, UpToDate experts consider select additional candidates for lumpectomy rather than mastectomy, although this practice has not been validated in randomized trials. Candidates for this approach may include those with small tumor size and long disease-free interval (eg, tumor size ≤2 cm and >48 months' time to relapse, respectively [55]). In such cases, adjuvant partial breast radiation may be considered. In pursuing BCS for recurrent disease, the patient should understand that there are only limited data supporting this approach and that mastectomy is the more standard procedure in this setting.

Observational data suggest that patients treated with repeat BCS at the time of recurrence have similar survival outcomes to those who undergo mastectomy, although these data are limited by bias inherent in observational studies.

•In a retrospective review of 161 patients with an ipsilateral tumor recurrence after initial BCT, patients treated with BCS for recurrent tumors ≤2 cm and >48 months' time to relapse had significantly fewer second recurrences compared with those with tumors ≤2 cm and <48 months' time to relapse (15 versus 31 percent) [55]. In addition, 71 percent of patients with tumors >2 cm treated with repeat BCS had a second recurrence, regardless of the time to relapse interval.

•In preliminary results of an observational cohort study of 343 patients who underwent repeat BCT with accelerated partial breast reirradiation, the six-year in-breast recurrence-free survival rate was 95 percent, and the overall survival rate was 86 percent [57].

•A prospective phase 2 single-arm trial, RTOG 1014, looked at repeat radiation with the partial breast 3D-conformal technique (1.5 Gy x 30 fractions twice daily) after second lumpectomy in patients who experienced in-breast failure after whole-breast irradiation >1 year previously [58]. Among 58 patients, a second breast conservation was achievable in 90 percent. Five percent experienced a second in-breast recurrence at five years. Distant metastasis-free survival and overall survival rates were both 95 percent. Grade 3 late adverse events occurred in 7 percent; there were no grade 4 or higher late treatment adverse events. While encouraging, the series is small. Moreover, the interval from the initial treatment to the recurrence was 13 years, suggesting that some of the patients likely had new primaries that may have had a better prognosis with repeat breast conservation, rather than "true recurrences." Additionally, the risk of reirradiation may be less pronounced further from the initial treatment. Whether these results apply equally well, both in regards to efficacy and safety, to patients with earlier recurrences remains to be seen.

INVESTIGATIONAL APPROACHES

Hyperthermia plus conventional RT — Hyperthermia is an investigational approach in the treatment of recurrent breast cancer. Hyperthermia in the temperature range of 40 to 45ºC is cytotoxic. Interest in combining heat and irradiation (thermoradiotherapy) was motivated by the observation that heat-induced and radiation therapy (RT)-induced injury could be synergistic and by the different mechanisms that underlie resistance to damage by either modality.

In a meta-analysis of five trials evaluating RT with and without hyperthermia for primary or recurrent, locally advanced breast cancer, the addition of hyperthermia to RT improved the complete response rate (59 versus 41 percent) but had no impact on overall survival (18 months in both arms) [59]. The greatest effect was observed in patients with recurrent lesions in previously irradiated areas, where further irradiation was limited to low doses. However, substantial heterogeneity among the patient populations and the treatment parameters, and the widely varying response rates in the various studies, limit the ability to determine what role, if any, was played by hyperthermia as an adjuvant to RT.

Results are also available from uncontrolled series that focus on women with recurrent breast cancer:

●The most favorable report of combined hyperthermia and RT (44 to 66 Gy, median 60 Gy) after a marginal resection included 37 patients who were treated for locally recurrent breast cancer between 1997 and 2001 [60]. With a median follow-up of 28 months, three-year local control at the chest wall was 81 percent.

●Others report disappointing local control rates (approximately 40 percent at five years) [61-64]. In the largest of these, 85 patients with locoregionally recurrent breast cancer were treated with the combined approach (mean total RT dose 59.5 Gy) between 1981 and 2001 [61]. The total RT dose was decreased in approximately one-half (mean total dose 43 Gy) because they had received prior external beam RT. A complete response was achieved in a similar number of previously irradiated and unirradiated patients, but it was low in both groups (56 and 47 percent, respectively). It is not clear whether any patient underwent an attempt at surgical resection prior to thermoradiotherapy.

Thus, the value of combining hyperthermia with RT in patients with locally recurrent breast cancer remains uncertain, but it remains an interesting area for future research.

Interstitial brachytherapy, after second lumpectomy — Reirradiation of the whole breast with standard external beam radiation after repeat BCS is not generally recommended, because of the increased risk of normal tissue morbidity (tissue necrosis, rib fracture, pulmonary fibrosis, and, for left-sided lesions, cardiac damage). However, pilot studies have demonstrated the feasibility and acceptable local rates of repeat BCS with interstitial brachytherapy or partial breast radiation in highly selected women (eg, small size recurrence, relapse >4 years) [27,48,58,65-67]. Local control rates ranged from 57 to 95 percent, with acceptable acute toxicity [27,58,65-68]. Further data are needed prior to routine clinical use of these modalities in patients with previous whole-breast radiation therapy.

Five- and 10 year follow-up from prospective studies with interstitial brachytherapy is encouraging. A study of 39 patients with ipsilateral breast tumor recurrence (IBTR) who underwent a repeat breast-conserving surgery (BCS) and multicatheter pulse dose rate (PDR) brachytherapy found that the five-year actuarial local control rate was 93 percent [69]. Five-year overall survival and disease-free survival were 87 and 77 percent, respectively. In a series of 11 patients followed for 10 years after repeat BCS and interstitial brachytherapy, 10 women were free of local recurrence [68].

Randomized trials, with specific eligibility criteria, are needed to determine the optimal approach for patients with IBTR following breast-conserving therapy (BCT) who may benefit from repeat BCS, with or without additional RT. Optimal radiation dosing and administration technique must also be determined [70-72]. At present, mastectomy remains the standard of care in the setting of an in-breast recurrence following prior BCS and radiation.

LOCAL MANAGEMENT OF LYMPH NODES — Like chest wall recurrences, the risk of a regional recurrence after initial treatment of breast cancer depends on many factors, including the tumor size, number of initially positive nodes, extent of prior axillary surgery, biologic subtype, and whether postmastectomy radiation therapy (RT) was given.

Most regional recurrences present as a palpable mass detected on routine follow-up examination. Patients with an isolated regional recurrence do worse than those who have an isolated chest wall recurrence. When only the regional nodes are involved, patients with an isolated axillary recurrence do better than those who recur in the supraclavicular nodes [13-15,17,18,73-76], largely because patients with a supraclavicular recurrence have particularly high rates of distant metastatic disease. (See "Clinical manifestations and evaluation of locoregional recurrences of breast cancer", section on 'Lymph node recurrence'.)

Surgical management

No clinical evidence of nodal disease — Axillary evaluation of the patient with an ipsilateral breast tumor recurrence (IBTR) or isolated chest wall recurrence should begin with a thorough physical examination and ultrasound (US) of the axilla, with fine needle aspiration (FNA) biopsy of any clinically suspicious lymph nodes. Discussion of management of patients with evidence of nodal recurrence is found below. (See 'Axillary recurrence' below and 'Isolated supraclavicular recurrence' below and 'Evidence of nodal recurrence' below.)

The decision of whether to restage the axilla in those with no clinical evidence of nodal recurrence is best considered in the context of a multidisciplinary tumor board discussion.

In general, our approach is as follows:

●We obtain an axillary US irrespective of whether palpable nodes are present. Any suspicious node found on axillary US should be biopsied, and a positive biopsy will reassign the patient to the clinically node-positive group. (See 'Evidence of nodal recurrence' below.)

●For patients with no clinical evidence of nodal disease:

•Who had a prior axillary lymph node dissection (ALND) initially, we do not re-explore the axilla. The interest in reoperative sentinel lymph node (SLN) biopsy after previous ALND is increasing, particularly when lymphoscintigraphy is added to identify sites of nonaxillary drainage [77,78]. However, this approach remains investigational.

•Who had no prior ALND, our approach is to perform sentinel node mapping and to perform a dissection only if axillary disease is found. Although this approach is controversial in patients who underwent mastectomy at the time of their initial cancer, several studies have shown that repeat SLN biopsy upon recurrence is often feasible in women who underwent breast-conserving therapy (BCT) with SLN biopsy for their initial cancer [78-82].

●The approach to patients with evidence of nodal disease is discussed below. (See 'Evidence of nodal recurrence' below.)

In the past, nearly all patients with recurrent disease had already undergone ALND as a component of upfront therapy. At present, many women have undergone SLN biopsy that, if negative, was not followed by ALND. This has implications for the need to restage the axilla at the time of recurrence and for management of the axilla in the face of an axillary regional recurrence. In older series where the majority of women had undergone ALND as a component of their primary therapy, approximately 18 to 27 percent of patients undergoing axillary exploration for a suspected invasive IBTR had positive nodes [39,51,83], although rates as high as 50 percent have been reported [84]. However, there are no data describing rates of nodal involvement associated with an IBTR in women who have had a negative SLN biopsy rather than ALND. (See "Overview of management of the regional lymph nodes in breast cancer".)

Evidence of nodal recurrence — The general approach to the patient with a regional breast cancer recurrence is to rule out distant metastases and, whenever possible, resect the area of recurrent disease. Regional nodal recurrences in inoperable sites have a less favorable outcome than those that are potentially resectable [85,86].

Regional nodal recurrences are relatively rare after initial treatment for breast cancer [32,85,87-90]. Although rates may increase with the widespread use of SLN biopsy, early follow-up from uncontrolled reports suggests that local recurrence rates are low in women with a negative SLN who do not undergo completion ALND. (See "Overview of management of the regional lymph nodes in breast cancer" and "Overview of sentinel lymph node biopsy in breast cancer".)

Most regional recurrences present as a palpable mass detected on routine follow-up examination. In most series, the axilla is the most commonly involved site [13,76,85,86,88], while others note a higher rate of failure in the supraclavicular nodes [87,90,91]. This distribution may change with the increasing use of SLN biopsy.

Survival rates at five years for those with locoregional recurrences range from approximately 25 to 70 percent, with the best prognosis seen among those with isolated axillary recurrences [87,88].

Axillary recurrence — Axillary recurrences, versus recurrences in other nodal sites, carry a better prognosis. (See 'Axillary versus supraclavicular or internal mammary nodal recurrence' below.)

There is a paucity of data to guide the postsurgical management of an axillary regional recurrence, and practice is variable. The general approach is to rule out distant metastases and, whenever possible, resect the area of recurrent disease. In surgical planning, an important issue to be considered is whether RT was previously administered to the axilla and the potential for injury to the brachial plexus and chronic lymphedema of the ipsilateral upper extremity. Multidisciplinary evaluation and management is essential.

●For patients with prior SLNB after initial diagnosis who present with axillary recurrence, we pursue a complete ALND (levels I and II).

●For those with prior ALND after initial diagnosis who present with axillary recurrence, an attempt at resection is also indicated. If the disease cannot be resected, then systemic therapy can sometimes be used to decrease the extent of disease prior to radiation.

The possibility of long-term disease-free survival with multimodality treatment including surgery is suggested by the following observations:

●One series included 44 patients with an axillary recurrence as the initial treatment failure site: 30 isolated to the axilla, 12 with axillary plus other locoregional recurrence, and 2 with axillary plus distant recurrence [85]. Treatment consisted of surgical resection in 20, irradiation in 2, chemotherapy in 20, and tamoxifen in 2. Multimodality therapy was given to 33 patients (75 percent), and 9 patients received systemic therapy alone.

At an average 27 months' post-treatment follow-up, complete and durable local control was achieved in 31 (71 percent), but distant metastases developed in 22 (50 percent). Patients who had locally uncontrolled recurrences were significantly more likely to develop distant metastases (77 versus 39 percent, respectively). Patients who received surgery as a component of therapy were more likely to have locally controlled disease (89 versus 41 percent). In contrast, omission of RT or systemic therapy did not correlate with control of disease or rates of distant metastases.

●In another retrospective series of 59 patients with an axillary recurrence after surgery for operable breast cancer, 41 of whom received surgery, the five-year actuarial survival rate was 39 percent [92].

Isolated supraclavicular recurrence — The optimal sequence of systemic and locoregional treatment is not established for patients presenting with isolated supraclavicular recurrence.

●For patients who are considered candidates for systemic therapy, we prefer initial systemic therapy, followed by restaging scans after three to six months of treatment. Choice of systemic therapy is discussed elsewhere. (See "Systemic therapy for locoregionally recurrent breast cancer".)

●At the time of restaging, if there is still no evidence of distant metastatic spread, surgery and/or RT can be considered, depending on the magnitude of the response, the volume of residual disease, whether RT was previously administered, as well as the expected morbidity of both therapies. RT alone may be used if the area was not previously irradiated, surgery may be performed if RT was previously given, or a combination approach may be employed if there has been an incomplete response to chemotherapy.

The Tumor, Node, Metastasis (TNM) staging classification for breast cancer considers supraclavicular disease as N3 involvement rather than a metastatic (M) site. (See "Tumor, node, metastasis (TNM) staging classification for breast cancer".)

Despite this, there continues to be debate as to whether patients with isolated supraclavicular relapse should be considered as having disseminated disease or locoregional disease for which aggressive treatment with curative intent is justified [93]. Outcomes are less favorable for patients with an isolated supraclavicular as compared with axillary regional recurrence [17].

All of the published data on treatment and outcomes among women with ipsilateral isolated supraclavicular node recurrences after either mastectomy or BCT come from retrospective analyses [87,88,94-101]. The following represents the range of findings:

●The largest series consisted of 305 patients derived from the Danish Breast Cancer Cooperative Group Database who had a supraclavicular recurrence, with or without other locoregional metastases, but without distant recurrence as the site of first recurrence [99]. Patients were treated between 1977 and 2003 with either initial mastectomy or BCT, and 70 (23 percent) had prior RT. Synchronous sites of locoregional recurrence were present at the time of supraclavicular recurrence in 117 (38 percent).

Locoregional treatment consisted of removal of at least the macroscopic tumor (19 percent) or curative RT (33 percent); only 10 percent had combined surgery plus RT. Overall, 78 patients (26 percent) had combined locoregional and systemic (endocrine and/or chemotherapy) therapy, while 49 percent received systemic therapy only and 25 percent had locoregional treatment alone.

Combined locoregional and systemic therapy resulted in the highest rate of initial remission compared with either locoregional therapy alone or systemic therapy alone (67 versus 64 and 40 percent, respectively). During the entire follow-up period, 66 patients (22 percent) remained free of evidence of disease progression, whereas 138 ultimately progressed locally and 96 progressed with distant metastases. Five-year rates of progression-free and overall survival were 15 and 24 percent, respectively. In multivariate analysis, type of treatment and histologic grade of differentiation were the only independent prognostic factors, with the best outcomes in patients who received combined locoregional and systemic therapy.

●Another retrospective series included 63 women with an isolated supraclavicular nodal recurrence after primary treatment for breast cancer (predominantly mastectomy) [98]. Treatment consisted of excisional biopsy or more radical surgery in 44, RT in 25, systemic chemotherapy in 51, and hormone therapy in 42. At a median follow-up of 58 months, the five-year distant metastasis-free survival rate was 15 percent. Five-year overall survival after recurrence was significantly better for women ≤40 years of age than for older women (43 and 16 percent, respectively).

●Long-term results from combined-modality therapy for isolated supraclavicular recurrence in 70 patients with prior BCT were reported by a group from MD Anderson [100]. In this study, all patients were treated with neoadjuvant chemotherapy followed by locoregional management (total or segmental mastectomy with ALND, before or after RT), additional postoperative chemotherapy, and tamoxifen if they had a hormone receptor-positive breast cancer. At a median follow-up of 11.6 years, the 10 year disease-free and overall survival rates were 32 and 31 percent, respectively.

Although they are not derived from randomized trials, taken together, these data support the view that approximately 15 to 30 percent of patients who present with an isolated supraclavicular nodal relapse will have a prolonged period of disease-free survival after aggressive multimodality therapy. Thus, these patients should be approached with curative intent.

Adjuvant nodal irradiation — For patients who have a chest wall or in-breast recurrence without evidence of nodal disease who have not had previous nodal radiation, we suggest radiation to the chest wall; regional lymph nodes are often included. However, for such patients who have already had nodal irradiation, we typically do not reirradiate the lymph nodes.

Similarly, for women with nodal recurrence who have not previously had radiation, we suggest postresection RT to the axilla, supraclavicular region, and chest wall, regardless of whether they were treated previously with ALND or not (however, at other institutions, surgery alone is favored for women who did not have an initial ALND, as long as the resection is complete). For women who have had previous axillary RT, limited field reirradiation may be considered in the setting of an incompletely resected axillary regional recurrence or for local control of inoperable and/or progressive local disease that is nonresponsive to systemic therapy. This should be particularly considered in cases in which the inoperable and/or progressive disease is symptomatic or is likely to become symptomatic based on location and there has been a substantial time interval from the prior radiation. The decision to reirradiate limited fields should be individualized after a thorough discussion of the risks and benefits with the patient.

When administering nodal irradiation, whether the internal mammary nodes (IMNs) should be included in the RT field is controversial:

●The decision by some institutions not to treat the IMNs unless they are radiographically suspicious is based upon the very low incidence of subsequent recurrence in this area and the potential for increased lung and cardiac morbidity with extension of the radiation fields.

●On the other hand, other institutions routinely include the IMN chain in the RT field, arguing that disease recurrence at this site can lead to direct sternal bone invasion and significant morbidity and that RT can be delivered more safely than in the past using modern radiation planning techniques.

PROGNOSIS AND PROGNOSTIC FACTORS — Locoregional recurrences (LRRs) are associated with a high risk of developing distant metastases and, consequently, poor survival. The risk is higher than that seen for newly diagnosed early-stage disease. For example, among patients in Danish Breast Cancer Group trials treated with a mastectomy, 50 percent who experienced an LRR then developed distant metastases within two years [102]. Similarly, in the National Surgical Adjuvant Breast and Bowel Project (NSABP) trials, among patients treated with breast-conserving therapy (BCT) who experienced an ipsilateral breast tumor recurrence (IBTR), the five-year distant disease-free survival (DDFS) was 67 percent in node-negative patients and 51 percent for node-positive patients in pooled analyses [87,103]. These rates are higher than those observed in newly diagnosed early-stage disease, in which five-year disease-free survival rates (distant or local) exceed 70 to 98 percent, depending on the stage. (See "Prognostic and predictive factors in early, non-metastatic breast cancer", section on 'Tumor stage'.)

Some local recurrences may actually represent new primaries, however, arising from residual normal breast after initial surgery. (See 'New primary versus true recurrence' below.)

Second LRRs are common after treatment of a first LRR, although distant recurrences are more likely [104,105]. The prognosis of patients experiencing a second LRR is comparable to that of patients experiencing distant metastases [105].

Recurrence after breast-conserving therapy versus mastectomy — Although there are studies that describe a similar overall prognosis for LRR recurrence after mastectomy versus BCT [6], postmastectomy recurrences are more likely to involve regional nodes, and these cases are associated with higher rates of simultaneous distant metastases and poorer cause-specific survival [106].

New primary versus true recurrence — One of the prognostic considerations for patients with isolated LRR is whether the disease represents a true recurrence versus a new primary, particularly for those with an IBTR. (See "Clinical manifestations and evaluation of locoregional recurrences of breast cancer", section on 'Distinguishing a new primary from a recurrence'.)

Although the literature has largely combined new primaries with true recurrences when reporting on local recurrence, compared with true recurrences, new primaries are associated with improved prognosis (better survival and fewer distant metastasis) but more contralateral breast carcinomas [107,108]. Patients who were identified by molecular testing as having a recurrent rather than second primary breast cancer were at significantly higher risk for distant metastatic disease [109,110].

If a recurrence is thought to be a new primary versus a recurrence, there may be implications for systemic therapy. (See "Systemic therapy for locoregionally recurrent breast cancer".)

Late versus early recurrence — Globally, early recurrences, defined as within 24 months, have a far worse prognosis than those occurring after more than 48 months [40,42,45,87,103,104,111-115].

Among patients treated for an LRR after mastectomy, the most consistently documented prognostic factor is the interval between initial diagnosis and recurrence. In most series, a disease-free interval of at least two years is associated with a significantly better outcome compared with shorter durations [6,9-12,17,111,115-117].

●In a representative report of 230 women with a chest wall or regional nodal recurrence after mastectomy, five-year survival rates were 50 and 35 percent for patients with a disease-free interval of two or more versus less than two years, respectively [111].

●In an observational study of 2669 patients with recurrence after BCT, those with a local recurrence two years or less from the time of BCT had a worse five-year overall survival compared with women with a longer interval (49 versus 85 percent) [87].

Skin involvement and extent of recurrence — Long-term local control and overall survival rates are also dependent upon the site and volume of the disease recurrence [9,17,31,34,45,51,111].

In most series, local control rates are highest with either limited breast, chest wall, or axillary node involvement and lower when there is both local and regional recurrence, particularly if the supraclavicular nodes are involved. In general, the greater the disease volume, the lower the likelihood of achieving long-term local control and relapse-free survival. Control of a diffuse inflammatory recurrence is more difficult than if disease is limited to an isolated nodule. This difference may reflect surgical resectability of the recurrent disease.

In one study, patients with a skin recurrence had a significantly higher five-year actuarial rate of development of distant diseases compared with patients with a recurrence that did not include the skin (60 versus 39 percent) [34]. Patients with a local recurrence identified by physical examination had a significantly shorter five-year disease-free survival compared with patients with detection by mammography alone (73 versus 91 percent) [45].

Treatable versus untreatable recurrence — The prognosis of a patient with LRR is also determined by the availability of effective treatment for the LRR.

As examples, patients with resectable disease have a better prognosis than those with unresectable disease. Most LRRs are locally limited and operable; 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 [118]. Invasion into the ribs or sternum is considered largely inoperable and has a poor prognosis, similar to distant metastases.

Additionally, patients who can receive radiation have a better outcome than those with recurrences in previously radiated sites, and patients who have the option of receiving effective systemic therapies have better outcomes than those with disease that has demonstrated primary resistance to front-line chemotherapy, endocrine therapy, and/or targeted therapies.

Axillary versus supraclavicular or internal mammary nodal recurrence — Among nodal recurrences, isolated axillary recurrences are most amenable to treatment and are associated with the best long-term survival [13,74,76,87-89]. Patients with disease in other nodal regions are highly likely to develop distant metastases, and they have a poor outcome.

For example, in one study, among patients with nodal recurrences, the five-year DDFS rates were 31.5 percent for axillary recurrences and 12.1 percent for supraclavicular events [87].

Others — Other poor prognostic factors include age 35 years and younger at initial diagnosis [104], node-positive status at initial diagnosis, estrogen receptor (ER)-negative breast cancer, administration of adjuvant chemotherapy [53], and invasive versus noninvasive recurrence [51,52].

SPECIAL CONSIDERATIONS DURING THE COVID-19 PANDEMIC — The COVID-19 pandemic has increased the complexity of cancer care. Important issues include balancing the risk from delaying cancer treatment versus harm from COVID-19, minimizing the number of clinic and hospital visits to reduce exposure whenever possible, mitigating the negative impacts of social distancing on delivery of care, and appropriately and fairly allocating limited healthcare resources. Specific guidance for decision-making for cancer surgery on a disease-by-disease basis is available from the American College of Surgeons, from the Society for Surgical Oncology, and from others. These and other recommendations for cancer care during active phases of the COVID-19 pandemic are discussed separately. (See "COVID-19: Considerations in patients with cancer".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Breast cancer" and "Society guideline links: Breast surgery".)

SUMMARY AND RECOMMENDATIONS — The management of patients with a locoregional recurrence after mastectomy is complex and usually requires multidisciplinary assessment and planning.

●Definition of locoregional recurrence – Locoregional recurrence of breast cancer is used to indicate a recurrence in either the ipsilateral breast, chest wall, or regional nodal basin. (See 'Introduction' above.)

●Management of chest wall/breast recurrence

•For patients in whom an upfront resection is feasible, with acceptable risks of morbidity and anticipated cosmetic outcome, we typically proceed with initial surgery and use pathologic staging from the resection specimen to guide decisions regarding adjuvant systemic therapy. However, there are exceptions (eg, patients with isolated supraclavicular recurrences or those with a heavy burden of disease), in which cases we administer systemic therapy first, to facilitate successful locoregional treatment and to be certain that early evidence of distant metastases does not emerge. Multidisciplinary tumor board discussion can be helpful. (See 'Sequencing local and systemic therapies' above.)

•For patients treated initially with mastectomy who develop a local recurrence only, we suggest wide local excision of all gross disease, whenever possible, for solitary or multiple nodules that are amenable to resection (Grade 2C). For those who did not previously receive radiation, we also suggest postmastectomy radiation (Grade 2C). Radiation is also appropriate in select women who previously were irradiated (depending on location, time course, and risk features of the disease). (See 'Surgical resection' above and 'Radiation' above.)

•For women who develop an ipsilateral breast tumor recurrence (IBTR) following breast-conserving therapy (BCT) and radiation, we suggest a mastectomy rather than repeat lumpectomy (Grade 2C). Although such patients are typically not treated with further radiation, chest wall radiation may be appropriate in rare high-risk cases (particularly if the time since last radiation was long). However, repeat BCT may be an appropriate alternative in select women (eg, those who were not initially treated with radiation or those with a small and late relapse). (See 'Preferred approach: Mastectomy' above and 'Repeat BCT as an alternative for select patients' above.)

●Management of lymph node recurrence

•The general approach to the patient with a regional breast cancer recurrence is to rule out distant metastases and, whenever possible, resect the area of recurrent disease. (See 'Evidence of nodal recurrence' above.)

•For patients without palpable axillary lymphadenopathy who have no evidence of distant recurrence, we perform an axillary ultrasound.

-For patients with no clinical nodal involvement (examination and ultrasound are negative), who had a prior axillary lymph node dissection (ALND) initially, we do not re-explore the axilla. (See 'No clinical evidence of nodal disease' above.)

-For patients with no clinical nodal involvement, who have not had an ALND, our approach is to perform sentinel node mapping. (See 'No clinical evidence of nodal disease' above.)

•For patients presenting with axillary recurrences (detected either clinically or based on sentinel node mapping):

-Without prior ALND, we suggest a complete ALND (levels I and II) (Grade 2C). (See 'Evidence of nodal recurrence' above.)

-With prior ALND, an attempt at resection is also indicated. If the disease cannot be resected, then systemic therapy can sometimes be used to decrease the extent of disease, which is then followed by radiation.

•For patients without prior nodal radiation who have experienced a locoregional recurrence of breast cancer, we suggest radiation to both the chest wall and regional lymph nodes rather than more limited or no radiation (Grade 2C). For such patients who have previously had nodal irradiation, we typically do not reirradiate the lymph nodes. However, an exception may be made in select women with axillary recurrences (eg, in the setting of an incompletely resected axillary regional recurrence, or for local control of inoperable and/or progressive local disease that is nonresponsive to systemic therapy). This should be particularly considered in cases in which the inoperable and/or progressive disease is symptomatic or is likely to become symptomatic based on location and there has been a substantial time interval from the prior radiation. (See 'Adjuvant nodal irradiation' above.)

•For patients with isolated supraclavicular recurrences who are considered candidates for systemic therapy, we suggest initial systemic therapy rather than upfront surgery (Grade 2C). At the time of restaging, if there is still no evidence of distant metastatic spread, surgery and/or radiation therapy (RT) can be considered, depending on the magnitude of the response, the volume of residual disease, whether RT was previously administered, as well as the expected morbidity of both therapies. (See 'Isolated supraclavicular recurrence' above.)

●Prognosis

•Locoregional recurrences are associated with a high risk of developing distant metastases and, consequently, poor survival. Better prognostic features include late rather than early recurrences (within two years) and isolated axillary recurrences rather than involvement of other nodal areas. (See 'Prognosis and prognostic factors' above.)